铅镉联合对大鼠肾脏的毒性研究
|
摘要
铅、镉是环境中两种常见的重金属污染物;近年来,由于工业生产中铅、镉使用量的增加及相关工业废物带来的污染加重,环境中的铅、镉含量呈快速上升趋势。由于铅、镉常从许多天然和人工污染源同时进入环境而引起复合污染,因此铅镉联合暴露给公众健康带来的危害引起了广泛关注。肾脏是慢性铅、镉毒性损伤的靶器官和蓄积部位,国内外研究者从职业性暴露、环境污染及动物试验多方面对铅镉所致肾毒性机理进行了广泛研究;但铅、镉单独肾毒性作用的报道较多,而对两者的联合肾毒性研究则相对较少。本研究以SD大鼠为试验动物,通过体内和体外试验相结合的方法较系统地探讨了铅、镉及其联合对大鼠肾脏的毒性损伤效应及可能的作用机理,为进一步认识铅镉及其联合肾毒性作用提供了理论依据。
一、体内试验1月龄雌性SD大鼠24只随机分为4组,每组6只,分别为对照组、铅组(300mgPbAc2/L)、镉组(50mgCdAc2/L)、铅镉联合组(300mgPbAc2/L+ 50mgCdAc2/L)。对照组大鼠自由饮用超纯水,其余各组自由饮用配置毒液,每天称量大鼠体重与饮水量,连续染毒8周,进行如下试验:①分别于染毒前一天、染毒后2、4、6、8周收集24h尿液,测定尿酶UALP、UNAG、UGGT、ULDH活性和尿蛋白UTP、Uα_1-MG、Uβ_2-MG、UmAlb含量的动态变化;同时测定尿液中Zn、Cu、Mn、Fe、Se排泄量的动态变化;②染毒结束,测定血清与肾皮质中Zn、Cu、Mn、Fe、Se、GSH、MDA含量和SOD、CAT、GSH-Px活性;③采用光学显微镜、透射电子显微镜观察染毒后大鼠肾皮质组织病理学及超微结构的变化;④采用荧光定量PCR法检测染毒后大鼠肾皮质中线粒体细胞色素氧化酶亚基COX-I、COX-II、COX-III mRNA表达量的变化;免疫组织化学法与荧光定量PCR法检测金属硫蛋白MT-1、MT-2在大鼠肾皮质中的表达。结果表明:①除染毒2周时Pb、Cd组Uα_1-MG含量与Pb组UALP活性外,Pb、Cd组其余各项指标(UNAG、UGGT、ULDH、UTP、Uβ_2-MG、UmAlb)均从染毒2周开始即显著或极显著高于对照组(P<0.05或P<0.01),且升高幅度与染毒时间呈正相关;铅镉联合组从2周开始,所测各项指标均显著高于对照组(P<0.05)。在整个试验过程中,联合组各项指标均高于Pb组、Cd组,且在不同染毒时间有显著差异;②染毒结束,各染毒组血清与肾皮质中SOD、CAT、GSH-Px活性与GSH、Zn、Cu、Mn、Fe、Se含量均显著低于对照组(P<0.05),但MDA含量均显著高于对照组(P<0.05);③除染毒2周时尿Zn含量外,Pb、Cd组其余4种微量元素(Cu、Mn、Fe、Se)均从染毒4周开始尿中排泄量显著增多(P<0.05);联合染毒除2周时尿Fe含量外,其它元素(Zn、Cu、Mn、Se)均从染毒2周开始尿中排泄量显著增多(P<0.05);④各染毒组肾皮质部肾小管和肾小球有明显组织学病理变化,同时超微结构变化明显,表现核染色质分布不均、染色质边聚、近端小管刷状缘微绒毛脱落、线粒体肿胀、嵴断裂、部分或完全消失,铅镉联合暴露的病理学损伤较铅、镉单独染毒严重;⑤各染毒组大鼠肾皮质COX-I、COX-II、COX-III基因表达量均显著低于对照组(P<0.05),以铅镉联合组降低幅度最大;⑥Pb组MT-1、MT-2表达量与对照组无显著差异(P>0.05),但Cd组和铅镉联合组MT-1、MT-2表达均显著高于对照组(P<0.05)。结合上述试验结果,可以得出以下结论:①铅镉单独或联合暴露可损伤大鼠肾小管的重吸收功能和肾小球的滤过功能,其肾损伤程度与染毒时间呈正相关;②铅镉染毒可导致肾组织抗氧化功能降低,抗氧化微量元素含量降低加剧了氧化应激介导的肾组织损伤,染毒组大鼠体内微量元素含量降低与其尿液中排泄量显著增加直接相关;③铅镉暴露可引起肾皮质显著病理学损伤和多种细胞器损伤,其中线粒体损伤较显著;④染毒组肾皮质COX-I、COX-II、COX-III基因表达量显著下降可能与铅镉暴露导致的线粒体脂质过氧化损伤有关,金属硫蛋白MT-1、MT-2基因表达量显著升高在铅镉联合肾毒性过程中发挥重要作用。总之,铅镉联合肾毒性呈协同效应。
二、体外试验采用机械筛网结合酶消化法建立大鼠原代肾小管上皮细胞(rPTCs)培养模型,在传一代细胞增殖活性最强时间段进行铅(0.5μmol/L、1μmol/L)、镉(2.5μmol/L、5μmol/L)单独或联合染毒。主要进行以下试验:①cck-8还原法测定不同组合的铅镉在不同染毒时间(3、6、12、24h)对rPTCs存活率的影响;②测定铅镉单独或联合染毒12h对rPTCs凋亡率、坏死率、乳酸脱氢酶释放率及凋亡形态学的影响,同时添加N-乙酰半胱氨酸(NAC),观察其对铅镉所致细胞毒性损伤的保护效果;③测定铅镉染毒12h对rPTCs胞内SOD、CAT、GSH-Px活性及GSH、MDA含量的影响;④测定铅镉染毒12h对rPTCs膜ATP酶(Ca~(2+)-ATPase、Na+/K+-ATPase)活性、胞内pH、线粒体膜电位、活性氧及钙离子水平的影响。结果表明,①铅镉单独染毒高剂量组从3h开始、低剂量组从6h开始,其细胞存活率显著低于对照组(P<0.05);铅镉联合组从3h开始,细胞存活率极显著低于对照组(P<0.01),且存活率降低幅度与染毒剂量、染毒时间呈正相关;②染毒12h,各染毒组细胞凋亡率、坏死率、乳酸脱氢酶释放率均极显著高于对照组(P<0.01),且铅镉联合组各项指标均高于各相关单独染毒组;各染毒组细胞表现核皱缩、呈新月形、染色质致密浓染、核碎裂等典型凋亡特征;NAC对铅镉所致细胞凋亡有显著保护效应,但对细胞坏死率和乳酸脱氢酶释放率无明显影响;③与对照组比较,染毒组SOD、CAT、GSH-Px活性和GSH含量均显著或极显著降低(P<0.05或P<0.01),而MDA含量均极显著升高(P<0.01);④染毒各组细胞内活性氧和钙离子水平均极显著高于对照组(P<0.01),线粒体膜电位水平、胞内pH、Ca~(2+)-ATPase与Na~+/K~+-ATPase活性均显著或极显著低于对照组(P<0.05或P<0.01)。上述试验结果可以得出以下结论:①铅镉暴露对rPTCs的毒性损伤呈浓度依赖性和时间依赖性,联合暴露呈协同毒性损伤;②细胞凋亡与细胞坏死是铅镉所致rPTCs死亡的2种死亡类型,其中凋亡性死亡在铅镉该剂量组合所致细胞损伤过程中发挥主导作用。氧化应激在铅镉染毒所致细胞凋亡性死亡过程中发挥重要作用,细胞内抗氧化酶活性降低进一步加剧铅镉对rPTCs的氧化损伤;抗氧化剂NAC对铅镉所致的肾小管上皮细胞毒性损伤有显著保护效应;③铅镉暴露导致rPTCs线粒体膜电位降低而促进细胞凋亡,同时细胞内酸化、钙离子超载、氧化还原平衡状态失调等一系列细胞内环境稳态失衡促进了细胞凋亡。总之,铅镉联合暴露对大鼠肾小管上皮细胞的损伤程度重于单独染毒,呈协同效应。
Lead (Pb) and cadmium (Cd) are now recognized to be two of most important heavy metal contaminants in the environment. Due to their increased industrial uses and environmental pollution with the related waste products, concentrations of lead and cadmium are increasing rapidly in the environment in recent years. Since the two elements are often released simultaneously in the environment from a number of natural and man made sources, adverse health effects caused by combined exposure to lead and cadmium has provoked a significant public health concern. The kidney is the target organ and the primary accumulation site of chronic lead and cadmium exposure. The nephrotoxicity induced by lead and/or cadmium have been extensively studied and widely reported in occupationally and environmentally exposed human subjects, as well as in various experimental models. Most studies were implicated in the single exposure of lead/cadmium on the kidney. However, systemic studies of toxic damage on the combination of lead and cadmium were little referred. In this study, the toxic effects of lead and/or cadmium on the kidney of Sprague-Dawley (SD) rats were investigated in vitro and in vivo, which will offer some theoretic evidences for further exploring the mechanism in nephrotoxicity of lead and/or cadmium.
1. In vivo studies The study was carried out on female one-month-old SD rats. Twenty- four rats were allocated randomly to four groups of six animals each. The experimental period was eight weeks. (1) Control: rats consumed distilled water as drinking water. (2) Lead treated group: rats consumed a solution of PbAc2 (300mg/L) as drinking water. (3) Cadmium treated group: rats consumed a solution of CdAc2 (50mg/L) as drinking water. (4) Pb+Cd treated group: these rats received both Pb and Cd at the doses, periods and ways of administration described above. During the experimental period, water consumption and weight gain were measured every day. A series of tests were carried out:①On the day before the experiment and at the end of 2, 4, 6 and 8 weeks of treatment, rats were kept for 24h urine collection. Activities of alkaline phosphatase (ALP), N-acetyl-β-D-glucosaminidase (NAG),γ-glutamyl-transpeptidase (GGT), lacticacid dehydrogenase (LDH) and contents of total protein (TP),α_1-microglobulin (α_1-MG),β_2-microglobulin (β_2-MG), microalbumen (mAlb) in urine were determined. Also, concentrations of Zn, Cu, Mn, Fe and Se in the urine were detected during the experiment.②At the end of treatment, the levels of Zn, Cu, Mn, Fe, Se, glutathione (GSH), malondialdehyde (MDA) and activities of total superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) in the renal cortex and serum were measured.③Changes in histopathology and ultrastructure of renal cortex were detected by light microscope and transmission electron-microscope, respectively.④The relative gene expression levels of cytochrome oxidase submits (COX-I, COX-II, COX-III) in the renal cortex were quantified by Fluorescent Quantitative-PCR (FQ-PCR). The expressions of metallothionein submits (MT-1, MT-2) in the renal cortex were detected by immunohistochemistry method and FQ-PCR, respectively. The results are as follows:①Compared with the control group, all of the indices(NAG, GGT, LDH, TP,β_2-MG, mAlb) except the contents ofα_1-MG in the Pb, Cd group and activities of ALP in the Pb group at the time of 2-week exposure increased significantly from the beginning of exposed for two weeks (P<0.05 or P<0.01). Especially the changes in the (Pb+Cd) group were the greatest (P<0.05). Positive correlation lied in the process between the degree of increase in activities of urinary enzymes/contents of urinary proteins in the exposed groups and the exposure time. During the experiment, the levels of indices in the (Pb+Cd) group were all higher than those in the Pb, Cd group. There is significant difference between the (Pb+Cd) group and Pb or Cd group in different times.②In comparison with the control group, activities of SOD, CAT, GSH-Px and contents of GSH, Zn, Cu, Mn, Fe, Se in the renal cortex and serum of the three exposed groups decreased significantly(P<0.05). However, the contents of MDA in these exposed groups were significantly increased than that of the control group (P<0.05).③As far as the Pb group and the Cd group is concerned, concentrations of trace elements (Cu, Mn, Fe, Se) in the urine except the concentrations of urinary Zn at the time of 2-week exposure increased significantly from the beginning of exposed for four weeks(P<0.05). Regarding the (Pb+Cd) group, the excretion of trace elements (Zn, Cu, Mn, Se) in the urine except that of urinary Fe increased significantly from the beginning of exposed for two weeks (P<0.05).④Obvious pathological changes in the renal tubule and glomeruli renis were observed in the renal cortex of these three exposed groups. Also, the changes in ultrastructure of renal cortex is obvious, which pyknosis of nucleus, chromatin assemble, partial loss of brush border microvilli in the proximal tubular cells, mitochondrial swelling, disappearance and fragmentation of carina were seen under transmission electronic microscope. The degree of pathological damage in the (Pb+Cd) group was more serious than that in the Pb/Cd group. Compared with the Pb or Cd group, more severe pathological damage was found in the (Pb+Cd) group.⑤The relative expression levels of cytochrome oxidase submits (COX-I, COX-II, COX-III) in the renal cortex of these three exposed groups were significantly lower than those in the control group (P<0.05). The most significant change occurred in the (Pb+Cd) group.⑥There is no significant difference in the expression level of MT-1 and MT-2 gene in the kidneys between the lead group and control group (P>0.05), whereas those in the cadmium group and (Pb+Cd) group were significantly higher than that in the control group (P<0.05). Based on these results, the conclusions are as following:①Tubular reabsorptive function and glomerular filtration function were damaged after exposed to lead and/or cadmium. The degree of renal injury is positively correlated with the increase of exposure time.②Exposure to lead and/or cadmium can induce the decrease of the anti-oxidative function in the kidneys of rats. Also the decreased contents of trace elements related to antioxidative function made the renal damage induced by oxidative stress worse. The decreased levels of these trace elements in the tissues exposed to lead and/or cadmium were due to an increase of their excretion in the urine.③Obvious pathological changes and damage of many organelles in the renal cortex were medicated by lead and/or cadmium. Among these organelles, mitochondria underwent the greatest changes.④The decreased expression levels of COX-I, COX-II, COX-III in the renal cortex exposed to lead and/or cadmium may be related to the mitochondrial lipid peroxidation. The increased expression level of MT-1 and MT-2 gene played an important role in the nephrotoxicity induced by lead and cadmium. In summary, there was an obvious synergistic effect of lead combined with cadmium on the kidney of rats.
2. In vitro studies The primary cultures of rat proximal tubular cells (rTECs) were cultured by mechanical grinding, filtering and chemical digestive methods. The first passage was used to perform the experimental design when it was in its highest cell viability. Effects of lead (0.5μmol/L, 1μmol/L) and/or cadmium (2.5μmol/L, 5μmol/L) on the rTECs were investigated in the following assays.①Effects of different doses of lead and/or cadmium on the survival rates in rPTCs for a time range of 3, 6, 12 and 24h were detected by using the cck-8 reduction method.②Effects of lead and/or cadmium on the apoptotic rates, necrotic rates, LDH release and apoptotic morphological changes in rPTCs over a 12 h period were investigated. In addition, the protective effect of N-acetyl-L-cysteine (NAC) against lead and/or cadmium induced cellular damage was investigated.③Activities of SOD, CAT, GSH-Px and contents of GSH, MDA in rPTCs were measured when exposed to lead and/or cadmium over a 12h period.④Activities of Ca~(2+)-ATPase and Na~+/K~+-ATPase, intracellular pH, levels of mitochondrial membrane potential (ΔΨ), reactive oxygen species (ROS) and intracellular [Ca~(2+)]i in rPTCs were detected after exposed to lead and/or cadmium for 12h. The results are as follows:①The cell survival rates in the single lead and cadmium groups were significantly lower than those of control groups since these cells were exposed to high-dose and low-dose groups for three and six hours, respectively (P<0.05). The cell survival rates in the combined groups were significantly lower than those of control groups after a 3-h exposure (P<0.01). Furthermore, the degree of decrease in the cell survival rate was positively correlated with the dose and the exposure time.②After exposure to lead and/or cadmium for 12h, the apoptotic rates, necrotic rates, LDH release in these exposed groups were significantly higher than those in the control group (P<0.01). Also, the above indices induced by (Pb+Cd) were always higher than those in the related Pb or Cd group in the same exposure time. After a 12-h exposure time, it showed morphological changes typical of apoptosis in the lead and/or cadmium groups, i.e., nuclear chromatin condensed and fragmented chromatin was characterized by a scattered, drop-like structure. Apoptosis induced by lead and/or cadmium can be efficiently prevented by NAC, but the necrotic rates and LDH release were not affected by NAC.③Compared with the control group, activities of SOD, CAT, GSH-Px and the GSH level in the exposed groups decreased significantly (P<0.05 or P<0.01); But the content of MDA increased significantly (P<0.01).④After exposed to lead and/or cadmium for 12h, intracellular ROS and [Ca~(2+)]_i in rPTCs increased significantly (P<0.01), while the mitochondrialΔΨ, intracellular pH, activities of Ca~(2+)-ATPase and Na~+/K~+-ATPase decreased significantly (P<0.05 or P<0.01). Based on these results, the conclusions are as follows:①Lead and/or cadmium exposure induced cellular death in rPTCs, depending on both the concentration and the exposure time. Synergistic effect lies in the administration of lead combined with cadmium.②Cellular death induced by lead and/or cadmium is medicated by two mechanisms, necrotic and apoptotic. The apoptotic mechanism played a chief role in the cellular death induced by lead and/or cadmium at these doses. Moreover, oxidative stress could be implicated in the apoptotic mechanism mediated by lead and/or cadmium. Decreased activities of anti-oxidative enzymes further enhanced oxidative damage in rPTCs caused by lead and/or cadmium. In addition, the cellular damage induced by lead and/or cadmium can be significantly prevented by NAC.③Depletion of mitochondrialΔΨand a disorder of intracellular homeostasis, i.e. intracellular acidification, calcium overload, disturbance in the prooxidant–antioxidant balance, promoted the development of apoptosis in rPTCs. In a word, there was an obvious synergistic effect of lead combined with cadmium on the cellular damage in rPTCs.
一、体内试验1月龄雌性SD大鼠24只随机分为4组,每组6只,分别为对照组、铅组(300mgPbAc2/L)、镉组(50mgCdAc2/L)、铅镉联合组(300mgPbAc2/L+ 50mgCdAc2/L)。对照组大鼠自由饮用超纯水,其余各组自由饮用配置毒液,每天称量大鼠体重与饮水量,连续染毒8周,进行如下试验:①分别于染毒前一天、染毒后2、4、6、8周收集24h尿液,测定尿酶UALP、UNAG、UGGT、ULDH活性和尿蛋白UTP、Uα_1-MG、Uβ_2-MG、UmAlb含量的动态变化;同时测定尿液中Zn、Cu、Mn、Fe、Se排泄量的动态变化;②染毒结束,测定血清与肾皮质中Zn、Cu、Mn、Fe、Se、GSH、MDA含量和SOD、CAT、GSH-Px活性;③采用光学显微镜、透射电子显微镜观察染毒后大鼠肾皮质组织病理学及超微结构的变化;④采用荧光定量PCR法检测染毒后大鼠肾皮质中线粒体细胞色素氧化酶亚基COX-I、COX-II、COX-III mRNA表达量的变化;免疫组织化学法与荧光定量PCR法检测金属硫蛋白MT-1、MT-2在大鼠肾皮质中的表达。结果表明:①除染毒2周时Pb、Cd组Uα_1-MG含量与Pb组UALP活性外,Pb、Cd组其余各项指标(UNAG、UGGT、ULDH、UTP、Uβ_2-MG、UmAlb)均从染毒2周开始即显著或极显著高于对照组(P<0.05或P<0.01),且升高幅度与染毒时间呈正相关;铅镉联合组从2周开始,所测各项指标均显著高于对照组(P<0.05)。在整个试验过程中,联合组各项指标均高于Pb组、Cd组,且在不同染毒时间有显著差异;②染毒结束,各染毒组血清与肾皮质中SOD、CAT、GSH-Px活性与GSH、Zn、Cu、Mn、Fe、Se含量均显著低于对照组(P<0.05),但MDA含量均显著高于对照组(P<0.05);③除染毒2周时尿Zn含量外,Pb、Cd组其余4种微量元素(Cu、Mn、Fe、Se)均从染毒4周开始尿中排泄量显著增多(P<0.05);联合染毒除2周时尿Fe含量外,其它元素(Zn、Cu、Mn、Se)均从染毒2周开始尿中排泄量显著增多(P<0.05);④各染毒组肾皮质部肾小管和肾小球有明显组织学病理变化,同时超微结构变化明显,表现核染色质分布不均、染色质边聚、近端小管刷状缘微绒毛脱落、线粒体肿胀、嵴断裂、部分或完全消失,铅镉联合暴露的病理学损伤较铅、镉单独染毒严重;⑤各染毒组大鼠肾皮质COX-I、COX-II、COX-III基因表达量均显著低于对照组(P<0.05),以铅镉联合组降低幅度最大;⑥Pb组MT-1、MT-2表达量与对照组无显著差异(P>0.05),但Cd组和铅镉联合组MT-1、MT-2表达均显著高于对照组(P<0.05)。结合上述试验结果,可以得出以下结论:①铅镉单独或联合暴露可损伤大鼠肾小管的重吸收功能和肾小球的滤过功能,其肾损伤程度与染毒时间呈正相关;②铅镉染毒可导致肾组织抗氧化功能降低,抗氧化微量元素含量降低加剧了氧化应激介导的肾组织损伤,染毒组大鼠体内微量元素含量降低与其尿液中排泄量显著增加直接相关;③铅镉暴露可引起肾皮质显著病理学损伤和多种细胞器损伤,其中线粒体损伤较显著;④染毒组肾皮质COX-I、COX-II、COX-III基因表达量显著下降可能与铅镉暴露导致的线粒体脂质过氧化损伤有关,金属硫蛋白MT-1、MT-2基因表达量显著升高在铅镉联合肾毒性过程中发挥重要作用。总之,铅镉联合肾毒性呈协同效应。
二、体外试验采用机械筛网结合酶消化法建立大鼠原代肾小管上皮细胞(rPTCs)培养模型,在传一代细胞增殖活性最强时间段进行铅(0.5μmol/L、1μmol/L)、镉(2.5μmol/L、5μmol/L)单独或联合染毒。主要进行以下试验:①cck-8还原法测定不同组合的铅镉在不同染毒时间(3、6、12、24h)对rPTCs存活率的影响;②测定铅镉单独或联合染毒12h对rPTCs凋亡率、坏死率、乳酸脱氢酶释放率及凋亡形态学的影响,同时添加N-乙酰半胱氨酸(NAC),观察其对铅镉所致细胞毒性损伤的保护效果;③测定铅镉染毒12h对rPTCs胞内SOD、CAT、GSH-Px活性及GSH、MDA含量的影响;④测定铅镉染毒12h对rPTCs膜ATP酶(Ca~(2+)-ATPase、Na+/K+-ATPase)活性、胞内pH、线粒体膜电位、活性氧及钙离子水平的影响。结果表明,①铅镉单独染毒高剂量组从3h开始、低剂量组从6h开始,其细胞存活率显著低于对照组(P<0.05);铅镉联合组从3h开始,细胞存活率极显著低于对照组(P<0.01),且存活率降低幅度与染毒剂量、染毒时间呈正相关;②染毒12h,各染毒组细胞凋亡率、坏死率、乳酸脱氢酶释放率均极显著高于对照组(P<0.01),且铅镉联合组各项指标均高于各相关单独染毒组;各染毒组细胞表现核皱缩、呈新月形、染色质致密浓染、核碎裂等典型凋亡特征;NAC对铅镉所致细胞凋亡有显著保护效应,但对细胞坏死率和乳酸脱氢酶释放率无明显影响;③与对照组比较,染毒组SOD、CAT、GSH-Px活性和GSH含量均显著或极显著降低(P<0.05或P<0.01),而MDA含量均极显著升高(P<0.01);④染毒各组细胞内活性氧和钙离子水平均极显著高于对照组(P<0.01),线粒体膜电位水平、胞内pH、Ca~(2+)-ATPase与Na~+/K~+-ATPase活性均显著或极显著低于对照组(P<0.05或P<0.01)。上述试验结果可以得出以下结论:①铅镉暴露对rPTCs的毒性损伤呈浓度依赖性和时间依赖性,联合暴露呈协同毒性损伤;②细胞凋亡与细胞坏死是铅镉所致rPTCs死亡的2种死亡类型,其中凋亡性死亡在铅镉该剂量组合所致细胞损伤过程中发挥主导作用。氧化应激在铅镉染毒所致细胞凋亡性死亡过程中发挥重要作用,细胞内抗氧化酶活性降低进一步加剧铅镉对rPTCs的氧化损伤;抗氧化剂NAC对铅镉所致的肾小管上皮细胞毒性损伤有显著保护效应;③铅镉暴露导致rPTCs线粒体膜电位降低而促进细胞凋亡,同时细胞内酸化、钙离子超载、氧化还原平衡状态失调等一系列细胞内环境稳态失衡促进了细胞凋亡。总之,铅镉联合暴露对大鼠肾小管上皮细胞的损伤程度重于单独染毒,呈协同效应。
Lead (Pb) and cadmium (Cd) are now recognized to be two of most important heavy metal contaminants in the environment. Due to their increased industrial uses and environmental pollution with the related waste products, concentrations of lead and cadmium are increasing rapidly in the environment in recent years. Since the two elements are often released simultaneously in the environment from a number of natural and man made sources, adverse health effects caused by combined exposure to lead and cadmium has provoked a significant public health concern. The kidney is the target organ and the primary accumulation site of chronic lead and cadmium exposure. The nephrotoxicity induced by lead and/or cadmium have been extensively studied and widely reported in occupationally and environmentally exposed human subjects, as well as in various experimental models. Most studies were implicated in the single exposure of lead/cadmium on the kidney. However, systemic studies of toxic damage on the combination of lead and cadmium were little referred. In this study, the toxic effects of lead and/or cadmium on the kidney of Sprague-Dawley (SD) rats were investigated in vitro and in vivo, which will offer some theoretic evidences for further exploring the mechanism in nephrotoxicity of lead and/or cadmium.
1. In vivo studies The study was carried out on female one-month-old SD rats. Twenty- four rats were allocated randomly to four groups of six animals each. The experimental period was eight weeks. (1) Control: rats consumed distilled water as drinking water. (2) Lead treated group: rats consumed a solution of PbAc2 (300mg/L) as drinking water. (3) Cadmium treated group: rats consumed a solution of CdAc2 (50mg/L) as drinking water. (4) Pb+Cd treated group: these rats received both Pb and Cd at the doses, periods and ways of administration described above. During the experimental period, water consumption and weight gain were measured every day. A series of tests were carried out:①On the day before the experiment and at the end of 2, 4, 6 and 8 weeks of treatment, rats were kept for 24h urine collection. Activities of alkaline phosphatase (ALP), N-acetyl-β-D-glucosaminidase (NAG),γ-glutamyl-transpeptidase (GGT), lacticacid dehydrogenase (LDH) and contents of total protein (TP),α_1-microglobulin (α_1-MG),β_2-microglobulin (β_2-MG), microalbumen (mAlb) in urine were determined. Also, concentrations of Zn, Cu, Mn, Fe and Se in the urine were detected during the experiment.②At the end of treatment, the levels of Zn, Cu, Mn, Fe, Se, glutathione (GSH), malondialdehyde (MDA) and activities of total superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) in the renal cortex and serum were measured.③Changes in histopathology and ultrastructure of renal cortex were detected by light microscope and transmission electron-microscope, respectively.④The relative gene expression levels of cytochrome oxidase submits (COX-I, COX-II, COX-III) in the renal cortex were quantified by Fluorescent Quantitative-PCR (FQ-PCR). The expressions of metallothionein submits (MT-1, MT-2) in the renal cortex were detected by immunohistochemistry method and FQ-PCR, respectively. The results are as follows:①Compared with the control group, all of the indices(NAG, GGT, LDH, TP,β_2-MG, mAlb) except the contents ofα_1-MG in the Pb, Cd group and activities of ALP in the Pb group at the time of 2-week exposure increased significantly from the beginning of exposed for two weeks (P<0.05 or P<0.01). Especially the changes in the (Pb+Cd) group were the greatest (P<0.05). Positive correlation lied in the process between the degree of increase in activities of urinary enzymes/contents of urinary proteins in the exposed groups and the exposure time. During the experiment, the levels of indices in the (Pb+Cd) group were all higher than those in the Pb, Cd group. There is significant difference between the (Pb+Cd) group and Pb or Cd group in different times.②In comparison with the control group, activities of SOD, CAT, GSH-Px and contents of GSH, Zn, Cu, Mn, Fe, Se in the renal cortex and serum of the three exposed groups decreased significantly(P<0.05). However, the contents of MDA in these exposed groups were significantly increased than that of the control group (P<0.05).③As far as the Pb group and the Cd group is concerned, concentrations of trace elements (Cu, Mn, Fe, Se) in the urine except the concentrations of urinary Zn at the time of 2-week exposure increased significantly from the beginning of exposed for four weeks(P<0.05). Regarding the (Pb+Cd) group, the excretion of trace elements (Zn, Cu, Mn, Se) in the urine except that of urinary Fe increased significantly from the beginning of exposed for two weeks (P<0.05).④Obvious pathological changes in the renal tubule and glomeruli renis were observed in the renal cortex of these three exposed groups. Also, the changes in ultrastructure of renal cortex is obvious, which pyknosis of nucleus, chromatin assemble, partial loss of brush border microvilli in the proximal tubular cells, mitochondrial swelling, disappearance and fragmentation of carina were seen under transmission electronic microscope. The degree of pathological damage in the (Pb+Cd) group was more serious than that in the Pb/Cd group. Compared with the Pb or Cd group, more severe pathological damage was found in the (Pb+Cd) group.⑤The relative expression levels of cytochrome oxidase submits (COX-I, COX-II, COX-III) in the renal cortex of these three exposed groups were significantly lower than those in the control group (P<0.05). The most significant change occurred in the (Pb+Cd) group.⑥There is no significant difference in the expression level of MT-1 and MT-2 gene in the kidneys between the lead group and control group (P>0.05), whereas those in the cadmium group and (Pb+Cd) group were significantly higher than that in the control group (P<0.05). Based on these results, the conclusions are as following:①Tubular reabsorptive function and glomerular filtration function were damaged after exposed to lead and/or cadmium. The degree of renal injury is positively correlated with the increase of exposure time.②Exposure to lead and/or cadmium can induce the decrease of the anti-oxidative function in the kidneys of rats. Also the decreased contents of trace elements related to antioxidative function made the renal damage induced by oxidative stress worse. The decreased levels of these trace elements in the tissues exposed to lead and/or cadmium were due to an increase of their excretion in the urine.③Obvious pathological changes and damage of many organelles in the renal cortex were medicated by lead and/or cadmium. Among these organelles, mitochondria underwent the greatest changes.④The decreased expression levels of COX-I, COX-II, COX-III in the renal cortex exposed to lead and/or cadmium may be related to the mitochondrial lipid peroxidation. The increased expression level of MT-1 and MT-2 gene played an important role in the nephrotoxicity induced by lead and cadmium. In summary, there was an obvious synergistic effect of lead combined with cadmium on the kidney of rats.
2. In vitro studies The primary cultures of rat proximal tubular cells (rTECs) were cultured by mechanical grinding, filtering and chemical digestive methods. The first passage was used to perform the experimental design when it was in its highest cell viability. Effects of lead (0.5μmol/L, 1μmol/L) and/or cadmium (2.5μmol/L, 5μmol/L) on the rTECs were investigated in the following assays.①Effects of different doses of lead and/or cadmium on the survival rates in rPTCs for a time range of 3, 6, 12 and 24h were detected by using the cck-8 reduction method.②Effects of lead and/or cadmium on the apoptotic rates, necrotic rates, LDH release and apoptotic morphological changes in rPTCs over a 12 h period were investigated. In addition, the protective effect of N-acetyl-L-cysteine (NAC) against lead and/or cadmium induced cellular damage was investigated.③Activities of SOD, CAT, GSH-Px and contents of GSH, MDA in rPTCs were measured when exposed to lead and/or cadmium over a 12h period.④Activities of Ca~(2+)-ATPase and Na~+/K~+-ATPase, intracellular pH, levels of mitochondrial membrane potential (ΔΨ), reactive oxygen species (ROS) and intracellular [Ca~(2+)]i in rPTCs were detected after exposed to lead and/or cadmium for 12h. The results are as follows:①The cell survival rates in the single lead and cadmium groups were significantly lower than those of control groups since these cells were exposed to high-dose and low-dose groups for three and six hours, respectively (P<0.05). The cell survival rates in the combined groups were significantly lower than those of control groups after a 3-h exposure (P<0.01). Furthermore, the degree of decrease in the cell survival rate was positively correlated with the dose and the exposure time.②After exposure to lead and/or cadmium for 12h, the apoptotic rates, necrotic rates, LDH release in these exposed groups were significantly higher than those in the control group (P<0.01). Also, the above indices induced by (Pb+Cd) were always higher than those in the related Pb or Cd group in the same exposure time. After a 12-h exposure time, it showed morphological changes typical of apoptosis in the lead and/or cadmium groups, i.e., nuclear chromatin condensed and fragmented chromatin was characterized by a scattered, drop-like structure. Apoptosis induced by lead and/or cadmium can be efficiently prevented by NAC, but the necrotic rates and LDH release were not affected by NAC.③Compared with the control group, activities of SOD, CAT, GSH-Px and the GSH level in the exposed groups decreased significantly (P<0.05 or P<0.01); But the content of MDA increased significantly (P<0.01).④After exposed to lead and/or cadmium for 12h, intracellular ROS and [Ca~(2+)]_i in rPTCs increased significantly (P<0.01), while the mitochondrialΔΨ, intracellular pH, activities of Ca~(2+)-ATPase and Na~+/K~+-ATPase decreased significantly (P<0.05 or P<0.01). Based on these results, the conclusions are as follows:①Lead and/or cadmium exposure induced cellular death in rPTCs, depending on both the concentration and the exposure time. Synergistic effect lies in the administration of lead combined with cadmium.②Cellular death induced by lead and/or cadmium is medicated by two mechanisms, necrotic and apoptotic. The apoptotic mechanism played a chief role in the cellular death induced by lead and/or cadmium at these doses. Moreover, oxidative stress could be implicated in the apoptotic mechanism mediated by lead and/or cadmium. Decreased activities of anti-oxidative enzymes further enhanced oxidative damage in rPTCs caused by lead and/or cadmium. In addition, the cellular damage induced by lead and/or cadmium can be significantly prevented by NAC.③Depletion of mitochondrialΔΨand a disorder of intracellular homeostasis, i.e. intracellular acidification, calcium overload, disturbance in the prooxidant–antioxidant balance, promoted the development of apoptosis in rPTCs. In a word, there was an obvious synergistic effect of lead combined with cadmium on the cellular damage in rPTCs.
引文
[1] Hernberg S. Lead poisoning in a historical perspective [J]. AM J Ind Med, 2000, 38: 244-254
[2]徐进,徐立红.环境铅污染及其毒性的研究进展[J].环境与职业医学,2005,22(3):271-273
[3]蒋云生.长期低浓度铅接触人群的铅性肾病[J].中华肾脏病杂志,1991,7(4):226
[4] Gerhardsson L, Chettle DR, Enqlyst V, et al. Kidney effects in long term exposed lead smelter workers [J]. Br J Ind Med, 1992, 49:186-192
[5]何燧源主编.环境毒物[M].北京:化学工业出版社,2002,51-56
[6]张正洁,李东红,许增贵.我国铅污染现状、原因及对策[J].环境保护科学,2005,31:41-43
[7]刘宗平主编.动物中毒病学[M].北京:中国农业出版社,2006,394-401
[8]王翔朴.肾脏毒理学[M].湖南:湖南科学技术出版社,2004:85-87
[9] Kadir MM, Janjua NZ, Kristensen S, et al. Status of children’s blood lead levels in Pakistan:Implications for research and policy [J]. Public health, 2008, 122: 708-715
[10] Gidlow DA. Lead toxicity [J]. Occup Med (Lond), 2004, 54: 76-81
[11]唐清.铅污染与儿童健康[J].城市环境与城市生态,2003,16(5): 48-50
[12]杨志新,刘树庆. Cd、Zn、Pb单因素及复合污染对土壤酶活性的影响[J].土壤与环境,2000,9 (1):15-18
[13]和文祥.土壤酶与重金属关系的研究现状[J].土壤与环境,2000,9 (2):139- 142
[14]赵春燕,孙军德,宁伟,等.重金属对土壤微生物酶活性的影响[J].土壤通报,2001,32 (2):92-94
[15] Kandeler E, Lufienegger G, Schwarz S. Influence of heavy metals on the functional diversity of soil microbial communities [J]. Bilogy and Fertility of Soils, 1997, 23: 299-306
[16] Khan KS, Xie ZM, Huang CY. Effects of cadmium, lead and zinc on size of m icrobial biomassin red soil [J]. Pedo sphere, 1998A, 8: 27-32
[17] Mukherji S, Maitra P. Toxic effects of lead on growth and metabolism of germinating rice (Oryza salivaL) seedsand mitosis of onion (Allium cepa L) [J]. Indian J Exp Biol, 1976, 14: 519-521
[18] Jarvis JC, Jones LHP, Hopper MJ. Cadmium uptake from solution by plants and its transport from roots to shoots [J]. Plant Soil, 1976, 44: 179-191
[19] Cataldo DA, Garland TR, Wildung RE. Cadmium uptake kinetics in intact soybean plants [J]. Plant Physiol, 1983, 73(3): 844-848
[20]孙铁珩主编.污染生态学[M].北京:科学出版社,2001,160-198
[21] Landrigan PJ, Boffetta P, Apostoli P. The reproductive toxicity and carcinogenicity of lead: a critical review [J]. Am J Ind Med, 2000, 38: 231-243
[22] Coyer RA. Mechanisms of lead and cadmium nephrotoxicity [J].Toxicol lett, 1989, 46: 153-162
[23]朱士雅.铅对大鼠慢性毒性研究[J].职业医学杂志,1985,2:2-4
[24] Cramér K, Goyer RA, Jagenburg R, et al. Renal ultrastructure, renal function, and parameters of lead toxicity in workers with different periods of lead exposure [J]. Br J In Med, 1974, 31: 113-127
[25] Greenberg A, Parkinson DK, Fetterolf DE, et al. Effects of elevated lead and cadmium burdenson renal function and calcium metabolism [J]. Arch Environ Health, 1986, 41: 69-76
[26] Wedeen RP, Maesaka JK, Weiner B, et al. Occupational lead nephropathy [J]. Am J Med, 1975, 59: 630-641
[27]林艳丽,王丽曾,张新民.铅中毒肾脏改变的病理形态观察[J].西北国防医学杂志,1999,20(4):272-273
[28] International Agency for Research on Cancer: Lead and lead compounds. In: Overall evaluations of carcinogenicity [M]. An updating of IARC Monographs, Vols, 1-42. IARC supplement 7.1987
[29] Sibergeld EK, Waalkes M, Rice JM. Lead as a carcinogen: experiment evidence and mechanisms of action [J]. Am J Ind Med, 2000, 38: 316-323
[30]金文达,雷义,陈锋.铅的肾脏毒性研究探讨[J].实用预防医学,2007,14(2):597-600
[31]黄瑞雪,熊敏如.铅性肾病的生物标志物研究[J].中国工业医学杂志,2003,16(4): 225-227
[32]王三虎,高星.铅的生物标志物研究[J].中国职业医学,2002,2(29): 50-51
[33] ACGIH, Threshold limit values and biological exposure indices for 1991-1992, Cincinnati [J]. American Conference of Governmental Industrial Hygienists (ACGIH), 1991, 58-70
[34]蒋云生,夏运成,徐锡萍,等.铅性肾病的流行病学分析[J].中华劳动卫生职业病杂志,1994,2(12):76-78
[35] Davies JM. Long term mortality study of chromate pigment workers who suffered lead poisoning [J]. Br J Ind Med, 1984, 41:170-178
[36] Pergande M, Leroyer A, Haguenoer JM, et al. Changed exertion of urinary proteins and enzymes by chronic exposure to lead [J]. Nephrol Dial Transplant, 1994, 9(6): 613-618
[37]蒋云生,夏运成,罗季安,等.长期低浓度铅接触人群的铅性肾病[J].中华肾脏病杂志,1991,7(4):226-227
[38] Dart RC, Hurlbut KM, Maiorino RM, et al. Pharmacokinetics meso-2, 3-dimercaptosuccinic acid in patients with lead poisoning and in healthy adults [J]. J Pediatr, 1994, 125: 309-316
[39] Gerhardsson L, Chettle DR, Englyst V, et al. Kidney effects in long term exposed lead smelter workers [J]. Br J Ind Med, 1992, 49: 186-192
[40] Petrucci R, Leonardi A, Battistuzzi G. The genetic polymorphism of delta-aminolevulinatedehydrates in Italy [J]. Hum Genet, 1982, 60: 289-290
[41] Wetmur JG, Kaya AH, Plewinska M, et al. Molecular characterization of the humanδ-aminolevulinate dehydrates-2(ALAD2) allele: implications for molecular screening of individual for genetic susceptibility to lead poisoning [J]. Am J Hum Genet, 1991, 49: 757-763
[42]杨水莲,叶细标. ALAD和VDR基因多态性与铅肾毒性易感性的关系[J].环境与职业医学,2002,19(6):271-273
[43] Schwartz BS, Lee BK, Lee GS, et al. Associations of blood lead, dimercaptosuccinic acid-cheatable lead, and tibia lead with polymorphisms in the vitamin D receptor andδ-aminolevulinic acid dehydratase genes [J]. Environ Health Perspect, 2000, 108(10): 949-954
[44] Schwartz BS, Stewart WF, Kelsey KT, et al. Associations of tibial lead levels with BsmI polymorphisms in the vitamin D receptor in former organolead manufacturing workers [J]. Environ Health Perspect, 2000, 108(3):199-203
[45] Ahamed M, Siddiqui MKJ. Low level lead exposure and oxidative stress: Current opinions [J]. Clinica Chimica Acta, 2007, 383: 57-64
[46] Donaldson WE, Knowles SO. Is lead toxicosis a reflection of altered fatty acid composition ofmembrane? [J]. Comp BiochemPhysiol C, 1993, 104: 377-379
[47] Knowles SO, Donaldson WE. Dietary modification of lead toxicity: effects on fatty acid and eicosanoid metabolism in chicks [J]. Comp Biochem Physiol, 1990, 95: 99-104
[48] Lawton L, Donaldson WE. Lead-induced tissue fatty acid alterations and lipid peroxidation [J]. Biol Trace Elem Res, 1991, 28: 83-87
[49] Adonaylo VN, Oteiza PI. Pb2+ promotes lipid peroxidation and alteration in membrane physical properties [J]. Toxicology, 1999, 132: 19-32
[50] Gurer H, Ozgunes H, Neal R, et al. Antioxidant effects of Nacetylcysteine and succimer in red blood cells from lead exposed rats [J]. Toxicology, 1998, 128:181-189
[51] Hsu PC, Hsu CC, Liu MY, et al. Lead-induced changes in spermatozoa function and metabolism [J]. J Toxicol Environ Health, 1998, 55: 45-64
[52] Ding Y, Gonick HC, Vaziri ND, et al. Lead-induced hypertension III: increased hydroxyl radical production [J]. Am J Hypertens, 2001, 14: 169-173
[53] Patra RC, Swarup D, Dwidedi SK. Antioxidant effects ofα-tocopherol, ascorbic acid and L-methionine on lead-induced oxidative stress of the liver, kidney and brain in rats [J]. Toxicology, 2001, 162: 81-88
[54] Gurer-Orhan H, Sabir HU, Ozgunes H. Correlation between clinical indicator of lead poisoning and oxidative stress parameters in controls and lead exposed workers [J]. Toxicology, 2004, 195: 147-154
[55] Kasperczyk S, Birkner E, Kasperczyk A, et al. Lipid, lipid peroxidation and 7-ketocholesterol in workers exposed to lead [J]. Human Exp Toxicol, 2005, 24: 287-295
[56] Sandhir R, Gill KD. Effect of lead on lipid peroxidation in liver of rats [J]. Biol Trace Elem Res, 1995, 21: 157-161
[57]王俊虹,周蔚,王世鑫.铅对大鼠肾脏SOD活性和MDA含量影响的研究[J].武警医学院学报,2002,11(3):146-148
[58]韩贻仁.分子细胞生物学[M].二版.北京:科学出版社,2003:648-661
[59] Franco R, Sánchez-Olea R, Reyes-Reyes EM, et al. Environmental toxicity, oxidative stress and apoptosis: MénageàTrois [J]. Mutation Research, 2009, doi:10.1016/j.mrgentox.2008.11.012
[60] Chetty CS, Vemuri MC, Campbell K, et al. Lead-induced cell death of human neuroblastoma cells involves GSH deprivation [J]. Cell Mol Biol Lett, 2005, 10: 413-423
[61] Sharifi AM, Mousavi SH, Bakhshayesh M, et al. Study of correlation between lead-induced cytotoxicity and nitric oxide production in PC12 cells [J]. Toxicol Lett, 2005, 160: 43-48
[62]文涛,孙黎光,彭博.慢性铅暴露小鼠脑海马c-fos、c-jun表达与学习记忆的关系[J].毒理学杂志,2005,19(3):236
[63] Chatzizacharias NA, Kouraklis GP, Theocharis SE. Disruption of FAK signaling: A side mechanism in cytotoxicity [J]. Toxicology, 2008, 245: 1-10
[64]蔡宇,余绍蕾,张荣华.枸杞多糖对染铅小鼠行为功能保护及脑细胞Fas抗原表达的影响[J].环境与职业医学,2005,22(6):533-534
[65] Pulido MD, Parrish AR. Metal-induced apoptosis: mechanisms [J]. Mutat Res, 2003, 533: 227-241
[66] Flora SJ, Saxena G, Mehta A. Reversal of lead-induced neuronal apoptosis by chelationtreatment in rats: role of reactive oxygen species and intracellular Ca2+ [J]. J Pharmacol Exp Ther, 2007, 322: 108-116
[67] Xu J, Ji LD, Xu LH.Lead-induced apoptosis in PC 12 cells: involvement of p53, Bcl-2 family and caspase-3 [J]. Toxicol Lett, 2006, 166: 160-167
[68] Winder C, Bonin T. The genotoxicity of lead [J]. Mutation Res, 1993, 285(1): 117-124
[69] Hartwig A. Interactions by carcinogenic metal compounds with DNA repair processes: toxicological implications [J]. Toxicol Lett, 2002, 127(1-3): 47-54
[70] Restrepo HG, Sicard D, Torres MM. DNA damage and repair in cells of lead exposed people [J]. Am J Ind Med, 2000, 38(3): 330-334
[71] Razmiafshari M, Kao J, d′Avignon A, et al. NMR identification of heavy metal-binding sites in a synthetic zinc finger peptide: toxicological implications for the interactions of xenobiotic metals with zinc finger proteins [J]. Toxicol Appl Pharmacol, 2001, 172(1): 1-10
[72] Quintanilla-Vega B, Hoover D J, Bal W, et al. Lead interaction with human protamine(HP2) as a mechanism of male reproductive toxicity [J]. Chem Res Toxicol, 2000, 13(7): 594-600
[73] Rydberg B. Radiation-induced DNA damage and chromatin structure [J]. Acta Oncol, 2001, 40(6): 682-685
[1]王文仲,徐兆发.镉的肾脏毒理学[J].中国工业医学杂志,2001,14(5):291-293
[2] Pham TN, Marion M, Denizeau F, et al. Cadmium-induced apoptosis in rat hepatocytes does not necessarily involve caspase-dependent pathways [J]. Toxicol in vitro, 2006, 20: 1331-1342
[3] Shaikh ZA, Zaman K, Tang W, et al. Treatment of chronic cadmium nephrotoxicity by N-acetyl cysteine [J]. Toxicol Lett, 1999, 104: 137-142
[4] Jones MM, Cherian MG. The search for chelate antagonists for chronic cadmium intoxication [J]. Toxicology, 1990, 62: 1-25
[5] Stoeppler M. Cadmium [M]. In: Merian, E. (Ed), Metals and their compounds in the environment, 1991, VCH, Weinheim, New York, Basel, Cambridge, pp. 803-851
[6] Waisberg M, Joseph P, Hale B et al. Molecular and cellular mechanisms of cadmium carcinogenesis [J]. Toxicology, 2003, 192: 95-117
[7] GB 3838-2002,中华人民共和国地表水环境质量标准[S].北京:中国环境科学出版社出版,2002
[8]天津大学图书馆.环境科学与工程学科信息数据库[DB/OL] http://202.113.6.254/hj/web,2003-3-25
[9]赵璇,吴天宝.我国饮用水源的重金属污染及治理技术深化问题[J].给水排水,1998,24(10):22-25
[10]王江平.入世后高浓度磷肥中镉的问题[J].磷肥与复肥,2002,17(5):11-15
[11] Thornton I. Sources and pathways of cadmium in the environment [J]. IARC Sci. Publ, 1992, 118: 149-162
[12]周锡爵.张士灌区镉污染及其解决和利用的途径[J].农业环境保护,1987,6(2):17-19
[13]刘立群.赣南土壤污染的防治途径[J].资源开发与保护杂志,1990,6(2):100-102
[14]王翔朴.肾脏毒理学[M].湖南:湖南科学技术出版社,2004:88-92
[15] Lars J, Bodil P, Carl Ge. Decreased gromerular filtration rate in solders exposed to cadmium [J]. Occup Environ Med, 1995, 52: 818-822
[16]刘杰,刘亚平.慢性和急性染镉所致小鼠肾损伤的比较[J].中华劳动卫生职业病杂志,1998,16(1):2
[17]刘宗平主编.动物中毒病学[M].北京:中国农业出版社,2006,394-401
[18]刘杰.镉的毒性和毒理学研究进展[J].中华劳动卫生职业病杂志,1998,16(1):2-4
[19] Carageorgiou H, Tzotzes V, Pantos C, et al. In vivo and in vitro effects of cadmiumon adult rat brain total antioxidant status, acetylcholinesterase, (Na+/K+) ATPase and Mg2+ATPase activities: protection by L-cysteine [J]. Basic Clin Pharmacol Toxicol, 2004, 94(3): 112-118
[20] Faurakov B, Bjerregaard HF. Evidence for cadmium mobilization of intra cellular calcium through a divalent cation receptor in renal distal epithelial A6 cells [J]. Pflugers Arch, 2002, 445(1): 40-50
[21] Kaplan M, Atakan IH, Aydo?du N, et al. Influence of N-acetylcysteine on renal toxicity of cadmium in rats [J]. Pediatr Nephrol, 2008, 23: 233-241
[22] Thijssen S, Cuypers A, Maringw J, et al. Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys [J]. Toxicology, 2007, 236: 29-41
[23] Nigam D, Shukla GS, Agarwal AK. Glutathione depletion and oxidative damage in mitochondria following exposure to cadmium in rat liver and kidney [J]. Toxicology Letters, 1999, 106: 151-157
[24] Morales AI, Vicente-Sánchez C, Sandoval JM, et al. Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties [J]. Food Chem Toxicol, 2006, 44: 2092-2100
[25] Waalkes MP, Poirier LA. In vitro cadmium–DNA interactions: cooperativity of cadmium binding and competitive antagonism by calcium, magnesium, and zinc [J]. Toxicol Appl Pharmacol, 1984, 75: 539-546
[26] International Agency for Research on Cancer, Berrylium, cadmium, mercury and exposures in the glass manufacturing industry, in: International Agency for Research on Cancer Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 58, IARC Scientific Publications, Lyon, 1993, pp. 119-237
[27] Dally H, Hartwig A. Induction and repair inhibition of oxidative DNA damage by nickel (II) and cadmium (II) in mammalian cells [J]. Carcinogenesis, 1997, 18: 1021-1026
[28] Joseph P. Mechanisms of cadmium carcinogenesis [J]. Toxicol Appl Pharmacol, 2009, doi: 10.1016/ j.taap.2009.01.011
[29] Bertin G, Averbeck D. Cadmium: cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences [J]. Biochimie, 2006, 88: 1549-1559
[30] Shaikh ZA, Vu TT, Zaman K. Oxidation stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants [J]. Toxicol Appl Pharmacol, 1999, 154(3): 256-263
[31] Pari L, Murugavel P. Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats [J]. Toxicology, 2007, 234: 44-50
[32] Leelank BN, Bansal MP. Effect of selenium supplementation on the glutathione redox system inthe kidney of mice after chronic cadmium exposures [J]. J Appli Toxicol, 1996, 17: 81-84
[33] Pari L, Murugavel P, Sitasawad SL, et al. Cytoprotective and antioxidant role of diallyl tetrasulfide on cadmium induced renal injury: An in vivo and in vitro study [J]. Life Sciences, 2007, 80: 650-658
[34] Fang YZ, Yang S, Wu G. Free radical, antioxidants and nutrition [J]. Nutrition, 2002, 18: 872-879
[35] Januel C, Fay LB, Ruggiero D, et al. Covalent coupling of reduced glutathione with ribose: loss of cosubstrate ability to glutathione peroxidase [J]. Biochim Biophys Acta, 2003, 1620: 125-132
[36] Masini A, Trenti T, Ceccarelli-Stanzani D, et al. The effect of ferric iron complex on isolated rat liver mitochondria.I. Respiratory and electrochemical responses [J]. Biochim Biophys Acta, 1985, 810: 20-26
[37] Bindoli A. Lipid peroxidation in mitochondria [J]. Free Radic Biol Med, 1988, 5: 247-261
[38] Castilho RF, Meinicke AR, Almeida AM, et al. Oxidative damage of mitochondria induced by Fe (II) citrate is potentiated by Ca2+ and includes lipid peroxidation and alterations in membrane proteins [J]. Arch Biochem Biophys, 1994, 308: 158-163
[39] Takeyama N, Miki S, Hirakawa A, et al. Role of the mitochondrial permeability transition and cytochrome C release in hydrogen peroxide-induced apoptosis [J]. Exp Cell Res, 2002, 274: 16-24
[40] Miyaguchi C, Muranaka S, Kanno T, et al. 17beta-estradiol suppresses ROS-induced apoptosis of CHO cells through inhibition of lipid peroxidation-coupled membrane permeability transition [J]. Physiol Chem Phys Med, NMR, 2004, 36: 21-35
[41] Alvarez-Barrientos A, O’Connor JE, Nieto Castillo R, et al. Use of flow cytometry and confocal microscopy techniques to investigate early CdCl2-induced nephrotoxicity in vitro [J]. Toxicol in Vitro, 2001, 15: 407-412
[42] Kim MS, Kim BJ, Woo HN, et al. Cadmium induces caspase-mediated cell death: suppression by Bcl-2 [J]. Toxicology, 2000, 145: 27-37
[43] Li M, Kondo T, Zhao QL, et al. Apoptosis induced by cadmium in human lymphoma U937cells through Ca2+-calpain and caspase-mitochondria-dependent pathways [J]. J Biol Chem, 2000, 275: 39702-39709
[44] Wang Y, Fang J, Leonard SS, et al. Cadmium inhibits the electron transfer chain and induces reactive oxygen species [J]. Free Radic Biol Med, 2004, 36: 1434-1443
[45] Misra PR, Smith GT, Waalkes WP. Evaluation of the direct genotoxic potential of cadmium in four different rodent cell lines [J]. Toxicology, 1998, 126: 103-114
[46] Liu F, Jan KY. DNA damage in arsenite- and cadmium-treated bovine aortic endothelial cells [J]. Free Radic Biol Med, 2000, 28: 55-63
[47] Mouron SA, Grillo CA, Dulout FN, et al. A comparative investigation of DNA strand breaks, sister chromatid exchanges and K-ras gene mutations induced by cadmium salts in cultured human cells [J]. Mutat Res, 2004, 568: 221-231
[48] Fotakis G, Cemeli E, Anderson D, et al. Cadmium chloride induced DNA and lysosomal damage in a hepatoma cell line [J]. Toxicol in Vitro, 2005, 19: 481-489
[49]王文仲,徐兆发,杨敬华,等.镉对小鼠肾脏细胞凋亡的影响[J].中国工业医学杂志,2004, 17(1):4-6
[50] Kondoh M, Araragi S, Sato K, et al. Cadmium induces apoptosis partly via caspase-9 activation in HL-60 cells [J]. Toxicology, 2002, 170: 111-117
[51] Shih YL, Lin CJ, Hsu SW, et al. Cadmium toxicity toward caspase-independent apoptosis through the mitochondria-calcium pathway in mtDNA-depleted cells [J]. Ann N Y Acad Sci., 2005, 1042: 497-505
[52]闫玲,苗琦.细胞器与细胞凋亡[J].生物物理学报,2002,18(3):271-276
[53] Vercesi AE, Kowaltowski AJ, Grijalba MT, et al. The role of reactive oxygen species in mitochondrial permeability transition [J]. Biosci Rep, 1997, 17: 43-52
[54] Lohmann RD, Beyersmann D. Cadmium- and zinc-mediated changes of the Ca2+-dependent endonuclease in apoptosis [J]. Biochem Biophys Res Commun, 1993, 190: 1097-1103
[55] Junnwirth A, Paulmichl M, Lang F. Cadmium enhances potassium conductance in cultured renal epitheloid (MDCK) cells [J]. Kidney Int, 1990, 37(6):1477-1486
[56] Fukumoto M, Kujiraoka T, Hara M, et al. Effect of cadmium on gap junctional intercellularcommunication in primary cultures of rat renal proximal tubular cells [J]. Life Sci, 2001, 69(3): 247-254
[57] Wang L, Cao J, Chen D, et al. Role of oxidative stress, apoptosis, and intracellular homeostasis in primary cultures of rat proximal tubular cells exposed to cadmium [J]. Biol Trace Elem Res, 2009, 127: 53-68
[58] Matsuoka M, Call KM. Cadmium-induced expression of immediate early genes in LLC-PK1 cells [J]. Kidney Int, 1995, 48: 383-389
[59] Garrett SH, Phillips V, Somji S, et al. Transient induction of metallothionein isoform 3 (MT-3), c-fos, c-jun and c-myc in human proximal tubule cells exposed to cadmium [J]. Toxicol Lett, 2002, 126: 69-80
[60] Thévenod F, Friedmann JM, Katsen AD, et al. Up-regulation of multidrug resistance P-glycoprotein via Nuclear Factor-kappaB activation protects kidney proximal tubule cells from cadmium- and reactive oxygen species-induced apoptosis [J]. J Biol Chem, 2000, 275(3): 1887-1896
[61] Thévenod F, Friedmamn JM. Cadmium-mediated oxidative stress in kidney proximal tubule cells induces degradation of Na+/K+-ATPase through proteasomal and endo-/lysosomal proteolytic pathways [J]. FASEB J, 1999, 13(13): 1751-1761
[62] Gennari A, Cortese E, Boveri M, et al. Sensitive endpoints for evaluating cadmium-induced acute toxicity in LLC-PK1 cells [J]. Toxicology, 2003, 183: 211-220
[63]姜傥,谭炳德,董秀清.镉对肾小管细胞内Na+-K+-ATP酶与钙稳态的变化[J].中华劳动卫生职业病杂志,1995,13(2):75-77
[64] Stinson LJ, Darmon AJ, Dagnino L, et al. Delayed apoptosis post-cadmium injury in renal proximal tubule epithelial cells [J]. Am J Nephrol, 2003, 23(1): 27-37
[65] Wang Z, Templeton DM. Induction of c-fos proto-oncogene in mesangial cells by cadmium [J]. J Biol Chem, 1998, 273(1): 73-79
[66] Ding W, Templeton DM. Activation of parallel mitogen-activated protein kinase cascades and induction of c-fos by cadmium [J]. Toxicol Appl Pharmacol, 2000, 162(2): 93-99
[67] Kang CD, Jang JH, Kim KW, et al. Activation of c-jun N-terminal kinase/stress-activatedprotein kinase and the decreased ratio of Bcl-2 to Bax are associated with the auto-oxidized dopamine-induced apoptosis in PC12 cells [J]. Neurosci Lett, 1998, 256(1): 37-40
[68] Watters D. Molecular mechanisms of ionizing radiation-induced apoptosis [J]. Immunol Cell Biol, 1999, 77(3): 263-271
[69] Dabrio M, Rodríguez AR, Bordin G, et al. Recent developments in quantification methods for metallothionein [J]. J Inorg Biochem, 2002, 88 (2): 123-134
[70] Waalkes MP, Coogan TP, Barter RA. Toxicological principles of metal carcinogenesis with special emphasis on cadmium [J]. Crit Rev Toxicol, 1992, 22: 175-201
[71] Shimoda R, Achanzar WE, Qu W, et al. Metallothionein is a potent negative regulator of apoptosis [J]. Toxicol Sci, 2003, 73: 294-300
[72] Cherian MG, Goyer RA. Metallothioneins and their role in the metabolism and toxicity of metals [J]. Life Sci, 1978, 23(1): 1-9
[73]裴秀丛,徐兆发.镉对大鼠肾小管上皮细胞E-cadherin影响[J].中国公共卫生,2006,22(2):160-162
[1]李君,潘家荣,魏益民.食品中铅镉联合毒性研究进展[J].食品研究与开发,2007,128(3):158-160
[2] Nolan CV, Shaikh ZA. Lead nephrotoxicity and associated disorders-biochemical-mechanisms [J]. Toxicology, 1992, 73: 127-146
[3] W?ostowski T, Krasowska A, Bonda E. Joint effects of dietary cadmium and polychlorinatedbiphenyls on metallothionein induction, lipid peroxidation and histopathology in the kidneys and liver of bank voles [J]. Ecotoxicol Environ Saf, 2008, 69: 403-410
[4]刘宗平,马卓,李文范,等.铅镉中毒发病机理的研究-绵羊动物模型的复制[J].中国兽医科技,1996,26(10):11-14
[5]王学谦,尹先仁,白雪涛.铅镉联合作用对大鼠肾小管上皮细胞脂质过氧化的影响[J].卫生研究,2002,31(4):232-234
[6] Bizarro P, Acevedo S, Ni?o-Cabrera G, et al. Ultrastructural modifications in the mitochondrion of mouse Sertoli cells after inhalation of lead, cadmium or lead–cadmium mixture [J]. Reprod Toxicol, 2003, 17: 561-566
[7]路浩,达剑森,梅莉,等.母鼠妊娠期铅镉联合暴露对仔鼠脑组织的氧化损伤及乙酰半胱氨酸的保护效应[J].中国兽医科学,2008,38(1):42-45
[8]王林,陈大伟,曹瑾,等.铅镉联合暴露对大鼠肾脏功能损伤的研究[J].毒理学杂志,2008,22(5):345-348
[9]马卓,刘宗平,张白银,等.绵羊铅镉联合中毒与硒解毒的试验病理学研究[J].中国兽医科技,1997,27(3):12-14
[10] Liu ZP. Lead poisoning combined with cadmium in sheep and horses in the vicinity of non–ferrous metal smelters [J]. The Science of the Total Environment, 2003, 309: 117-126
[11] Haneef SS, Swarup D, Dwivedi SK, et al. Effects of concurrent exposure to lead and cadmium on renal function in goats [J]. Small Rumin Res, 1998, 28: 257-261
[12] Nolan CV, Shaikh ZA. Lead nephrotoxicity and associated disorders: Biochemical mechanism [J]. Toxicology, 1992, 73: 127-146
[13] Garcia TA, Corredor L. Biochemical changes in the kidneysafter perinatal intoxication with lead and/or cadmium and their antagonistic effects when coadministered [J]. Ecotoxicol Environ Safe, 2004, 57: 184-189
[14] Mahaffey KR, Capar SG,Gladen BC, et al. Concurrent exposure to lead, cadmium, and arsenic. Effects on toxicity and tissue metal concentrations in the rat [J]. J Lab Clin Med, 1981, 98: 463-481
[15] Salovsky P, Shopova V, Dancheva V. Combined effects of cadmium and lead on some biochemical markers in rat Bronchoalveolar Lavage Fluid [J]. Toxicol Lett (supple), 1995, 78: 73
[1] Cooper GP, Manalis RS. Interactions of Pb and Cd on acetylcholine release at the frog neuromuscular junction [J]. Toxicol Appl Pharmacol, 1984, 74: 411-416
[2] Waisberg M, Joseph P, Hale B, et al. Molecular and cellular mechanisms of cadmium carcinogenesis [J]. Toxicology, 2003, 192: 95-117
[3] Ercal N, Treeratphan P, Hammond TC, et al. In vivo indices of oxidative stress in lead exposed C57BL/6 mice are reduced by treatment with meso-2, 3-dimercaptosuccinic acid or N-acetyl cysteine [J]. Free Rad Biol Med, 1996, 21: 157-161
[4] Sharma RP, Street JC. Public health aspects of toxic heavy metals in animal feed [J]. J Am Vet Med Assoc, 1980, 177: 149-153
[5] Morales AI, Vicente-Sánchez C, Jerkic M, et al. Effect of quercetin on metallothionein, nitric oxide synthases and cyclooxygenase-2 expression on experimental chronic cadmium nephrotoxicity in rats [J]. Toxicol Appl Pharmacol, 2006, 210: 128-135
[6] Thijssen S, Cuypers A, Maringwa J, et al. Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys [J]. Toxicology 2007, 236: 29-41
[7] Chwe?atiuk E, W?ostowski T, Krasowska A, et al. The effect of orally administered melatonin on tissue accumulation and toxicity of cadmium in mice [J]. J Trace Elem Med Biol, 2006, 19: 259-265
[8] Antonio Garcia T, Corredor L. Biochemical changes in the kidneys after perinatal intoxication with lead and/or cadmium and their antagonistic effects when coadministered [J]. Ecotoxicol Environ Saf, 2004, 57: 184-189
[9] Campana O, Sarasquete C, Blasco J. Effect of lead on ALA-D activity, metallothionein levels, and lipid peroxidation in blood, kidney, and liver of the toadfish Halobatrachus didactylus [J]. Ecotoxicol Environ Saf, 2003, 55: 116-125
[10] Shaikh ZA, Zaman K, Tang W, et al. Treatment of chronic cadmium nephrotoxicity by N-acetyl cysteine [J]. Toxicol Lett, 1999, 104: 137-142
[11]刘宗平主编.动物中毒病学[M].北京:中国农业出版社,2006,394-401
[12] Swierkosz TA, Mitchell JA, Warner TD, et al. Co-induction of nitric oxide synthase and cyclo-oxygenase: interactions between nitric oxide and prostanoids [J]. Br J Pharmacol, 1995, 114: 1335-1342
[1]刘宗平主编.动物中毒病学[M].北京:中国农业出版社,2006,394-401
[2] Haneef SS, Swarup D, Dwivedi SK, et al. Effects of concurrent exposure to lead and cadmium on renal function in goats [J]. Small Rumin Res, 1998, 28: 257-261
[3] Antonio Garcia T, Corredor L. Biochemical changes in the kidneys after perinatal intoxication with lead and/or cadmium and their antagonistic effects when coadministered [J]. Ecotoxicol Environ Saf, 2004, 57: 184-189
[4]王学谦,白雪涛,尹先仁.铅镉联合作用对大鼠肾小管上皮细胞β-乙酰氨基葡萄糖苷酶的影响[J].环境与健康杂志,2002,14:306-309
[5]王翔朴.肾脏毒理学[M].湖南:湖南科学技术出版社,2004:16-24
[6]朱国文,李熙建.肾脏功能不同程度损害时尿中几种微量蛋白与尿酶变化分析[J].国际检验医学杂志,2007,28:489-491
[7] Lars J, Bodil P, Carl Ge. Decreased gromerular filtration rate in solders exposed to cadmium [J]. Occup Environ Med, 1995, 52: 818-822
[8] Akesson A, Lundh T, Vahter M, et al. Tubular and glomerular kidney effects in Swedish women with low environmental cadmium exposure [J]. Environ Health Perspect, 2005, 113: 1627-1631
[9] Raab WP. Diagnostic value of urinary enzyme determinations [J]. Clin Chem, 1972, 18: 5-25
[10] Sivaprasad TR, Malarkodi SP, Palaninathan V. Therapeutic efficacy of lipoic acid in combination with dimercaptosuccinic acid against lead-induced renal tubular defects and on isolated brush-border enzyme activities [J]. Chem-Biol Interact, 2004, 147: 259-271
[11] Tanimoto A, Hamada T, Koidao O. Cell death and regeneration of renal proximal tubular cells in rats with sub-chronic cadmium intoxication [J]. Toxicol Pathol, 1993, 21: 341-352
[12]刘杰,刘亚平,Curtis DK.慢性和急性染镉所致小鼠肾损害的比较[J].中华劳动卫生职业病杂志,1998,16:9
[13]王海燕.肾脏病学[M].第二版,北京:人民卫生出版社,1996,1387-1388
[14] Wedeen RP, Udasin I, Fiedler N, et al. Urinary biomarkers as indicators of renal disease [J]. Ren Fail, 1999, 21: 241-249
[15] Morales AI, Vicente-Sánchez C, Sandoval JM, et al. Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties [J]. Food Chem Toxicol, 2006, 44: 2092-2100
[16] Zalups RK, Barfuss DW. Nephrotoxicity of inorganic mercury L-cysteine co-administered with [J]. Toxicology, 1996, 109: 15-29
[17] Stroo WE, Hook JB. Enzymes of renal origin in urine as indicators of nephrotoxicity [J]. Toxicol Appl Pharmacol, 1977, 39: 423-434
[18] Porter GA. Urinary biomarkers and nephrotoxicity [J]. Miner Electrolyte Metab, 1994, 20: 181-186
[19] Rodriguez-Barbero A, López-Novoa JM, Arévalo M. Involvement of platelet-activating factor in gentamicin nephrotoxicity in rats [J]. Exp Nephrol, 1997, 5: 47-54
[20] Tomlinson PA, Dalton RN, Hartley B, et al. Low molecular weight protein excretion in glomerular disease: a comparative analysis [J]. Pediatr Nephrol, 1997, 11: 285-290
[21] Gruener N. Early detection of changes in kidney function in workers exposed to solvents and heavy metals [J]. Isr J Med Sci, 1992, 28: 605-607
[22] Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NHF) and the national institute of diabetes and digestive and kidney diseases (NIDDK) [J]. Am J Kidney Dis, 2003, 42: 617-622
[23] Komori T, Yoshimura M, Inoue H, et al. Clinical significance of urinary free dopamine as a marker of renal function [J]. Rinsbo byori, 1996, 44: 477-482
[24] Lee JI, Kim MJ, Park CS, et al. Influence of ascorbic acid on BUN, creatinine, resistive index in canine renal ischemia-reperfusion injury [J]. J Vet Sci, 2006, 7: 79-81
[1]刘宗平.动物中毒病学[M].北京:中国农业出版社,2006:394-402
[2] Shaikh ZA, Vu TT, Zaman K. Oxidation stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants [J]. Toxicol Appl Pharm, 1999, 154: 256-263
[3] Thijssen S, Cuypers A, Maringw J, et al. Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys [J]. Toxicology, 2007, 236: 29-41
[4] Farmand F, Ehdaie A, Roberts CK, et al. Lead-induced dysregulation of superoxide dismutases, catalase, glutathione peroxidase, and guanylate cyclase [J]. Environmental Research, 2005, 98: 33-39
[5] Patra RC, Swarup D, Dwivedi SK. Antioxidant effects ofαtocopherol, ascorbic acid and L-methionine on lead induced oxidative stress to the liver, kidney and brain in rats [J]. Toxicology, 2001, 162: 81-88
[6] Dimri U, Ranjan R, Kumar N, et al. Changes in oxidative stress indices, zinc and copper concentrations in blood in canine demodicosis [J]. Vet Parasitol, 2008, 154: 98-102
[7] Gurer H, Ozgunes H, Neal R, et al. Antioxidant effects of N-acetyl cysteine and succimer in redblood cells from lead exposed rats [J]. Toxicology, 1998, 128: 181-189
[8] Nigam D, Shukla GS, Agarwal AK. Glutathione depletion and oxidative damage in mitochondria following exposure to cadmium in rat liver and kidney [J]. Toxicol Lett, 1999, 106: 151-157
[9] Jurczuk M, Moniuszko-Jakoniuk J, Brzóska MM. Involvement of some low-molecular thiols in the peroxidative mechanisms of lead and ethanol action on rat liver and kidney [J]. Toxicology, 2006, 219: 11-21
[10] Pari L, Murugavel P. Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats [J]. Toxicology, 2007, 234: 44-50
[11] Shaikh ZA, Zaman K, Tang W, et al. Treatment of chronic cadmium nephrotoxicity by N-acetyl cysteine [J]. Toxicol Lett, 1999, 104: 137-142
[12] Leelank BN, Bansal MP. Effect of selenium supplementation on the glutathione redox system in the kidney of mice after chronic cadmium exposures [J]. J Appl Toxicol, 1996, 17: 81-84
[13] Fang YZ, Yang S, Wu G. Free radical, antioxidants and nutrition [J]. Nutrition, 2002, 18: 872-879
[14] Januel C, Fay LB, Ruggiero D, et al. Covalent coupling of reduced glutathione with ribose: loss of cosubstrate ability to glutathione peroxidase [J]. Biochim Biophys Acta, 2003, 1620: 125-132
[15] Huang YL, Sheu JY, Lin TH. Association between oxidative stress and changes of trace elements in patients with breast cancer [J]. Clin Biochem, 1999, 32: 131-136
[16] Fraga CG. Relevance, essentiality and toxicity of trace elements in human health [J]. Molecular Aspects of Medicine, 2005, 26: 235-244
[17] Horsburgh MJ, Wharton SJ, Karavolos M, et al. Manganese: elemental defence for a life with oxygen? [J]. TRENDS in Microbiology, 2002, 10: 496-501
[18] Uriu-Adams JY, Keen CL. Copper, oxidative stress, and human health [J]. Mol Aspects Med, 2005, 26: 268-298
[19] Rao L, Puschner B, Prolla TA. Gene expression profiling of low selenium status in the mouse intestine: transcriptional activation of genes linked to DNA damage, cell cycle control andoxidative stress [J]. J Nutr, 2001, 131: 3175-3181
[20] Taylor CG, Towner RA, Janzen EG, et al. MRI detection of hyperoxia-induced lung edema in Zn-deficient rats [J]. Free Radic Biol Med, 1990, 9: 229-233
[21] Oteiza PI, Olin KL, Fraga CG, et al. Zinc deficiency causes oxidative damage to proteins, lipids and DNA in rat testes [J]. J Nutr, 1995, 125: 823-829
[22] Parsons SE, Disilvestro RA. Effects of mild Zinc deficiency, plus or minus an acute-phase response, on glactosamine-induced hepatitis in rats [J]. Br J Nutr, 1994, 72: 611-618
[23] Kraus A, Roth HP, Kirchgessner M. Supplementation with vitamin C, vitamin E or beta carotene influences osmotic fragility and oxidative damage of erythrocytes of zinc-deficient rats [J]. J Nutr, 1997, 127: 1290-1296
[24] Kaushal N, Bansal MP. Dietary selenium variation-induced oxidative stress modulates CDC2/cyclin B1 expression and apoptosis of germ cells in mice testis [J]. J Nutr Biochem, 2007, 18: 553-564
[25]刘宗平.现代动物营养代谢病[M].北京.化学工业出版社,2003,277-280
[26] Morales AI, Vicente-Sánchez C, Sandoval JM, et al. Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties [J]. Food Chem Toxicol, 2006, 44: 2092-2100
[27] Kosanovic M, Jokanovic M. The association of exposure to cadmium through cigarette smoke with pregnancy-induced hypertension in a selenium deficient population [J]. Environ Toxicol Pharmacol, 2007, 24: 72-78
[28] Badiello R, Feroci G, Fini A. Interaction between trace elements: selenium and cadmium ions [J]. J Trace Elem Med Biol, 1996, 10: 156-162
[1] Morales AI, Vicente-Sánchez C, Sandoval JM, et al. Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties [J]. Food Chem Toxicol, 2006, 44: 2092-2100
[2] Hotter G, Fels LM, Closa D, et al. Altered levels of urinary prostanoids in lead-exposed workers [J]. Toxicol lett, 1995, 77: 309-312
[3] Smith DR, Kahng MW, Quintanilla-Vega B, et al. High-affinity renal lead-binding proteins in environmentally-exposed humans [J]. Chem Biol Interact, 1998, 115: 39-52
[4] Lin JL, Lin-Tan DT, Li YJ, et al. Low-level environmental exposure to lead and progressive chronic kidney diseases [J]. Am J Med, 2006, 119: 707
[5] Khalil-Manesh F, Gonick HC, Cohen AH, et al. Experimental model of lead nephropathy. I. Continuous high dose lead administration [J]. Kidney Int, 1992, 41: 1192-1203
[6] El-Sokkary GH, Abdel-Rahman GH, Kamel ES. Melatonin protects against lead-induced hepatic and renal toxicity in male rats [J]. Toxicology, 2005, 213: 25-33
[7] Shaikh ZA, Vu TT, Zaman K. Oxidation stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants [J]. Toxicol Appl Pharm, 1999, 154: 256-263
[8] Goyer RA. Mechanisms of lead and cadmium nephrotoxicity [J]. Toxicol lett, 1989, 46: 153-162
[9]王翔朴.肾脏毒理学[M].湖南:湖南科学技术出版社,2004:7-9
[1]刘宗平.现代动物营养代谢病[M].北京.化学工业出版社,2003,277-280
[2] Garcia TA, Corredor L. Biochemical changes in the kidneys after perinatal intoxication with lead and/or cadmium and their antagonistic effects when coadministered [J]. Ecotoxicology andEnvironmental Safety, 2004, 57: 184-189
[3] Sato M, Bremner I. Oxygen free radicals and metallothionein [J]. Free Radic Biol Med, 1993, 14: 325-337
[4]郭宝林,贾志海,张玉枝.畜禽铜营养研究进展[J].饲料工业,2005,26(10):48-51
[5] Cao J, Luo XG. Effect of dietary iron on concentration, age, and length of iron feeding on feed intake and tissue iron concentration of broiler chicks for use as bioassay of supplemental iron sources [J]. Poult Sci, 1996, 75: 495
[6] Casalino E, Cesare S, Clemente L. Enzyme activity alteration by cadmium administration to rats: the possibility of iron involvement in lipid peroxidation [J]. Arch Biochem Biophys, 1997, 346:171-179
[7] El-Heni J, Messaoudi I, Hammouda F, et al. Protective effects of selenium (Se) and zinc (Zn) on cadmium (Cd) toxicity in the liver and kidney of the rat: Histology and Cd accumulation [J]. Food Chem Toxicol, 2008, 46: 3522-3527
[1] Foster KA, Galeffi F, Gerich FJ, et al. Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration [J]. Prog Neurobiol, 2006, 79: 136-171
[2] Capaldi RA. Structure and function of cytochrome c oxidase [J]. Annu Rev Biochem, 1990, 59: 569-596
[3] Hong WK, Han EH, Kim DG, et al. Amyloid-beta-peptide reduces the expression level of mitochondrial cytochrome oxidase subunits [J]. Neurochem Res, 2007, 32: 1483-1488
[4] Speijer D, Breek CKD, Muijsers AO, et al. The sequence of a small subunit of cytochrome c oxidase from Crithidiafasciculata which is homologous to mammalian subunitIV [J]. FEBS Letters, 1996, 381: 123-126
[5] Nolan CV, Shaikh ZA. Lead nephrotoxicity and associated disorders: biochemical mechanisms [J]. Toxicology 1992, 73: 127-146
[6] W?ostowski T, Krasowska A, Bonda E. Joint effects of dietary cadmium and polychlorinated biphenyls on metallothionein induction, lipid peroxidation and histopathology in the kidneysand liver of bank voles [J]. Ecotoxicol Environ Saf 2008, 69: 403-410
[7] Alvarez-Barrientos A, O’Connor JE, Nieto Castillo R, et al. Use of flow cytometry and confocal microscopy techniques to investigate early CdCl2-induced nephrotoxicity in vitro [J]. Toxicol in Vitro, 2001, 15: 407-412
[8] Heid CA, Stevens J, Livak JK, et al. Real time quantitative PCR [J]. Genome Res, 1996, 6: 986-994
[9] Livak KJ, Schittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) Method [J]. Methods, 2001, 25: 402-408
[10] Hiquchi R, Fockler C, Dollinqer G, et al. Kinetic PCR analysis: real-time monitoring of DNA amplification reactions [J]. Biotechnology (NY), 1993, 11: 1026-1030
[11] Ke LD, Chen Z, Yung WK. A reliability test of standard-based quantitative PCR: exogenous standards [J]. Mol Cell Probes, 2000, 14(2): 127
[12] Becker KD Pan, Whitely CB. Real-time quantitative polymerase chain reaction to assess gene transfer [J]. Hum Gene Ther, 1999, 10: 2559
[13] Higgins JA, Ezzell J, Hinnebusch BJ, et al. 5′nuclease PCR assay to detect Yersinia pestis [J]. J Clin Microbiol, 1998, 36: 2284-2288
[14] Bustin S. Absolute quantification of mRNA using Real-time reverse transcription polymerase chain reaction assays [J]. J Mol Endocrinol, 2000, 25: 169
[15] Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR [J]. Nucleic Acids Res, 2001, 29: 2002-2007
[16] Kenneth JL, Thomas DS. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method [J]. Methods, 2001, 25: 402-408
[17] Fieller E. Some problems in interval estimation [J]. J Roy Statist Soc Ser B, 1954, 16: 175-185
[18] Sen T, Sen N, Tripathi G, et al. Lipid peroxidation associated cardiolipin loss and membrane depolarization in rat brain mitochondria [J]. Neurochem Int, 2006, 49: 20-27
[19] Kim HL, Choi YK, Kim DH, et al. Tetrahydropteridine deficiency impairs mitochondrial function in Dictyostelium discoideum Ax2 [J]. FEBS Letters, 2007, 581: 5430-5434
[20] Tsukihara T, Aoyama H, Yamashita E, et al. Structures of metal sites of oxidized bovine heartcytochrome c oxidase at 2.8 A [J]. Science, 1995, 269: 1069-1074
[21] Onyango IG, Bennett JP, Tuttle JB. Endogenous oxidative stress in sporadic Alzheimer’s disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids [J]. Neurobiology of disease, 2005, 19: 312-322
[22] Zhu XW, Raina AK, Lee H, et al. Oxidative stress signalling in Alzheimer’s disease [J]. Brain Research, 2004, 1000: 32-39
[23] Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs [J]. Physiol Rev, 1979, 59: 527-605
[24] Sohal RS, Toroser D, Brégère C, et al. Age-related decrease in expression of mitochondrial DNA encoded subunits of cytochrome c oxidase in Drosophila melanogaster [J]. Mech Ageing Dev, 2008, 129: 558-561
[25] Khalimonchuk O, R?del G. Biogenesis of cytochrome c oxidase [J]. Mitochondrion, 2005, 5: 363-388
[26] Rahman S, Taanman JW, Cooper JM, et al. A Missense Mutation of Cytochrome Oxidase Subunit II Causes Defective Assembly and Myopathy [J]. Am J Hum Genet, 1999, 65: 1030-1039
[27] Hosler JP, Ferguson-Miller S, Mills DA. Energy transduction: proton transfer through the respiratory complexes [J]. Annu Rev Biochem 2006, 75: 165-187
[28] Ferguson M, Mockett RJ, Shen Y, et al. Age-associated decline in mitochondrial respiration and electron transport in Drosophila melanogaster [J]. Biochem J, 2005, 390, 501-511
[29] Hüttemann M, Schmidt TR, Grossman LI. A third isoform of cytochrome c oxidase subunit VIII is present in mammals [J]. Gene, 2003, 312: 95-102
[1]韩新燕,许梓荣.哺乳动物金属硫蛋白的研究进展[J].中国兽医科技,2003,33(11):28-31
[2] Quafe CJ, Findley SD, Fricksin JC, et al. Induction of new metallothionein isoform (MT-IV) occurs during differentiation of stratified squamous epithelia [J]. Biochemistry, 1994, 33: 7250-7259
[3] Lu J, Jin T, Nordberg G, et al. Metallothionein gene expression in peripheral lymphocytes and renal dysfunction in a population environmentally exposed to cadmium [J]. Toxicol Appl pharmacol, 2005, 206: 150-156
[4] Conrad CC, Walter CA, Richardson A, et al. Cadmium toxicity and distribution in metallothionein-I and II deficient transgenic mice [J]. J Toxicol Environ Health, 1997, 52: 527-543
[5] Zangger K, ?z G, Haslinger E, et al. Nitric oxide selectively releases metals from the N-terminal domain of metallothioneins: potential role at inflammatory sites [J]. FASEB J, 2001, 15: 1303-1305
[6]刘学忠,郑志高,王捍东.金属硫蛋白生物学功能研究进展[J].畜牧兽医杂志,2004,23(2): 19-21
[7] K?gi JHR. Overview of metallothionein [J]. Methods Enzymol, 1991, 205: 613-626
[8] Tom M, Chen N, Segev M, et al. Quantifying fish metallothionein transcript by real time PCR for its utilization as an environmental biomarker [J]. Mar Pollut Bull, 2004, 48: 705-710
[9] Thijssen S, Cuypers A, Maringwa J, et al. Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys [J]. Toxicology, 2007, 236: 29-41
[10] W?ostowski T, Krasowska A, Bonda E. Joint effects of dietary cadmium and polychlorinated biphenyls on metallothionein induction, lipid peroxidation and histopathology in the kidneys and liver of bank voles [J]. Ecotoxicol Environ Saf, 2008, 69: 403-410
[11] Choi CY, An KW, Nelson ER, et al. Cadmium affects the expression of metallothionein (MT) and glutathione peroxidase (GPX) mRNA in goldfish, Carassius auratus [J]. Comp Biochem Physiol C Toxicol Pharmacol, 2007, 145: 595-600
[12] Qu W, Diwan BA, Liu J, et al. The metallothionein-null phenotype is associated withheightened sensitivity to lead toxicity and an inability to form inclusion bodies [J]. Am J Pathol, 2002, 160: 1047-1056
[13] Jamieson JA, Stringer DM, Zahradka P, et al. Dietary zinc attenuates renal lead deposition but metallothionein is not directly involved [J]. Biometals, 2008, 21: 29-40
[14] Liu ZP. Lead poisoning combined with cadmium in sheep and horses in the vicinity of non-ferrous metal smelters [J]. Sci Total Environ, 2003, 309: 117-126
[15] Demuynck S, Grumiaux F, Mottier V, et al. Metallothionein response following cadmium exposure in the oligochaete Eisenia fetida [J]. Comp Biochem Physiol C Toxicol Pharmacol, 2006, 144: 34-46
[16] Park JD, Liu Y, Klaassen CD. Protective effect of metallothionein against the toxicity of cadmium and other metals [J]. Toxicology, 2001, 163: 93-100
[17] Chan HM, Cherian MG. Protective roles of metallothionein and glutathione in hepatotoxicity of cadmium [J]. Toxicology, 1992, 72: 281-290
[18] Klaassen CD, Liu J. Induction of metallothionein as an adaptive mechanism affecting the magnitude and progression of toxicological injury [J]. Environ Health Perspect, 1998, 106: 297-300
[19] Liu Y, Liu J, Habeebu SS, et al. Susceptibility of MT-null mice to chronic CdCl2-induced nephrotoxicity indicates that renal injury is not mediated by the CdMT complex [J]. Toxicol Sci, 1998, 46: 197-203
[20] Bremner I. Interaction between metallothionein and trace metals [J]. Progr in Food Nutr Sci, 1987, 11: 1-37
[21] Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response [J]. Biochem J, 1990, 265: 621-636
[22] Tamai KT, Liu X, Silar P, et al. Heat shock transcription factor activates yeast metalloth- ionein gene expression in response to heat and glucose starvation via distinct siganlling pathways [J]. Mol Cell Biol, 1994, 141: 8155-8165
[23] Durnam DM, Palmiter RD. Transcriptional regulation of the mouse metallothionein I gene by heavy metals [J]. J Biol Chem, 1981, 256: 5712-5716
[24] Palmiter RD. Molecular biology of metallothionein in animal tissues [J]. Eisei Kagaku, 1987, 24: 128-131
[25] Maracine M, Segner H. Cytotoxicity of metals in isolated fish cells: importance of the cellular glutathione status [J]. Comp Biochem Physiol. A, 1998, 120: 83-88
[26] Campana O, Sarasquete C, Blasco J. Effect of lead on ALA-D activity, metallothionein levels, and lipid peroxidation in blood, kidney, and liver of the toadfish Halobatrachus didactylus [J]. Ecotoxicol Environ Saf, 2003, 55: 116-125
[27] Gong Q, Hart BA. Effect of thiols on cadmium-induced expression of metallothionein and other oxidant stress genes in rat lung epithelial cells [J]. Toxicology, 1997, 119: 179-191
[28] Roels HA, Hoet P, Lison D. Usefulness of biomarkers of exposure to inorganic mercury, lead, or cadmium in controlling occupational and environmental risks of nephrotoxicity [J]. Ren Fail, 1999, 21: 251-262
[29] Baudrimont M, Andress S, Durrieu G, et al. The key role of metallothioneins in the bivalve Corbicula fluminea during the depuration phase, after in situ exposure to Cd and Zn [J]. Aquat Toxicol, 2003, 63: 89-102
[1] Goyer RA. Mechanisms of lead and cadmium nephrotoxicity [J]. Toxicol lett, 1989, 46: 153-162
[2] Pieter J, Boogaard J, Paul Z, et al. Primary culture of proximal tubular cells from normal rat kidney as an in vitro model to study mechanisms of nephrotoxicity: Toxicity of nephrotoxicants at low concentrations during prolonged exposure [J]. Biochemical Pharmacology, 1990, 39: 1335-1345
[3] Pieter J, Boogaard J, Fred N, et al. Renal proximal tubular cells in suspension or in primary culture as in vitro models to study nephrotoxicity [J]. Chemico-Biological Interactions, 1990, 76: 251-291
[4] Foidart, Willems J, Dechenne C, et al. Biosynthesis of basement membrane collagen in culture of renal glomerular and tubular epithelial cells [J]. Diabete Metab, 1975, 1: 227-234
[5] Rudolfs K, Zalups, Lawrence H, et al. Methods in renal toxicology [M]. Canada, crc press, 1996
[6]郑丰,黎磊石.大黄对体外肾小管细胞增殖的影响[J].医学研究生学报,1991,3(4):46
[7]王东,吴雄飞,金锡御.大鼠肾小管上皮细胞的原代培养及传代[J].中华实用外科杂志,1999,16(2):179-180
[8]刘晓玲,邢淑华. Percoll法分离培养肾小管上皮细胞[J].徐州医学院学报,2006,26(2):100-103
[9] Lawrence H, Lash. In Vitro methods of assessing renal damage [J]. Toxicologic Pathology, 1998, 26: 33-42
[10]王洪复.骨细胞图谱与骨细胞体外培养技术[M].上海:上海科学技术出版社,2001
[11] Toutain H, Vauclin-Jacques N, Fillastre JP, et al. Biochemical, functional, and morphological characterization of a primary culture of rabbit proximal tubule cells [J]. Exp Cell Res, 1991, 194: 9-18
[12]严玉澄,钱家麒,戴慧莉,等.人近端肾小管上皮细胞的原代培养[J].上海第二医科大学学报,2005,25(4):388-390
[13] Mattila PM, Nietosvaara YA, Ustinov JK, et al. Antigen expression in different parenchymal cell types of rat kidney and heart [J]. Kid Int, 1989, 36: 228-233
[14]张卓然.培养细胞学与细胞培养技术[M]. 1版.上海:上海科学技术出版社,2004:425
[1] Cooper GP, Manalis RS. Interactions of lead and cadmium on acetylcholine release at the frog neuromuscular junction [J]. Toxicol Appl Pharmacol, 1984, 74: 411-416
[2] Xu J, Ji LD, Xu LH. Lead-induced apoptosis in PC 12 cells: involvement of p53, bcl-2 family and caspase-3 [J]. Toxicol Lett, 2006, 166: 160-167
[3] Sandhir R, Julka D, Gill KD. Lipoperoxidative damage on lead exposure in rat brain and its implications on membrane bound enzymes [J]. Pharmacol Toxicol, 1994, 74: 66-71
[4] Loghman-Adham M. Renal effects of environmental and occupational lead exposure [J]. Environ Health Perspect, 1997, 105: 928-939
[5] Patra RC, Swarup D, Dwidedi SK. Antioxidant effects ofαtocopherol, ascorbic acid and L-methionine on lead-induced oxidative stress of the liver, kidney and brain in rats [J]. Toxicology, 2001, 162: 81-88
[6] Goyer RA. Mechanisms of lead and cadmium nephrotoxicity [J]. Toxicol lett, 1989, 46: 153-162
[7] Morales AI, Vicente-Sánchez C, Jerkic M, et al. Effect of quercetin on metallothionein, nitric oxide synthases and cyclooxygenase-2 expression on experimental chronic cadmium nephrotoxicity in rats [J]. Toxicol Appl Pharmacol, 2006, 210: 128-135
[8] Alvarez-Barrientos A, O’Connor JE, Nieto Castillo R, et al. Use of flow cytometry and confocal microscopy techniques to investigate early CdCl2-induced nephrotoxicity in vitro [J]. Toxicol in Vitro, 2001, 15: 407-412
[9] Gennari A, Cortese E, Boveri M, et al. Sensitive endpoints for evaluating cadmium-induced acute toxicity in LLC-PK1 cells [J]. Toxicology, 2003, 183: 211-220
[10] Thévenod F, Friedmann JM. Cadmium-mediated oxidative stress in kidney proximal tubulecells induces degradation of Na+/K+-ATPase through proeasomal and endo-/lysosomal proteotic pathway [J]. The FASEB Journal, 1999, 13: 1751-1761
[11] Pedraza-Chaverri J, Maldonado PD, Barrera D, et al. Protective effect of diallyl sulfide on oxidative stress and nephrotoxicity induced by gentamicin in rats [J]. Mol Cell Biochem, 2003, 254: 125-130
[12] Haneef SS, Swarup D, Dwivedi SK, et al. Effects of concurrent exposure to lead and cadmium on renal function in goats [J]. Small Rumin Res, 1998, 28: 257-261
[13] Antonio Garcia T, Corredor L. Biochemical changes in the kidneys after perinatal intoxication with lead and/or cadmium and their antagonistic effects when coadministered [J]. Ecotoxicol Environ Saf, 2004, 57: 184-189
[14]王学谦,白雪涛,尹先仁.铅镉联合作用对大鼠肾小管上皮细胞β-乙酰氨基葡萄糖苷酶的影响[J].环境与健康杂志,2002,14:306-309
[15]赵斌,葛金芳,朱娟娟,等.小议在MTT法测细胞增殖抑制率中IC50的计算方法[J].安徽医药,2007,11(9):834-836
[16] Vermes I, Haanen C, Steffens-Nakken H, et al. A novel assay for apoptosis, flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein-labeled Annexin V [J]. J Immunol Meth, 1995, 184: 39-51
[17] Koh JY, Choi DW. Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay [J]. J Neurosci Methods, 1987, 20: 83-90
[18] Liu Y, Zhang SP, Cai YQ. Cytoprotective effects of selenium on cadmium-induced LLC-PK1 cells apoptosis by activating JNK pathway [J]. Toxicol in Vitro, 2007, 21: 677-684
[19] Chin TA, Templeton DM. Effects of CdCl2 and Cd-metallothionein on cultured mesangial cells [J].Toxicol Appl Pharmacol, 1992, 116: 133-141
[21] Skoczyńska A, Wróbel J, Andrzejak R. Lead-cadmium interaction effect on the responsiveness of rat mesenteric vessels to norepinephrine and angiotensinⅡ[J].Toxicology, 2001, 162: 157-170
[22] Salovsky P, Shopova V, Dancheva V, et al. Combined effects of cadmium and lead on some biochemical markers in rat bronchoalveolar lavage fluid [J].Toxicol Lett (supple), 1995, 78: 73
[23]王林,陈大伟,曹瑾,等.铅镉联合暴露对大鼠肾脏功能损伤的研究[J].毒理学杂志,2008,22(5):22-25
[24] Bizarro P, Acevedo S, Ni?o-Cabrera G, et al. Ultrastructural modifications in the mitochondrion of mouse Sertoli cells after inhalation of lead, cadmium or lead-cadmium mixture [J]. Reprod Toxicol, 2003, 17: 561-566
[25] Nampoothiri LP, Gupta S. Simultaneous effect of lead and cadmium on granulosa cells: A cellular model for ovarian toxicity [J]. Reprod Toxicol, 2006, 21: 179-185
[26] Wang L, Cao J, Chen D, et al. Role of oxidative stress, apoptosis, and intracellular homeostasis in primary cultures of rat proximal tubular cells exposed to cadmium [J]. Biol Trace Elem Res, 2009, 127: 53-68
[27]龚伟.铅、镉引起细胞死亡机理及硒抗铅、镉毒性效应的研究[D].北京:中国农业大学,1999
[28]魏雪涛,黄超峰,乔杨铮,等.重金属镉和铅对巨噬细胞和成纤维细胞的Hormesis效应[J].毒理学杂志(增刊),2005,19(3):235
[29] Thijssen S, Cuypers A, Maringw J, et al. Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys [J]. Toxicology, 2007, 236(1): 29-41
[30] Shaikh ZA, Vu TT, Zaman K. Oxidation stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants [J]. Toxicol Appl Pharmacol, 1999, 154: 256-263
[31] Lavrentiadou SN, Chan C, Kawcak T, et al. Ceramide-mediated apoptosis in lung epithelial cells is regulated by glutathione [J]. Am J Respir Cell Mol Biol, 2001, 25: 676-684
[32]韩贻仁.分子细胞生物学[M].二版.北京:科学出版社,2003:648-661
[33] Shabani A, Rabbani A. Lead nitrate induced apoptosis in alveolar macrophages from rat lung [J]. Toxicology, 2000, 149: 109-114
[34] De la Fuente H, Portales-Perez D, Baranda L, et al. Effect of arsenic, cadmium and lead on the induction of apoptosis of normal human mononuclear cells [J]. Clin Exp Immunol, 2002, 129: 69-77
[35]夏世钧,吴中亮.分子毒理学基础[M].武汉:湖北科学技术出版社,2001:87-90
[36] Fox DA, Srivastava D, Poblenza A, et al. Lead-induced Alterations in Gene Expression and Activity of Retinal cGMP PDE Results in Calcium Overload and Rod-selective Apoptosis [J]. Toxicol in Vitro, 1998, 12: 597-598
[37] Pham TN, Marion M, Denizeau F, et al. Cadmium-induced apoptosis in rat hepatocytes does not necessarily involve caspase-dependent pathways [J].Toxicol in Vitro, 2006, 20: 1331-1342
[38] Waisberg M, Joseph P, Hale B, etal. Molecular and cellular mechanisms of cadmium carcinogenesis [J]. Toxicology, 2003, 192: 95-117
[39] Pathak N, Khandelwal S. Oxidative stress and apoptotic changes in murine splenocytes exposed to cadmium [J]. Toxicology, 2006, 220: 26-36
[1] Slater TF. Free-radical mechanisms in tissue injury [J]. Biochem J, 1984, 222: 1-15
[2] Sen T, Sen N, Tripathi G, et al. Lipid peroxidation associated cardiolipin loss and membrane depolarization in rat brain mitochondria [J]. Neurochem Int, 2006, 49: 20-27
[3] Niki E, Yoshida Y, Saito Y, et al. Lipid peroxidation: mechanism, inhibition, and biological effects [J]. Biochem Biophys Res Commun, 2005, 336: 1-9
[4] Uchida K. 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress [J]. Prog Lipid Res, 2003, 42: 318-343
[5] Luo J, Shi R. Acroline induced oxidative stress in brain mitochondria [J]. Neurochem Int, 2005, 46: 243-252
[6] Pathak N, Khandelwal S. Influence of cadmium on murine thymocytes: potentiation of apoptosis and oxidative stress [J]. Toxicol Lett, 2006, 165: 121-132
[7] Scaduto RC, Grotyohann LW. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives [J]. Biophys J, 1999, 76: 469-477
[8] Dimri U, Ranjan R, Kumar N, et al. Changes in oxidative stress indices, zinc and copper concentrations in blood in canine demodicosis [J]. Vet Parasitol, 2008, 154: 98-102
[9] Huxtable RJ. Physiological action of taurine [J]. J Physiol Revi, 1992, 72: 101-142
[10] Sieg DJ, Billings RE. Lead/cytokine-mediated oxidative DNA damage in cultured mouse hepatocytes [J]. Toxicol Appl Pharmacol, 1997, 142: 106-115
[11] Kelly SA, Havrilla CM, Brady TC, et al. Oxidative stress in toxicology: established mammalian and emerging piscine model systems [J]. Environ Health Perspect, 1998, 106: 375-384
[12] Findel T, Holbrook NJ. Oxidants, oxidative stress and the bilolgy of aging [J]. Nature, 2000, 408: 239-247
[13] Gurer H, Ozgunes H, Neal R, et al. Antioxidant effects of N-acetyl cysteine and succimer in red blood cells from lead exposed rats [J]. Toxicology, 1998, 128: 181-189
[14] Pari L, Murugavel P. Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats [J]. Toxicology, 2007, 234: 44-50
[15] Thévenod F. Nephrotoxicity and the proximal tubule [J]. Insights from cadmium. Nephron Physiol, 2003, 93: 87-93
[16] Sies H, Akerboom TP. Glutathione disulfide (GSSG) efflux from cells and tissues [J]. Methods Enzymol, 1984, 105: 445-451
[17] Leelank BN, Bansal MP. Effect of selenium supplementation on the glutathione redox system in the kidney of mice after chronic cadmium exposures [J]. J Appl Toxicol, 1996, 17: 81-84
[18] Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple [J]. Free Radic Biol Med, 2001, 30: 1191-1212
[19] Nigam D, Shukla GS, Agarwal AK. Glutathione depletion and oxidative damage in mitochondria following exposure to cadmium in rat liver and kidney [J]. Toxicol Lett, 1999, 106: 151-157
[20] Higuchi Y. Chromosomal DNA fragmentation in apoptosis and necrosis induced by oxidative stress [J]. Biochem Pharmacol, 2003, 66: 1527-1535
[21]孔繁翔.环境生物学[M].北京:高教出版社,2000,68
[22] Fang YZ, Yang S, Wu G. Free radical, antioxidants and nutrition [J]. Nutrition, 2002, 18: 872-879
[23] Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine [M]. Clarendon Press, 1989, Oxford
[24] Januel C, Fay LB, Ruggiero D, et al. Covalent coupling of reduced glutathione with ribose: loss of cosubstrate ability to glutathione peroxidase [J]. Biochim Biophys Acta, 2003, 1620: 125-132
[25] Foster KA, Galeffi F, Gerich FJ, et al. Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration [J]. Prog Neurobiol, 2006, 79: 136-171
[26] Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications [J]. Drug Resist Updat, 2004, 7: 97-110
[27] Ye JL, Mao WP, Wu AL, et al. Cadmium-induced apoptosis in human normal liver L-02 cellsby acting on mitochondria and regulating Ca2+ signals [J]. Environ Toxicol Pharmacol, 2007, 24: 45-54
[28] Pham TND, Marion M, Denizeau F, et al. Cadmium-induced apoptosis in rat hepatocytes does not necessarily involve caspase-dependent pathways [J]. Toxicol in Vitro, 2006, 20: 1331-1342
[29] Turrens JF. Mitochondrial formation of reactive oxygen species [J]. J Physiol, 2003, 552: 335-344
[30] Djavaheri-Mergny M, Wietzerbin J, Besancon F, et al. 2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production [J]. Oncogene, 2003, 22: 2558-2567
[31] Chen F, Vallyathan V, Castranova V, et al. Cell apoptosis induced by carcinogenic metals [J]. Mol Cell Biochem, 2001, 222: 183-188
[32] Alvarez-Barrientos A, O’Connor JE, Nieto Castillo R, et al. Use of flow cytometry and confocal microscopy techniques to investigate early CdCl2-induced nephrotoxicity in vitro [J]. Toxicol in Vitro, 2001, 15: 407-412
[33] Kim MS, Kim BJ, Woo HN, et al. Cadmium induces caspase-mediated cell death: suppression by Bcl-2 [J]. Toxicology, 2000, 145: 27-37
[34] Li M, Kondo T, Zhao QL, et al. Apoptosis induced by cadmium in human lymphoma U937 cells through Ca2+-calpain and caspase-mitochondria-dependent pathways [J]. J Biol Chem, 2000, 275: 39702-39709
[35] Chen L, Yang X, Jiao H, et al. Tea catechins protect against lead-induced ROS formation, mitochondrial dysfunction, and calcium dysregulation in PC12 cells [J]. Chem Res Toxicol, 2003, 16: 1155-1161
[1] Vasiliev JM, Gelfand IM. Surface changes disturbing intracellular homeostasis as a factor inducing cell growth and division [J]. Curr Mod Biol, 1968, 2: 43-55
[2] Missiaen L, Robberecht W, Bosch LV, et al. Abnormal intracellular Ca2+ homeostasis and disease [J]. Cell calcium, 2000, 28: 1-21
[3] Monti DM, Gesualdi NM, Matou?ek J, et al. The cytosolic ribonuclease inhibitor contributes to intracellular redox homeostasis [J]. FEBS Lett, 2007, 581: 930-934
[4] Dearborn DG, Waller RL, Brattin WJ. Intracellular Ca2+ homeostasis in lymphocytes from patients with mucoviscidosis [J].Cell calcium, 1984, 5: 306
[5] Lange Y, Steck TL. The role of intracellular cholesterol transport in cholesterol homeostasis [J]. Trends Cell Biol, 1996, 6: 205-208
[6] Silver IA, Deas J, Erecinska M. Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells [J]. Neuroscience, 1997, 78: 589-601
[7] Wang L, Cao J, Chen D, et al. Role of oxidative stress, apoptosis, and intracellular homeostasis in primary cultures of rat proximal tubular cells exposed to cadmium [J]. Biol Trace Elem Res, 2009, 127: 53-68
[8] Dyatlov VA, Dyatlova OM, Parsons PJ, et al. Lipopolysaccharide and interleukin-6 enhance lead entry into cerebellar neurons: application of a new and sensitive flow cytometric technique to measure intracellular lead and calcium concentrations [J]. Neurotoxicology, 1998, 19: 293-302
[9] Hirpara JL, Clément MV, Pervaiz S. Intracellular acidification triggered by mitochondrial-derived hydrogen peroxide is an effector mechanism for drug-induced apoptosis in tumor cells [J]. J Biol Chem, 2001, 276: 514-521
[10] Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with the Folin phenol reagent [J]. J Biol Chem, 1951, 193: 265-275
[11]厉为良.细胞内pH、钙离子与细胞凋亡[J].国外医学·生理、病理科学与临床分册,1998,18(2):131-134
[12] Voehringer DW. Bcl-2 and glutathione: alterations in cellular redox state that regulate apoptosis sensitivity [J]. Free Radic Biol Med, 1999, 27: 945-950
[13] Moran LK, Guteridge JM, Quinlan GJ. Thiols in cellular redox signaling and control [J]. Curr Med Chem, 2001, 8: 763-772
[14] Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple [J]. Free Radic Biol Med, 2001, 30: 1191-1212
[15] Masella R, Benedetto R, VarìR, et al. Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes [J]. J Nutr Biochem, 2005, 16: 577-586
[16] Lavrentiadou SN, Chan C, Kawcak T, et al. Ceramide-mediated apoptosis in lung epithelial cells is regulated by glutathione [J]. Am J Respir Cell Mol Biol, 2001, 25: 676-684
[17] Nigam D, Shukla GS, Agarwal AK. Glutathione depletion and oxidative damage in mitochondria following exposure to cadmium in rat liver and kidney [J]. Toxicol Lett, 1999, 106: 151-157
[18] Valko M, Morris H, Cronin MTD. Metals, toxicity and oxidative stress [J]. Curr Med Chem, 2005, 12: 1161-1208
[19] Gaido ML, Cidlowski JA. Identification, purification and characterization of a calcium- dependent endonuclease (NUC18) from apoptotic rat thymocytes [J]. J Biol Chem, 1991, 266: 18580-18585
[20] Orrenius S, Mccabe MJ, Nicotera P. Ca2+-dependent mechanisms of cytotoxicity and programmed cell death [J]. Toxicol Lett, 1992, 64: 357-364
[21] McConkey DJ, Orrenius S. The Role of Calcium in the Regulation of Apoptosis [J]. BiochemBiophys Res Commun, 1997, 239: 357-366
[22] Hu Q, Chang J, Tao L, et al. Endoplasmic reticulum mediated necrosis-like apoptosis of HeLa cells induced by Ca2+ oscillation [J]. J Biochem Mol Biol, 2005, 38: 709-716
[23] Rekasi Z, Czompoly T, Schally AV, et al. Antagonist of growth hormone releasing hormone induces apoptosis in LNCaP human prostate cancer cells through a Ca2+-dependent pathway [J]. Proc Natl Acad Sci, 2005, 102: 3435-3440
[24] Foster KA, Galeffi F, Gerich FJ, et al. Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration [J]. Prog Neurobiol, 2006, 79: 136-171
[25] Grammatopoulos TN, Johnson V, Moore SA, et al. Angiotensin type 2 receptor neuroprotection against chemical hypoxia is dependent on the delayed rectifier K+ channel, Na+/Ca2+ exchanger and Na+/K+ ATPase in primary cortical cultures [J]. Neurosci Res, 2004, 50: 299-306
[26] Altschuld RA. Intracellular calcium regulatory system during ischemia and reperfusion [J]. EXS, 1996, 76: 87-97
[27] Doliba NM, Doliba NM, Chang Q, et al. Mitochondrial oxidative phosphorylation in heart from stressed cardiomyopathic hamsters [J]. J Mol Cell Cardiol, 1999, 31: 543-553
[28] Blaustein MP. Sodium ions, calcium ions, blood pressure regulation and hypertension: a reassessment and a hypothesis [J]. Am J Physiol Cell Physiol, 1977, 232: C165-C173
[29] Fujita T, Inoue H, Kitamura T, et al. Senescence marker protein-30 (SMP30) rescues cell death by enhancing plasma membrane Ca2+-pumping activity in HepG2 cells [J]. Biochem Biophys Res Commun, 1998, 250: 374-380
[30] Qin XJ, Li YN, Liang X, et al. The dysfunction of ATPases due to impaired mitochondrial respiration in phosgene-induced pulmonary edema [J]. Biochem Biophys Res Commun, 2008, 367: 150-155
[31] Wang XQ, Xiao AY, Sheline C, et al. Apoptotic insults impair Na+/K+-ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress [J]. J Cell Sci, 2003, 116: 2099-2110
[32]边肖海,霍静,郑曙民.细胞内酸化对宫颈癌Hela细胞凋亡的影响[J].长治医学院学报,2005, 19(2):81-83
[33] Matsuyama S, Llopis J, Deveraux QL, et al. Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis [J]. Nat Cell Biol, 2000, 2: 318-325
[34] Clément MV, Ponton A, Pervaiz S. Apoptosis induced by hydrogen peroxide is mediated by decreased superoxide anion concentration and reduction of intracellular milieu [J]. FEBS Lett, 1998, 440: 13-18
[2]徐进,徐立红.环境铅污染及其毒性的研究进展[J].环境与职业医学,2005,22(3):271-273
[3]蒋云生.长期低浓度铅接触人群的铅性肾病[J].中华肾脏病杂志,1991,7(4):226
[4] Gerhardsson L, Chettle DR, Enqlyst V, et al. Kidney effects in long term exposed lead smelter workers [J]. Br J Ind Med, 1992, 49:186-192
[5]何燧源主编.环境毒物[M].北京:化学工业出版社,2002,51-56
[6]张正洁,李东红,许增贵.我国铅污染现状、原因及对策[J].环境保护科学,2005,31:41-43
[7]刘宗平主编.动物中毒病学[M].北京:中国农业出版社,2006,394-401
[8]王翔朴.肾脏毒理学[M].湖南:湖南科学技术出版社,2004:85-87
[9] Kadir MM, Janjua NZ, Kristensen S, et al. Status of children’s blood lead levels in Pakistan:Implications for research and policy [J]. Public health, 2008, 122: 708-715
[10] Gidlow DA. Lead toxicity [J]. Occup Med (Lond), 2004, 54: 76-81
[11]唐清.铅污染与儿童健康[J].城市环境与城市生态,2003,16(5): 48-50
[12]杨志新,刘树庆. Cd、Zn、Pb单因素及复合污染对土壤酶活性的影响[J].土壤与环境,2000,9 (1):15-18
[13]和文祥.土壤酶与重金属关系的研究现状[J].土壤与环境,2000,9 (2):139- 142
[14]赵春燕,孙军德,宁伟,等.重金属对土壤微生物酶活性的影响[J].土壤通报,2001,32 (2):92-94
[15] Kandeler E, Lufienegger G, Schwarz S. Influence of heavy metals on the functional diversity of soil microbial communities [J]. Bilogy and Fertility of Soils, 1997, 23: 299-306
[16] Khan KS, Xie ZM, Huang CY. Effects of cadmium, lead and zinc on size of m icrobial biomassin red soil [J]. Pedo sphere, 1998A, 8: 27-32
[17] Mukherji S, Maitra P. Toxic effects of lead on growth and metabolism of germinating rice (Oryza salivaL) seedsand mitosis of onion (Allium cepa L) [J]. Indian J Exp Biol, 1976, 14: 519-521
[18] Jarvis JC, Jones LHP, Hopper MJ. Cadmium uptake from solution by plants and its transport from roots to shoots [J]. Plant Soil, 1976, 44: 179-191
[19] Cataldo DA, Garland TR, Wildung RE. Cadmium uptake kinetics in intact soybean plants [J]. Plant Physiol, 1983, 73(3): 844-848
[20]孙铁珩主编.污染生态学[M].北京:科学出版社,2001,160-198
[21] Landrigan PJ, Boffetta P, Apostoli P. The reproductive toxicity and carcinogenicity of lead: a critical review [J]. Am J Ind Med, 2000, 38: 231-243
[22] Coyer RA. Mechanisms of lead and cadmium nephrotoxicity [J].Toxicol lett, 1989, 46: 153-162
[23]朱士雅.铅对大鼠慢性毒性研究[J].职业医学杂志,1985,2:2-4
[24] Cramér K, Goyer RA, Jagenburg R, et al. Renal ultrastructure, renal function, and parameters of lead toxicity in workers with different periods of lead exposure [J]. Br J In Med, 1974, 31: 113-127
[25] Greenberg A, Parkinson DK, Fetterolf DE, et al. Effects of elevated lead and cadmium burdenson renal function and calcium metabolism [J]. Arch Environ Health, 1986, 41: 69-76
[26] Wedeen RP, Maesaka JK, Weiner B, et al. Occupational lead nephropathy [J]. Am J Med, 1975, 59: 630-641
[27]林艳丽,王丽曾,张新民.铅中毒肾脏改变的病理形态观察[J].西北国防医学杂志,1999,20(4):272-273
[28] International Agency for Research on Cancer: Lead and lead compounds. In: Overall evaluations of carcinogenicity [M]. An updating of IARC Monographs, Vols, 1-42. IARC supplement 7.1987
[29] Sibergeld EK, Waalkes M, Rice JM. Lead as a carcinogen: experiment evidence and mechanisms of action [J]. Am J Ind Med, 2000, 38: 316-323
[30]金文达,雷义,陈锋.铅的肾脏毒性研究探讨[J].实用预防医学,2007,14(2):597-600
[31]黄瑞雪,熊敏如.铅性肾病的生物标志物研究[J].中国工业医学杂志,2003,16(4): 225-227
[32]王三虎,高星.铅的生物标志物研究[J].中国职业医学,2002,2(29): 50-51
[33] ACGIH, Threshold limit values and biological exposure indices for 1991-1992, Cincinnati [J]. American Conference of Governmental Industrial Hygienists (ACGIH), 1991, 58-70
[34]蒋云生,夏运成,徐锡萍,等.铅性肾病的流行病学分析[J].中华劳动卫生职业病杂志,1994,2(12):76-78
[35] Davies JM. Long term mortality study of chromate pigment workers who suffered lead poisoning [J]. Br J Ind Med, 1984, 41:170-178
[36] Pergande M, Leroyer A, Haguenoer JM, et al. Changed exertion of urinary proteins and enzymes by chronic exposure to lead [J]. Nephrol Dial Transplant, 1994, 9(6): 613-618
[37]蒋云生,夏运成,罗季安,等.长期低浓度铅接触人群的铅性肾病[J].中华肾脏病杂志,1991,7(4):226-227
[38] Dart RC, Hurlbut KM, Maiorino RM, et al. Pharmacokinetics meso-2, 3-dimercaptosuccinic acid in patients with lead poisoning and in healthy adults [J]. J Pediatr, 1994, 125: 309-316
[39] Gerhardsson L, Chettle DR, Englyst V, et al. Kidney effects in long term exposed lead smelter workers [J]. Br J Ind Med, 1992, 49: 186-192
[40] Petrucci R, Leonardi A, Battistuzzi G. The genetic polymorphism of delta-aminolevulinatedehydrates in Italy [J]. Hum Genet, 1982, 60: 289-290
[41] Wetmur JG, Kaya AH, Plewinska M, et al. Molecular characterization of the humanδ-aminolevulinate dehydrates-2(ALAD2) allele: implications for molecular screening of individual for genetic susceptibility to lead poisoning [J]. Am J Hum Genet, 1991, 49: 757-763
[42]杨水莲,叶细标. ALAD和VDR基因多态性与铅肾毒性易感性的关系[J].环境与职业医学,2002,19(6):271-273
[43] Schwartz BS, Lee BK, Lee GS, et al. Associations of blood lead, dimercaptosuccinic acid-cheatable lead, and tibia lead with polymorphisms in the vitamin D receptor andδ-aminolevulinic acid dehydratase genes [J]. Environ Health Perspect, 2000, 108(10): 949-954
[44] Schwartz BS, Stewart WF, Kelsey KT, et al. Associations of tibial lead levels with BsmI polymorphisms in the vitamin D receptor in former organolead manufacturing workers [J]. Environ Health Perspect, 2000, 108(3):199-203
[45] Ahamed M, Siddiqui MKJ. Low level lead exposure and oxidative stress: Current opinions [J]. Clinica Chimica Acta, 2007, 383: 57-64
[46] Donaldson WE, Knowles SO. Is lead toxicosis a reflection of altered fatty acid composition ofmembrane? [J]. Comp BiochemPhysiol C, 1993, 104: 377-379
[47] Knowles SO, Donaldson WE. Dietary modification of lead toxicity: effects on fatty acid and eicosanoid metabolism in chicks [J]. Comp Biochem Physiol, 1990, 95: 99-104
[48] Lawton L, Donaldson WE. Lead-induced tissue fatty acid alterations and lipid peroxidation [J]. Biol Trace Elem Res, 1991, 28: 83-87
[49] Adonaylo VN, Oteiza PI. Pb2+ promotes lipid peroxidation and alteration in membrane physical properties [J]. Toxicology, 1999, 132: 19-32
[50] Gurer H, Ozgunes H, Neal R, et al. Antioxidant effects of Nacetylcysteine and succimer in red blood cells from lead exposed rats [J]. Toxicology, 1998, 128:181-189
[51] Hsu PC, Hsu CC, Liu MY, et al. Lead-induced changes in spermatozoa function and metabolism [J]. J Toxicol Environ Health, 1998, 55: 45-64
[52] Ding Y, Gonick HC, Vaziri ND, et al. Lead-induced hypertension III: increased hydroxyl radical production [J]. Am J Hypertens, 2001, 14: 169-173
[53] Patra RC, Swarup D, Dwidedi SK. Antioxidant effects ofα-tocopherol, ascorbic acid and L-methionine on lead-induced oxidative stress of the liver, kidney and brain in rats [J]. Toxicology, 2001, 162: 81-88
[54] Gurer-Orhan H, Sabir HU, Ozgunes H. Correlation between clinical indicator of lead poisoning and oxidative stress parameters in controls and lead exposed workers [J]. Toxicology, 2004, 195: 147-154
[55] Kasperczyk S, Birkner E, Kasperczyk A, et al. Lipid, lipid peroxidation and 7-ketocholesterol in workers exposed to lead [J]. Human Exp Toxicol, 2005, 24: 287-295
[56] Sandhir R, Gill KD. Effect of lead on lipid peroxidation in liver of rats [J]. Biol Trace Elem Res, 1995, 21: 157-161
[57]王俊虹,周蔚,王世鑫.铅对大鼠肾脏SOD活性和MDA含量影响的研究[J].武警医学院学报,2002,11(3):146-148
[58]韩贻仁.分子细胞生物学[M].二版.北京:科学出版社,2003:648-661
[59] Franco R, Sánchez-Olea R, Reyes-Reyes EM, et al. Environmental toxicity, oxidative stress and apoptosis: MénageàTrois [J]. Mutation Research, 2009, doi:10.1016/j.mrgentox.2008.11.012
[60] Chetty CS, Vemuri MC, Campbell K, et al. Lead-induced cell death of human neuroblastoma cells involves GSH deprivation [J]. Cell Mol Biol Lett, 2005, 10: 413-423
[61] Sharifi AM, Mousavi SH, Bakhshayesh M, et al. Study of correlation between lead-induced cytotoxicity and nitric oxide production in PC12 cells [J]. Toxicol Lett, 2005, 160: 43-48
[62]文涛,孙黎光,彭博.慢性铅暴露小鼠脑海马c-fos、c-jun表达与学习记忆的关系[J].毒理学杂志,2005,19(3):236
[63] Chatzizacharias NA, Kouraklis GP, Theocharis SE. Disruption of FAK signaling: A side mechanism in cytotoxicity [J]. Toxicology, 2008, 245: 1-10
[64]蔡宇,余绍蕾,张荣华.枸杞多糖对染铅小鼠行为功能保护及脑细胞Fas抗原表达的影响[J].环境与职业医学,2005,22(6):533-534
[65] Pulido MD, Parrish AR. Metal-induced apoptosis: mechanisms [J]. Mutat Res, 2003, 533: 227-241
[66] Flora SJ, Saxena G, Mehta A. Reversal of lead-induced neuronal apoptosis by chelationtreatment in rats: role of reactive oxygen species and intracellular Ca2+ [J]. J Pharmacol Exp Ther, 2007, 322: 108-116
[67] Xu J, Ji LD, Xu LH.Lead-induced apoptosis in PC 12 cells: involvement of p53, Bcl-2 family and caspase-3 [J]. Toxicol Lett, 2006, 166: 160-167
[68] Winder C, Bonin T. The genotoxicity of lead [J]. Mutation Res, 1993, 285(1): 117-124
[69] Hartwig A. Interactions by carcinogenic metal compounds with DNA repair processes: toxicological implications [J]. Toxicol Lett, 2002, 127(1-3): 47-54
[70] Restrepo HG, Sicard D, Torres MM. DNA damage and repair in cells of lead exposed people [J]. Am J Ind Med, 2000, 38(3): 330-334
[71] Razmiafshari M, Kao J, d′Avignon A, et al. NMR identification of heavy metal-binding sites in a synthetic zinc finger peptide: toxicological implications for the interactions of xenobiotic metals with zinc finger proteins [J]. Toxicol Appl Pharmacol, 2001, 172(1): 1-10
[72] Quintanilla-Vega B, Hoover D J, Bal W, et al. Lead interaction with human protamine(HP2) as a mechanism of male reproductive toxicity [J]. Chem Res Toxicol, 2000, 13(7): 594-600
[73] Rydberg B. Radiation-induced DNA damage and chromatin structure [J]. Acta Oncol, 2001, 40(6): 682-685
[1]王文仲,徐兆发.镉的肾脏毒理学[J].中国工业医学杂志,2001,14(5):291-293
[2] Pham TN, Marion M, Denizeau F, et al. Cadmium-induced apoptosis in rat hepatocytes does not necessarily involve caspase-dependent pathways [J]. Toxicol in vitro, 2006, 20: 1331-1342
[3] Shaikh ZA, Zaman K, Tang W, et al. Treatment of chronic cadmium nephrotoxicity by N-acetyl cysteine [J]. Toxicol Lett, 1999, 104: 137-142
[4] Jones MM, Cherian MG. The search for chelate antagonists for chronic cadmium intoxication [J]. Toxicology, 1990, 62: 1-25
[5] Stoeppler M. Cadmium [M]. In: Merian, E. (Ed), Metals and their compounds in the environment, 1991, VCH, Weinheim, New York, Basel, Cambridge, pp. 803-851
[6] Waisberg M, Joseph P, Hale B et al. Molecular and cellular mechanisms of cadmium carcinogenesis [J]. Toxicology, 2003, 192: 95-117
[7] GB 3838-2002,中华人民共和国地表水环境质量标准[S].北京:中国环境科学出版社出版,2002
[8]天津大学图书馆.环境科学与工程学科信息数据库[DB/OL] http://202.113.6.254/hj/web,2003-3-25
[9]赵璇,吴天宝.我国饮用水源的重金属污染及治理技术深化问题[J].给水排水,1998,24(10):22-25
[10]王江平.入世后高浓度磷肥中镉的问题[J].磷肥与复肥,2002,17(5):11-15
[11] Thornton I. Sources and pathways of cadmium in the environment [J]. IARC Sci. Publ, 1992, 118: 149-162
[12]周锡爵.张士灌区镉污染及其解决和利用的途径[J].农业环境保护,1987,6(2):17-19
[13]刘立群.赣南土壤污染的防治途径[J].资源开发与保护杂志,1990,6(2):100-102
[14]王翔朴.肾脏毒理学[M].湖南:湖南科学技术出版社,2004:88-92
[15] Lars J, Bodil P, Carl Ge. Decreased gromerular filtration rate in solders exposed to cadmium [J]. Occup Environ Med, 1995, 52: 818-822
[16]刘杰,刘亚平.慢性和急性染镉所致小鼠肾损伤的比较[J].中华劳动卫生职业病杂志,1998,16(1):2
[17]刘宗平主编.动物中毒病学[M].北京:中国农业出版社,2006,394-401
[18]刘杰.镉的毒性和毒理学研究进展[J].中华劳动卫生职业病杂志,1998,16(1):2-4
[19] Carageorgiou H, Tzotzes V, Pantos C, et al. In vivo and in vitro effects of cadmiumon adult rat brain total antioxidant status, acetylcholinesterase, (Na+/K+) ATPase and Mg2+ATPase activities: protection by L-cysteine [J]. Basic Clin Pharmacol Toxicol, 2004, 94(3): 112-118
[20] Faurakov B, Bjerregaard HF. Evidence for cadmium mobilization of intra cellular calcium through a divalent cation receptor in renal distal epithelial A6 cells [J]. Pflugers Arch, 2002, 445(1): 40-50
[21] Kaplan M, Atakan IH, Aydo?du N, et al. Influence of N-acetylcysteine on renal toxicity of cadmium in rats [J]. Pediatr Nephrol, 2008, 23: 233-241
[22] Thijssen S, Cuypers A, Maringw J, et al. Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys [J]. Toxicology, 2007, 236: 29-41
[23] Nigam D, Shukla GS, Agarwal AK. Glutathione depletion and oxidative damage in mitochondria following exposure to cadmium in rat liver and kidney [J]. Toxicology Letters, 1999, 106: 151-157
[24] Morales AI, Vicente-Sánchez C, Sandoval JM, et al. Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties [J]. Food Chem Toxicol, 2006, 44: 2092-2100
[25] Waalkes MP, Poirier LA. In vitro cadmium–DNA interactions: cooperativity of cadmium binding and competitive antagonism by calcium, magnesium, and zinc [J]. Toxicol Appl Pharmacol, 1984, 75: 539-546
[26] International Agency for Research on Cancer, Berrylium, cadmium, mercury and exposures in the glass manufacturing industry, in: International Agency for Research on Cancer Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 58, IARC Scientific Publications, Lyon, 1993, pp. 119-237
[27] Dally H, Hartwig A. Induction and repair inhibition of oxidative DNA damage by nickel (II) and cadmium (II) in mammalian cells [J]. Carcinogenesis, 1997, 18: 1021-1026
[28] Joseph P. Mechanisms of cadmium carcinogenesis [J]. Toxicol Appl Pharmacol, 2009, doi: 10.1016/ j.taap.2009.01.011
[29] Bertin G, Averbeck D. Cadmium: cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences [J]. Biochimie, 2006, 88: 1549-1559
[30] Shaikh ZA, Vu TT, Zaman K. Oxidation stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants [J]. Toxicol Appl Pharmacol, 1999, 154(3): 256-263
[31] Pari L, Murugavel P. Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats [J]. Toxicology, 2007, 234: 44-50
[32] Leelank BN, Bansal MP. Effect of selenium supplementation on the glutathione redox system inthe kidney of mice after chronic cadmium exposures [J]. J Appli Toxicol, 1996, 17: 81-84
[33] Pari L, Murugavel P, Sitasawad SL, et al. Cytoprotective and antioxidant role of diallyl tetrasulfide on cadmium induced renal injury: An in vivo and in vitro study [J]. Life Sciences, 2007, 80: 650-658
[34] Fang YZ, Yang S, Wu G. Free radical, antioxidants and nutrition [J]. Nutrition, 2002, 18: 872-879
[35] Januel C, Fay LB, Ruggiero D, et al. Covalent coupling of reduced glutathione with ribose: loss of cosubstrate ability to glutathione peroxidase [J]. Biochim Biophys Acta, 2003, 1620: 125-132
[36] Masini A, Trenti T, Ceccarelli-Stanzani D, et al. The effect of ferric iron complex on isolated rat liver mitochondria.I. Respiratory and electrochemical responses [J]. Biochim Biophys Acta, 1985, 810: 20-26
[37] Bindoli A. Lipid peroxidation in mitochondria [J]. Free Radic Biol Med, 1988, 5: 247-261
[38] Castilho RF, Meinicke AR, Almeida AM, et al. Oxidative damage of mitochondria induced by Fe (II) citrate is potentiated by Ca2+ and includes lipid peroxidation and alterations in membrane proteins [J]. Arch Biochem Biophys, 1994, 308: 158-163
[39] Takeyama N, Miki S, Hirakawa A, et al. Role of the mitochondrial permeability transition and cytochrome C release in hydrogen peroxide-induced apoptosis [J]. Exp Cell Res, 2002, 274: 16-24
[40] Miyaguchi C, Muranaka S, Kanno T, et al. 17beta-estradiol suppresses ROS-induced apoptosis of CHO cells through inhibition of lipid peroxidation-coupled membrane permeability transition [J]. Physiol Chem Phys Med, NMR, 2004, 36: 21-35
[41] Alvarez-Barrientos A, O’Connor JE, Nieto Castillo R, et al. Use of flow cytometry and confocal microscopy techniques to investigate early CdCl2-induced nephrotoxicity in vitro [J]. Toxicol in Vitro, 2001, 15: 407-412
[42] Kim MS, Kim BJ, Woo HN, et al. Cadmium induces caspase-mediated cell death: suppression by Bcl-2 [J]. Toxicology, 2000, 145: 27-37
[43] Li M, Kondo T, Zhao QL, et al. Apoptosis induced by cadmium in human lymphoma U937cells through Ca2+-calpain and caspase-mitochondria-dependent pathways [J]. J Biol Chem, 2000, 275: 39702-39709
[44] Wang Y, Fang J, Leonard SS, et al. Cadmium inhibits the electron transfer chain and induces reactive oxygen species [J]. Free Radic Biol Med, 2004, 36: 1434-1443
[45] Misra PR, Smith GT, Waalkes WP. Evaluation of the direct genotoxic potential of cadmium in four different rodent cell lines [J]. Toxicology, 1998, 126: 103-114
[46] Liu F, Jan KY. DNA damage in arsenite- and cadmium-treated bovine aortic endothelial cells [J]. Free Radic Biol Med, 2000, 28: 55-63
[47] Mouron SA, Grillo CA, Dulout FN, et al. A comparative investigation of DNA strand breaks, sister chromatid exchanges and K-ras gene mutations induced by cadmium salts in cultured human cells [J]. Mutat Res, 2004, 568: 221-231
[48] Fotakis G, Cemeli E, Anderson D, et al. Cadmium chloride induced DNA and lysosomal damage in a hepatoma cell line [J]. Toxicol in Vitro, 2005, 19: 481-489
[49]王文仲,徐兆发,杨敬华,等.镉对小鼠肾脏细胞凋亡的影响[J].中国工业医学杂志,2004, 17(1):4-6
[50] Kondoh M, Araragi S, Sato K, et al. Cadmium induces apoptosis partly via caspase-9 activation in HL-60 cells [J]. Toxicology, 2002, 170: 111-117
[51] Shih YL, Lin CJ, Hsu SW, et al. Cadmium toxicity toward caspase-independent apoptosis through the mitochondria-calcium pathway in mtDNA-depleted cells [J]. Ann N Y Acad Sci., 2005, 1042: 497-505
[52]闫玲,苗琦.细胞器与细胞凋亡[J].生物物理学报,2002,18(3):271-276
[53] Vercesi AE, Kowaltowski AJ, Grijalba MT, et al. The role of reactive oxygen species in mitochondrial permeability transition [J]. Biosci Rep, 1997, 17: 43-52
[54] Lohmann RD, Beyersmann D. Cadmium- and zinc-mediated changes of the Ca2+-dependent endonuclease in apoptosis [J]. Biochem Biophys Res Commun, 1993, 190: 1097-1103
[55] Junnwirth A, Paulmichl M, Lang F. Cadmium enhances potassium conductance in cultured renal epitheloid (MDCK) cells [J]. Kidney Int, 1990, 37(6):1477-1486
[56] Fukumoto M, Kujiraoka T, Hara M, et al. Effect of cadmium on gap junctional intercellularcommunication in primary cultures of rat renal proximal tubular cells [J]. Life Sci, 2001, 69(3): 247-254
[57] Wang L, Cao J, Chen D, et al. Role of oxidative stress, apoptosis, and intracellular homeostasis in primary cultures of rat proximal tubular cells exposed to cadmium [J]. Biol Trace Elem Res, 2009, 127: 53-68
[58] Matsuoka M, Call KM. Cadmium-induced expression of immediate early genes in LLC-PK1 cells [J]. Kidney Int, 1995, 48: 383-389
[59] Garrett SH, Phillips V, Somji S, et al. Transient induction of metallothionein isoform 3 (MT-3), c-fos, c-jun and c-myc in human proximal tubule cells exposed to cadmium [J]. Toxicol Lett, 2002, 126: 69-80
[60] Thévenod F, Friedmann JM, Katsen AD, et al. Up-regulation of multidrug resistance P-glycoprotein via Nuclear Factor-kappaB activation protects kidney proximal tubule cells from cadmium- and reactive oxygen species-induced apoptosis [J]. J Biol Chem, 2000, 275(3): 1887-1896
[61] Thévenod F, Friedmamn JM. Cadmium-mediated oxidative stress in kidney proximal tubule cells induces degradation of Na+/K+-ATPase through proteasomal and endo-/lysosomal proteolytic pathways [J]. FASEB J, 1999, 13(13): 1751-1761
[62] Gennari A, Cortese E, Boveri M, et al. Sensitive endpoints for evaluating cadmium-induced acute toxicity in LLC-PK1 cells [J]. Toxicology, 2003, 183: 211-220
[63]姜傥,谭炳德,董秀清.镉对肾小管细胞内Na+-K+-ATP酶与钙稳态的变化[J].中华劳动卫生职业病杂志,1995,13(2):75-77
[64] Stinson LJ, Darmon AJ, Dagnino L, et al. Delayed apoptosis post-cadmium injury in renal proximal tubule epithelial cells [J]. Am J Nephrol, 2003, 23(1): 27-37
[65] Wang Z, Templeton DM. Induction of c-fos proto-oncogene in mesangial cells by cadmium [J]. J Biol Chem, 1998, 273(1): 73-79
[66] Ding W, Templeton DM. Activation of parallel mitogen-activated protein kinase cascades and induction of c-fos by cadmium [J]. Toxicol Appl Pharmacol, 2000, 162(2): 93-99
[67] Kang CD, Jang JH, Kim KW, et al. Activation of c-jun N-terminal kinase/stress-activatedprotein kinase and the decreased ratio of Bcl-2 to Bax are associated with the auto-oxidized dopamine-induced apoptosis in PC12 cells [J]. Neurosci Lett, 1998, 256(1): 37-40
[68] Watters D. Molecular mechanisms of ionizing radiation-induced apoptosis [J]. Immunol Cell Biol, 1999, 77(3): 263-271
[69] Dabrio M, Rodríguez AR, Bordin G, et al. Recent developments in quantification methods for metallothionein [J]. J Inorg Biochem, 2002, 88 (2): 123-134
[70] Waalkes MP, Coogan TP, Barter RA. Toxicological principles of metal carcinogenesis with special emphasis on cadmium [J]. Crit Rev Toxicol, 1992, 22: 175-201
[71] Shimoda R, Achanzar WE, Qu W, et al. Metallothionein is a potent negative regulator of apoptosis [J]. Toxicol Sci, 2003, 73: 294-300
[72] Cherian MG, Goyer RA. Metallothioneins and their role in the metabolism and toxicity of metals [J]. Life Sci, 1978, 23(1): 1-9
[73]裴秀丛,徐兆发.镉对大鼠肾小管上皮细胞E-cadherin影响[J].中国公共卫生,2006,22(2):160-162
[1]李君,潘家荣,魏益民.食品中铅镉联合毒性研究进展[J].食品研究与开发,2007,128(3):158-160
[2] Nolan CV, Shaikh ZA. Lead nephrotoxicity and associated disorders-biochemical-mechanisms [J]. Toxicology, 1992, 73: 127-146
[3] W?ostowski T, Krasowska A, Bonda E. Joint effects of dietary cadmium and polychlorinatedbiphenyls on metallothionein induction, lipid peroxidation and histopathology in the kidneys and liver of bank voles [J]. Ecotoxicol Environ Saf, 2008, 69: 403-410
[4]刘宗平,马卓,李文范,等.铅镉中毒发病机理的研究-绵羊动物模型的复制[J].中国兽医科技,1996,26(10):11-14
[5]王学谦,尹先仁,白雪涛.铅镉联合作用对大鼠肾小管上皮细胞脂质过氧化的影响[J].卫生研究,2002,31(4):232-234
[6] Bizarro P, Acevedo S, Ni?o-Cabrera G, et al. Ultrastructural modifications in the mitochondrion of mouse Sertoli cells after inhalation of lead, cadmium or lead–cadmium mixture [J]. Reprod Toxicol, 2003, 17: 561-566
[7]路浩,达剑森,梅莉,等.母鼠妊娠期铅镉联合暴露对仔鼠脑组织的氧化损伤及乙酰半胱氨酸的保护效应[J].中国兽医科学,2008,38(1):42-45
[8]王林,陈大伟,曹瑾,等.铅镉联合暴露对大鼠肾脏功能损伤的研究[J].毒理学杂志,2008,22(5):345-348
[9]马卓,刘宗平,张白银,等.绵羊铅镉联合中毒与硒解毒的试验病理学研究[J].中国兽医科技,1997,27(3):12-14
[10] Liu ZP. Lead poisoning combined with cadmium in sheep and horses in the vicinity of non–ferrous metal smelters [J]. The Science of the Total Environment, 2003, 309: 117-126
[11] Haneef SS, Swarup D, Dwivedi SK, et al. Effects of concurrent exposure to lead and cadmium on renal function in goats [J]. Small Rumin Res, 1998, 28: 257-261
[12] Nolan CV, Shaikh ZA. Lead nephrotoxicity and associated disorders: Biochemical mechanism [J]. Toxicology, 1992, 73: 127-146
[13] Garcia TA, Corredor L. Biochemical changes in the kidneysafter perinatal intoxication with lead and/or cadmium and their antagonistic effects when coadministered [J]. Ecotoxicol Environ Safe, 2004, 57: 184-189
[14] Mahaffey KR, Capar SG,Gladen BC, et al. Concurrent exposure to lead, cadmium, and arsenic. Effects on toxicity and tissue metal concentrations in the rat [J]. J Lab Clin Med, 1981, 98: 463-481
[15] Salovsky P, Shopova V, Dancheva V. Combined effects of cadmium and lead on some biochemical markers in rat Bronchoalveolar Lavage Fluid [J]. Toxicol Lett (supple), 1995, 78: 73
[1] Cooper GP, Manalis RS. Interactions of Pb and Cd on acetylcholine release at the frog neuromuscular junction [J]. Toxicol Appl Pharmacol, 1984, 74: 411-416
[2] Waisberg M, Joseph P, Hale B, et al. Molecular and cellular mechanisms of cadmium carcinogenesis [J]. Toxicology, 2003, 192: 95-117
[3] Ercal N, Treeratphan P, Hammond TC, et al. In vivo indices of oxidative stress in lead exposed C57BL/6 mice are reduced by treatment with meso-2, 3-dimercaptosuccinic acid or N-acetyl cysteine [J]. Free Rad Biol Med, 1996, 21: 157-161
[4] Sharma RP, Street JC. Public health aspects of toxic heavy metals in animal feed [J]. J Am Vet Med Assoc, 1980, 177: 149-153
[5] Morales AI, Vicente-Sánchez C, Jerkic M, et al. Effect of quercetin on metallothionein, nitric oxide synthases and cyclooxygenase-2 expression on experimental chronic cadmium nephrotoxicity in rats [J]. Toxicol Appl Pharmacol, 2006, 210: 128-135
[6] Thijssen S, Cuypers A, Maringwa J, et al. Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys [J]. Toxicology 2007, 236: 29-41
[7] Chwe?atiuk E, W?ostowski T, Krasowska A, et al. The effect of orally administered melatonin on tissue accumulation and toxicity of cadmium in mice [J]. J Trace Elem Med Biol, 2006, 19: 259-265
[8] Antonio Garcia T, Corredor L. Biochemical changes in the kidneys after perinatal intoxication with lead and/or cadmium and their antagonistic effects when coadministered [J]. Ecotoxicol Environ Saf, 2004, 57: 184-189
[9] Campana O, Sarasquete C, Blasco J. Effect of lead on ALA-D activity, metallothionein levels, and lipid peroxidation in blood, kidney, and liver of the toadfish Halobatrachus didactylus [J]. Ecotoxicol Environ Saf, 2003, 55: 116-125
[10] Shaikh ZA, Zaman K, Tang W, et al. Treatment of chronic cadmium nephrotoxicity by N-acetyl cysteine [J]. Toxicol Lett, 1999, 104: 137-142
[11]刘宗平主编.动物中毒病学[M].北京:中国农业出版社,2006,394-401
[12] Swierkosz TA, Mitchell JA, Warner TD, et al. Co-induction of nitric oxide synthase and cyclo-oxygenase: interactions between nitric oxide and prostanoids [J]. Br J Pharmacol, 1995, 114: 1335-1342
[1]刘宗平主编.动物中毒病学[M].北京:中国农业出版社,2006,394-401
[2] Haneef SS, Swarup D, Dwivedi SK, et al. Effects of concurrent exposure to lead and cadmium on renal function in goats [J]. Small Rumin Res, 1998, 28: 257-261
[3] Antonio Garcia T, Corredor L. Biochemical changes in the kidneys after perinatal intoxication with lead and/or cadmium and their antagonistic effects when coadministered [J]. Ecotoxicol Environ Saf, 2004, 57: 184-189
[4]王学谦,白雪涛,尹先仁.铅镉联合作用对大鼠肾小管上皮细胞β-乙酰氨基葡萄糖苷酶的影响[J].环境与健康杂志,2002,14:306-309
[5]王翔朴.肾脏毒理学[M].湖南:湖南科学技术出版社,2004:16-24
[6]朱国文,李熙建.肾脏功能不同程度损害时尿中几种微量蛋白与尿酶变化分析[J].国际检验医学杂志,2007,28:489-491
[7] Lars J, Bodil P, Carl Ge. Decreased gromerular filtration rate in solders exposed to cadmium [J]. Occup Environ Med, 1995, 52: 818-822
[8] Akesson A, Lundh T, Vahter M, et al. Tubular and glomerular kidney effects in Swedish women with low environmental cadmium exposure [J]. Environ Health Perspect, 2005, 113: 1627-1631
[9] Raab WP. Diagnostic value of urinary enzyme determinations [J]. Clin Chem, 1972, 18: 5-25
[10] Sivaprasad TR, Malarkodi SP, Palaninathan V. Therapeutic efficacy of lipoic acid in combination with dimercaptosuccinic acid against lead-induced renal tubular defects and on isolated brush-border enzyme activities [J]. Chem-Biol Interact, 2004, 147: 259-271
[11] Tanimoto A, Hamada T, Koidao O. Cell death and regeneration of renal proximal tubular cells in rats with sub-chronic cadmium intoxication [J]. Toxicol Pathol, 1993, 21: 341-352
[12]刘杰,刘亚平,Curtis DK.慢性和急性染镉所致小鼠肾损害的比较[J].中华劳动卫生职业病杂志,1998,16:9
[13]王海燕.肾脏病学[M].第二版,北京:人民卫生出版社,1996,1387-1388
[14] Wedeen RP, Udasin I, Fiedler N, et al. Urinary biomarkers as indicators of renal disease [J]. Ren Fail, 1999, 21: 241-249
[15] Morales AI, Vicente-Sánchez C, Sandoval JM, et al. Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties [J]. Food Chem Toxicol, 2006, 44: 2092-2100
[16] Zalups RK, Barfuss DW. Nephrotoxicity of inorganic mercury L-cysteine co-administered with [J]. Toxicology, 1996, 109: 15-29
[17] Stroo WE, Hook JB. Enzymes of renal origin in urine as indicators of nephrotoxicity [J]. Toxicol Appl Pharmacol, 1977, 39: 423-434
[18] Porter GA. Urinary biomarkers and nephrotoxicity [J]. Miner Electrolyte Metab, 1994, 20: 181-186
[19] Rodriguez-Barbero A, López-Novoa JM, Arévalo M. Involvement of platelet-activating factor in gentamicin nephrotoxicity in rats [J]. Exp Nephrol, 1997, 5: 47-54
[20] Tomlinson PA, Dalton RN, Hartley B, et al. Low molecular weight protein excretion in glomerular disease: a comparative analysis [J]. Pediatr Nephrol, 1997, 11: 285-290
[21] Gruener N. Early detection of changes in kidney function in workers exposed to solvents and heavy metals [J]. Isr J Med Sci, 1992, 28: 605-607
[22] Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NHF) and the national institute of diabetes and digestive and kidney diseases (NIDDK) [J]. Am J Kidney Dis, 2003, 42: 617-622
[23] Komori T, Yoshimura M, Inoue H, et al. Clinical significance of urinary free dopamine as a marker of renal function [J]. Rinsbo byori, 1996, 44: 477-482
[24] Lee JI, Kim MJ, Park CS, et al. Influence of ascorbic acid on BUN, creatinine, resistive index in canine renal ischemia-reperfusion injury [J]. J Vet Sci, 2006, 7: 79-81
[1]刘宗平.动物中毒病学[M].北京:中国农业出版社,2006:394-402
[2] Shaikh ZA, Vu TT, Zaman K. Oxidation stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants [J]. Toxicol Appl Pharm, 1999, 154: 256-263
[3] Thijssen S, Cuypers A, Maringw J, et al. Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys [J]. Toxicology, 2007, 236: 29-41
[4] Farmand F, Ehdaie A, Roberts CK, et al. Lead-induced dysregulation of superoxide dismutases, catalase, glutathione peroxidase, and guanylate cyclase [J]. Environmental Research, 2005, 98: 33-39
[5] Patra RC, Swarup D, Dwivedi SK. Antioxidant effects ofαtocopherol, ascorbic acid and L-methionine on lead induced oxidative stress to the liver, kidney and brain in rats [J]. Toxicology, 2001, 162: 81-88
[6] Dimri U, Ranjan R, Kumar N, et al. Changes in oxidative stress indices, zinc and copper concentrations in blood in canine demodicosis [J]. Vet Parasitol, 2008, 154: 98-102
[7] Gurer H, Ozgunes H, Neal R, et al. Antioxidant effects of N-acetyl cysteine and succimer in redblood cells from lead exposed rats [J]. Toxicology, 1998, 128: 181-189
[8] Nigam D, Shukla GS, Agarwal AK. Glutathione depletion and oxidative damage in mitochondria following exposure to cadmium in rat liver and kidney [J]. Toxicol Lett, 1999, 106: 151-157
[9] Jurczuk M, Moniuszko-Jakoniuk J, Brzóska MM. Involvement of some low-molecular thiols in the peroxidative mechanisms of lead and ethanol action on rat liver and kidney [J]. Toxicology, 2006, 219: 11-21
[10] Pari L, Murugavel P. Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats [J]. Toxicology, 2007, 234: 44-50
[11] Shaikh ZA, Zaman K, Tang W, et al. Treatment of chronic cadmium nephrotoxicity by N-acetyl cysteine [J]. Toxicol Lett, 1999, 104: 137-142
[12] Leelank BN, Bansal MP. Effect of selenium supplementation on the glutathione redox system in the kidney of mice after chronic cadmium exposures [J]. J Appl Toxicol, 1996, 17: 81-84
[13] Fang YZ, Yang S, Wu G. Free radical, antioxidants and nutrition [J]. Nutrition, 2002, 18: 872-879
[14] Januel C, Fay LB, Ruggiero D, et al. Covalent coupling of reduced glutathione with ribose: loss of cosubstrate ability to glutathione peroxidase [J]. Biochim Biophys Acta, 2003, 1620: 125-132
[15] Huang YL, Sheu JY, Lin TH. Association between oxidative stress and changes of trace elements in patients with breast cancer [J]. Clin Biochem, 1999, 32: 131-136
[16] Fraga CG. Relevance, essentiality and toxicity of trace elements in human health [J]. Molecular Aspects of Medicine, 2005, 26: 235-244
[17] Horsburgh MJ, Wharton SJ, Karavolos M, et al. Manganese: elemental defence for a life with oxygen? [J]. TRENDS in Microbiology, 2002, 10: 496-501
[18] Uriu-Adams JY, Keen CL. Copper, oxidative stress, and human health [J]. Mol Aspects Med, 2005, 26: 268-298
[19] Rao L, Puschner B, Prolla TA. Gene expression profiling of low selenium status in the mouse intestine: transcriptional activation of genes linked to DNA damage, cell cycle control andoxidative stress [J]. J Nutr, 2001, 131: 3175-3181
[20] Taylor CG, Towner RA, Janzen EG, et al. MRI detection of hyperoxia-induced lung edema in Zn-deficient rats [J]. Free Radic Biol Med, 1990, 9: 229-233
[21] Oteiza PI, Olin KL, Fraga CG, et al. Zinc deficiency causes oxidative damage to proteins, lipids and DNA in rat testes [J]. J Nutr, 1995, 125: 823-829
[22] Parsons SE, Disilvestro RA. Effects of mild Zinc deficiency, plus or minus an acute-phase response, on glactosamine-induced hepatitis in rats [J]. Br J Nutr, 1994, 72: 611-618
[23] Kraus A, Roth HP, Kirchgessner M. Supplementation with vitamin C, vitamin E or beta carotene influences osmotic fragility and oxidative damage of erythrocytes of zinc-deficient rats [J]. J Nutr, 1997, 127: 1290-1296
[24] Kaushal N, Bansal MP. Dietary selenium variation-induced oxidative stress modulates CDC2/cyclin B1 expression and apoptosis of germ cells in mice testis [J]. J Nutr Biochem, 2007, 18: 553-564
[25]刘宗平.现代动物营养代谢病[M].北京.化学工业出版社,2003,277-280
[26] Morales AI, Vicente-Sánchez C, Sandoval JM, et al. Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties [J]. Food Chem Toxicol, 2006, 44: 2092-2100
[27] Kosanovic M, Jokanovic M. The association of exposure to cadmium through cigarette smoke with pregnancy-induced hypertension in a selenium deficient population [J]. Environ Toxicol Pharmacol, 2007, 24: 72-78
[28] Badiello R, Feroci G, Fini A. Interaction between trace elements: selenium and cadmium ions [J]. J Trace Elem Med Biol, 1996, 10: 156-162
[1] Morales AI, Vicente-Sánchez C, Sandoval JM, et al. Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties [J]. Food Chem Toxicol, 2006, 44: 2092-2100
[2] Hotter G, Fels LM, Closa D, et al. Altered levels of urinary prostanoids in lead-exposed workers [J]. Toxicol lett, 1995, 77: 309-312
[3] Smith DR, Kahng MW, Quintanilla-Vega B, et al. High-affinity renal lead-binding proteins in environmentally-exposed humans [J]. Chem Biol Interact, 1998, 115: 39-52
[4] Lin JL, Lin-Tan DT, Li YJ, et al. Low-level environmental exposure to lead and progressive chronic kidney diseases [J]. Am J Med, 2006, 119: 707
[5] Khalil-Manesh F, Gonick HC, Cohen AH, et al. Experimental model of lead nephropathy. I. Continuous high dose lead administration [J]. Kidney Int, 1992, 41: 1192-1203
[6] El-Sokkary GH, Abdel-Rahman GH, Kamel ES. Melatonin protects against lead-induced hepatic and renal toxicity in male rats [J]. Toxicology, 2005, 213: 25-33
[7] Shaikh ZA, Vu TT, Zaman K. Oxidation stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants [J]. Toxicol Appl Pharm, 1999, 154: 256-263
[8] Goyer RA. Mechanisms of lead and cadmium nephrotoxicity [J]. Toxicol lett, 1989, 46: 153-162
[9]王翔朴.肾脏毒理学[M].湖南:湖南科学技术出版社,2004:7-9
[1]刘宗平.现代动物营养代谢病[M].北京.化学工业出版社,2003,277-280
[2] Garcia TA, Corredor L. Biochemical changes in the kidneys after perinatal intoxication with lead and/or cadmium and their antagonistic effects when coadministered [J]. Ecotoxicology andEnvironmental Safety, 2004, 57: 184-189
[3] Sato M, Bremner I. Oxygen free radicals and metallothionein [J]. Free Radic Biol Med, 1993, 14: 325-337
[4]郭宝林,贾志海,张玉枝.畜禽铜营养研究进展[J].饲料工业,2005,26(10):48-51
[5] Cao J, Luo XG. Effect of dietary iron on concentration, age, and length of iron feeding on feed intake and tissue iron concentration of broiler chicks for use as bioassay of supplemental iron sources [J]. Poult Sci, 1996, 75: 495
[6] Casalino E, Cesare S, Clemente L. Enzyme activity alteration by cadmium administration to rats: the possibility of iron involvement in lipid peroxidation [J]. Arch Biochem Biophys, 1997, 346:171-179
[7] El-Heni J, Messaoudi I, Hammouda F, et al. Protective effects of selenium (Se) and zinc (Zn) on cadmium (Cd) toxicity in the liver and kidney of the rat: Histology and Cd accumulation [J]. Food Chem Toxicol, 2008, 46: 3522-3527
[1] Foster KA, Galeffi F, Gerich FJ, et al. Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration [J]. Prog Neurobiol, 2006, 79: 136-171
[2] Capaldi RA. Structure and function of cytochrome c oxidase [J]. Annu Rev Biochem, 1990, 59: 569-596
[3] Hong WK, Han EH, Kim DG, et al. Amyloid-beta-peptide reduces the expression level of mitochondrial cytochrome oxidase subunits [J]. Neurochem Res, 2007, 32: 1483-1488
[4] Speijer D, Breek CKD, Muijsers AO, et al. The sequence of a small subunit of cytochrome c oxidase from Crithidiafasciculata which is homologous to mammalian subunitIV [J]. FEBS Letters, 1996, 381: 123-126
[5] Nolan CV, Shaikh ZA. Lead nephrotoxicity and associated disorders: biochemical mechanisms [J]. Toxicology 1992, 73: 127-146
[6] W?ostowski T, Krasowska A, Bonda E. Joint effects of dietary cadmium and polychlorinated biphenyls on metallothionein induction, lipid peroxidation and histopathology in the kidneysand liver of bank voles [J]. Ecotoxicol Environ Saf 2008, 69: 403-410
[7] Alvarez-Barrientos A, O’Connor JE, Nieto Castillo R, et al. Use of flow cytometry and confocal microscopy techniques to investigate early CdCl2-induced nephrotoxicity in vitro [J]. Toxicol in Vitro, 2001, 15: 407-412
[8] Heid CA, Stevens J, Livak JK, et al. Real time quantitative PCR [J]. Genome Res, 1996, 6: 986-994
[9] Livak KJ, Schittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) Method [J]. Methods, 2001, 25: 402-408
[10] Hiquchi R, Fockler C, Dollinqer G, et al. Kinetic PCR analysis: real-time monitoring of DNA amplification reactions [J]. Biotechnology (NY), 1993, 11: 1026-1030
[11] Ke LD, Chen Z, Yung WK. A reliability test of standard-based quantitative PCR: exogenous standards [J]. Mol Cell Probes, 2000, 14(2): 127
[12] Becker KD Pan, Whitely CB. Real-time quantitative polymerase chain reaction to assess gene transfer [J]. Hum Gene Ther, 1999, 10: 2559
[13] Higgins JA, Ezzell J, Hinnebusch BJ, et al. 5′nuclease PCR assay to detect Yersinia pestis [J]. J Clin Microbiol, 1998, 36: 2284-2288
[14] Bustin S. Absolute quantification of mRNA using Real-time reverse transcription polymerase chain reaction assays [J]. J Mol Endocrinol, 2000, 25: 169
[15] Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR [J]. Nucleic Acids Res, 2001, 29: 2002-2007
[16] Kenneth JL, Thomas DS. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method [J]. Methods, 2001, 25: 402-408
[17] Fieller E. Some problems in interval estimation [J]. J Roy Statist Soc Ser B, 1954, 16: 175-185
[18] Sen T, Sen N, Tripathi G, et al. Lipid peroxidation associated cardiolipin loss and membrane depolarization in rat brain mitochondria [J]. Neurochem Int, 2006, 49: 20-27
[19] Kim HL, Choi YK, Kim DH, et al. Tetrahydropteridine deficiency impairs mitochondrial function in Dictyostelium discoideum Ax2 [J]. FEBS Letters, 2007, 581: 5430-5434
[20] Tsukihara T, Aoyama H, Yamashita E, et al. Structures of metal sites of oxidized bovine heartcytochrome c oxidase at 2.8 A [J]. Science, 1995, 269: 1069-1074
[21] Onyango IG, Bennett JP, Tuttle JB. Endogenous oxidative stress in sporadic Alzheimer’s disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids [J]. Neurobiology of disease, 2005, 19: 312-322
[22] Zhu XW, Raina AK, Lee H, et al. Oxidative stress signalling in Alzheimer’s disease [J]. Brain Research, 2004, 1000: 32-39
[23] Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs [J]. Physiol Rev, 1979, 59: 527-605
[24] Sohal RS, Toroser D, Brégère C, et al. Age-related decrease in expression of mitochondrial DNA encoded subunits of cytochrome c oxidase in Drosophila melanogaster [J]. Mech Ageing Dev, 2008, 129: 558-561
[25] Khalimonchuk O, R?del G. Biogenesis of cytochrome c oxidase [J]. Mitochondrion, 2005, 5: 363-388
[26] Rahman S, Taanman JW, Cooper JM, et al. A Missense Mutation of Cytochrome Oxidase Subunit II Causes Defective Assembly and Myopathy [J]. Am J Hum Genet, 1999, 65: 1030-1039
[27] Hosler JP, Ferguson-Miller S, Mills DA. Energy transduction: proton transfer through the respiratory complexes [J]. Annu Rev Biochem 2006, 75: 165-187
[28] Ferguson M, Mockett RJ, Shen Y, et al. Age-associated decline in mitochondrial respiration and electron transport in Drosophila melanogaster [J]. Biochem J, 2005, 390, 501-511
[29] Hüttemann M, Schmidt TR, Grossman LI. A third isoform of cytochrome c oxidase subunit VIII is present in mammals [J]. Gene, 2003, 312: 95-102
[1]韩新燕,许梓荣.哺乳动物金属硫蛋白的研究进展[J].中国兽医科技,2003,33(11):28-31
[2] Quafe CJ, Findley SD, Fricksin JC, et al. Induction of new metallothionein isoform (MT-IV) occurs during differentiation of stratified squamous epithelia [J]. Biochemistry, 1994, 33: 7250-7259
[3] Lu J, Jin T, Nordberg G, et al. Metallothionein gene expression in peripheral lymphocytes and renal dysfunction in a population environmentally exposed to cadmium [J]. Toxicol Appl pharmacol, 2005, 206: 150-156
[4] Conrad CC, Walter CA, Richardson A, et al. Cadmium toxicity and distribution in metallothionein-I and II deficient transgenic mice [J]. J Toxicol Environ Health, 1997, 52: 527-543
[5] Zangger K, ?z G, Haslinger E, et al. Nitric oxide selectively releases metals from the N-terminal domain of metallothioneins: potential role at inflammatory sites [J]. FASEB J, 2001, 15: 1303-1305
[6]刘学忠,郑志高,王捍东.金属硫蛋白生物学功能研究进展[J].畜牧兽医杂志,2004,23(2): 19-21
[7] K?gi JHR. Overview of metallothionein [J]. Methods Enzymol, 1991, 205: 613-626
[8] Tom M, Chen N, Segev M, et al. Quantifying fish metallothionein transcript by real time PCR for its utilization as an environmental biomarker [J]. Mar Pollut Bull, 2004, 48: 705-710
[9] Thijssen S, Cuypers A, Maringwa J, et al. Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys [J]. Toxicology, 2007, 236: 29-41
[10] W?ostowski T, Krasowska A, Bonda E. Joint effects of dietary cadmium and polychlorinated biphenyls on metallothionein induction, lipid peroxidation and histopathology in the kidneys and liver of bank voles [J]. Ecotoxicol Environ Saf, 2008, 69: 403-410
[11] Choi CY, An KW, Nelson ER, et al. Cadmium affects the expression of metallothionein (MT) and glutathione peroxidase (GPX) mRNA in goldfish, Carassius auratus [J]. Comp Biochem Physiol C Toxicol Pharmacol, 2007, 145: 595-600
[12] Qu W, Diwan BA, Liu J, et al. The metallothionein-null phenotype is associated withheightened sensitivity to lead toxicity and an inability to form inclusion bodies [J]. Am J Pathol, 2002, 160: 1047-1056
[13] Jamieson JA, Stringer DM, Zahradka P, et al. Dietary zinc attenuates renal lead deposition but metallothionein is not directly involved [J]. Biometals, 2008, 21: 29-40
[14] Liu ZP. Lead poisoning combined with cadmium in sheep and horses in the vicinity of non-ferrous metal smelters [J]. Sci Total Environ, 2003, 309: 117-126
[15] Demuynck S, Grumiaux F, Mottier V, et al. Metallothionein response following cadmium exposure in the oligochaete Eisenia fetida [J]. Comp Biochem Physiol C Toxicol Pharmacol, 2006, 144: 34-46
[16] Park JD, Liu Y, Klaassen CD. Protective effect of metallothionein against the toxicity of cadmium and other metals [J]. Toxicology, 2001, 163: 93-100
[17] Chan HM, Cherian MG. Protective roles of metallothionein and glutathione in hepatotoxicity of cadmium [J]. Toxicology, 1992, 72: 281-290
[18] Klaassen CD, Liu J. Induction of metallothionein as an adaptive mechanism affecting the magnitude and progression of toxicological injury [J]. Environ Health Perspect, 1998, 106: 297-300
[19] Liu Y, Liu J, Habeebu SS, et al. Susceptibility of MT-null mice to chronic CdCl2-induced nephrotoxicity indicates that renal injury is not mediated by the CdMT complex [J]. Toxicol Sci, 1998, 46: 197-203
[20] Bremner I. Interaction between metallothionein and trace metals [J]. Progr in Food Nutr Sci, 1987, 11: 1-37
[21] Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response [J]. Biochem J, 1990, 265: 621-636
[22] Tamai KT, Liu X, Silar P, et al. Heat shock transcription factor activates yeast metalloth- ionein gene expression in response to heat and glucose starvation via distinct siganlling pathways [J]. Mol Cell Biol, 1994, 141: 8155-8165
[23] Durnam DM, Palmiter RD. Transcriptional regulation of the mouse metallothionein I gene by heavy metals [J]. J Biol Chem, 1981, 256: 5712-5716
[24] Palmiter RD. Molecular biology of metallothionein in animal tissues [J]. Eisei Kagaku, 1987, 24: 128-131
[25] Maracine M, Segner H. Cytotoxicity of metals in isolated fish cells: importance of the cellular glutathione status [J]. Comp Biochem Physiol. A, 1998, 120: 83-88
[26] Campana O, Sarasquete C, Blasco J. Effect of lead on ALA-D activity, metallothionein levels, and lipid peroxidation in blood, kidney, and liver of the toadfish Halobatrachus didactylus [J]. Ecotoxicol Environ Saf, 2003, 55: 116-125
[27] Gong Q, Hart BA. Effect of thiols on cadmium-induced expression of metallothionein and other oxidant stress genes in rat lung epithelial cells [J]. Toxicology, 1997, 119: 179-191
[28] Roels HA, Hoet P, Lison D. Usefulness of biomarkers of exposure to inorganic mercury, lead, or cadmium in controlling occupational and environmental risks of nephrotoxicity [J]. Ren Fail, 1999, 21: 251-262
[29] Baudrimont M, Andress S, Durrieu G, et al. The key role of metallothioneins in the bivalve Corbicula fluminea during the depuration phase, after in situ exposure to Cd and Zn [J]. Aquat Toxicol, 2003, 63: 89-102
[1] Goyer RA. Mechanisms of lead and cadmium nephrotoxicity [J]. Toxicol lett, 1989, 46: 153-162
[2] Pieter J, Boogaard J, Paul Z, et al. Primary culture of proximal tubular cells from normal rat kidney as an in vitro model to study mechanisms of nephrotoxicity: Toxicity of nephrotoxicants at low concentrations during prolonged exposure [J]. Biochemical Pharmacology, 1990, 39: 1335-1345
[3] Pieter J, Boogaard J, Fred N, et al. Renal proximal tubular cells in suspension or in primary culture as in vitro models to study nephrotoxicity [J]. Chemico-Biological Interactions, 1990, 76: 251-291
[4] Foidart, Willems J, Dechenne C, et al. Biosynthesis of basement membrane collagen in culture of renal glomerular and tubular epithelial cells [J]. Diabete Metab, 1975, 1: 227-234
[5] Rudolfs K, Zalups, Lawrence H, et al. Methods in renal toxicology [M]. Canada, crc press, 1996
[6]郑丰,黎磊石.大黄对体外肾小管细胞增殖的影响[J].医学研究生学报,1991,3(4):46
[7]王东,吴雄飞,金锡御.大鼠肾小管上皮细胞的原代培养及传代[J].中华实用外科杂志,1999,16(2):179-180
[8]刘晓玲,邢淑华. Percoll法分离培养肾小管上皮细胞[J].徐州医学院学报,2006,26(2):100-103
[9] Lawrence H, Lash. In Vitro methods of assessing renal damage [J]. Toxicologic Pathology, 1998, 26: 33-42
[10]王洪复.骨细胞图谱与骨细胞体外培养技术[M].上海:上海科学技术出版社,2001
[11] Toutain H, Vauclin-Jacques N, Fillastre JP, et al. Biochemical, functional, and morphological characterization of a primary culture of rabbit proximal tubule cells [J]. Exp Cell Res, 1991, 194: 9-18
[12]严玉澄,钱家麒,戴慧莉,等.人近端肾小管上皮细胞的原代培养[J].上海第二医科大学学报,2005,25(4):388-390
[13] Mattila PM, Nietosvaara YA, Ustinov JK, et al. Antigen expression in different parenchymal cell types of rat kidney and heart [J]. Kid Int, 1989, 36: 228-233
[14]张卓然.培养细胞学与细胞培养技术[M]. 1版.上海:上海科学技术出版社,2004:425
[1] Cooper GP, Manalis RS. Interactions of lead and cadmium on acetylcholine release at the frog neuromuscular junction [J]. Toxicol Appl Pharmacol, 1984, 74: 411-416
[2] Xu J, Ji LD, Xu LH. Lead-induced apoptosis in PC 12 cells: involvement of p53, bcl-2 family and caspase-3 [J]. Toxicol Lett, 2006, 166: 160-167
[3] Sandhir R, Julka D, Gill KD. Lipoperoxidative damage on lead exposure in rat brain and its implications on membrane bound enzymes [J]. Pharmacol Toxicol, 1994, 74: 66-71
[4] Loghman-Adham M. Renal effects of environmental and occupational lead exposure [J]. Environ Health Perspect, 1997, 105: 928-939
[5] Patra RC, Swarup D, Dwidedi SK. Antioxidant effects ofαtocopherol, ascorbic acid and L-methionine on lead-induced oxidative stress of the liver, kidney and brain in rats [J]. Toxicology, 2001, 162: 81-88
[6] Goyer RA. Mechanisms of lead and cadmium nephrotoxicity [J]. Toxicol lett, 1989, 46: 153-162
[7] Morales AI, Vicente-Sánchez C, Jerkic M, et al. Effect of quercetin on metallothionein, nitric oxide synthases and cyclooxygenase-2 expression on experimental chronic cadmium nephrotoxicity in rats [J]. Toxicol Appl Pharmacol, 2006, 210: 128-135
[8] Alvarez-Barrientos A, O’Connor JE, Nieto Castillo R, et al. Use of flow cytometry and confocal microscopy techniques to investigate early CdCl2-induced nephrotoxicity in vitro [J]. Toxicol in Vitro, 2001, 15: 407-412
[9] Gennari A, Cortese E, Boveri M, et al. Sensitive endpoints for evaluating cadmium-induced acute toxicity in LLC-PK1 cells [J]. Toxicology, 2003, 183: 211-220
[10] Thévenod F, Friedmann JM. Cadmium-mediated oxidative stress in kidney proximal tubulecells induces degradation of Na+/K+-ATPase through proeasomal and endo-/lysosomal proteotic pathway [J]. The FASEB Journal, 1999, 13: 1751-1761
[11] Pedraza-Chaverri J, Maldonado PD, Barrera D, et al. Protective effect of diallyl sulfide on oxidative stress and nephrotoxicity induced by gentamicin in rats [J]. Mol Cell Biochem, 2003, 254: 125-130
[12] Haneef SS, Swarup D, Dwivedi SK, et al. Effects of concurrent exposure to lead and cadmium on renal function in goats [J]. Small Rumin Res, 1998, 28: 257-261
[13] Antonio Garcia T, Corredor L. Biochemical changes in the kidneys after perinatal intoxication with lead and/or cadmium and their antagonistic effects when coadministered [J]. Ecotoxicol Environ Saf, 2004, 57: 184-189
[14]王学谦,白雪涛,尹先仁.铅镉联合作用对大鼠肾小管上皮细胞β-乙酰氨基葡萄糖苷酶的影响[J].环境与健康杂志,2002,14:306-309
[15]赵斌,葛金芳,朱娟娟,等.小议在MTT法测细胞增殖抑制率中IC50的计算方法[J].安徽医药,2007,11(9):834-836
[16] Vermes I, Haanen C, Steffens-Nakken H, et al. A novel assay for apoptosis, flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein-labeled Annexin V [J]. J Immunol Meth, 1995, 184: 39-51
[17] Koh JY, Choi DW. Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay [J]. J Neurosci Methods, 1987, 20: 83-90
[18] Liu Y, Zhang SP, Cai YQ. Cytoprotective effects of selenium on cadmium-induced LLC-PK1 cells apoptosis by activating JNK pathway [J]. Toxicol in Vitro, 2007, 21: 677-684
[19] Chin TA, Templeton DM. Effects of CdCl2 and Cd-metallothionein on cultured mesangial cells [J].Toxicol Appl Pharmacol, 1992, 116: 133-141
[21] Skoczyńska A, Wróbel J, Andrzejak R. Lead-cadmium interaction effect on the responsiveness of rat mesenteric vessels to norepinephrine and angiotensinⅡ[J].Toxicology, 2001, 162: 157-170
[22] Salovsky P, Shopova V, Dancheva V, et al. Combined effects of cadmium and lead on some biochemical markers in rat bronchoalveolar lavage fluid [J].Toxicol Lett (supple), 1995, 78: 73
[23]王林,陈大伟,曹瑾,等.铅镉联合暴露对大鼠肾脏功能损伤的研究[J].毒理学杂志,2008,22(5):22-25
[24] Bizarro P, Acevedo S, Ni?o-Cabrera G, et al. Ultrastructural modifications in the mitochondrion of mouse Sertoli cells after inhalation of lead, cadmium or lead-cadmium mixture [J]. Reprod Toxicol, 2003, 17: 561-566
[25] Nampoothiri LP, Gupta S. Simultaneous effect of lead and cadmium on granulosa cells: A cellular model for ovarian toxicity [J]. Reprod Toxicol, 2006, 21: 179-185
[26] Wang L, Cao J, Chen D, et al. Role of oxidative stress, apoptosis, and intracellular homeostasis in primary cultures of rat proximal tubular cells exposed to cadmium [J]. Biol Trace Elem Res, 2009, 127: 53-68
[27]龚伟.铅、镉引起细胞死亡机理及硒抗铅、镉毒性效应的研究[D].北京:中国农业大学,1999
[28]魏雪涛,黄超峰,乔杨铮,等.重金属镉和铅对巨噬细胞和成纤维细胞的Hormesis效应[J].毒理学杂志(增刊),2005,19(3):235
[29] Thijssen S, Cuypers A, Maringw J, et al. Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys [J]. Toxicology, 2007, 236(1): 29-41
[30] Shaikh ZA, Vu TT, Zaman K. Oxidation stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants [J]. Toxicol Appl Pharmacol, 1999, 154: 256-263
[31] Lavrentiadou SN, Chan C, Kawcak T, et al. Ceramide-mediated apoptosis in lung epithelial cells is regulated by glutathione [J]. Am J Respir Cell Mol Biol, 2001, 25: 676-684
[32]韩贻仁.分子细胞生物学[M].二版.北京:科学出版社,2003:648-661
[33] Shabani A, Rabbani A. Lead nitrate induced apoptosis in alveolar macrophages from rat lung [J]. Toxicology, 2000, 149: 109-114
[34] De la Fuente H, Portales-Perez D, Baranda L, et al. Effect of arsenic, cadmium and lead on the induction of apoptosis of normal human mononuclear cells [J]. Clin Exp Immunol, 2002, 129: 69-77
[35]夏世钧,吴中亮.分子毒理学基础[M].武汉:湖北科学技术出版社,2001:87-90
[36] Fox DA, Srivastava D, Poblenza A, et al. Lead-induced Alterations in Gene Expression and Activity of Retinal cGMP PDE Results in Calcium Overload and Rod-selective Apoptosis [J]. Toxicol in Vitro, 1998, 12: 597-598
[37] Pham TN, Marion M, Denizeau F, et al. Cadmium-induced apoptosis in rat hepatocytes does not necessarily involve caspase-dependent pathways [J].Toxicol in Vitro, 2006, 20: 1331-1342
[38] Waisberg M, Joseph P, Hale B, etal. Molecular and cellular mechanisms of cadmium carcinogenesis [J]. Toxicology, 2003, 192: 95-117
[39] Pathak N, Khandelwal S. Oxidative stress and apoptotic changes in murine splenocytes exposed to cadmium [J]. Toxicology, 2006, 220: 26-36
[1] Slater TF. Free-radical mechanisms in tissue injury [J]. Biochem J, 1984, 222: 1-15
[2] Sen T, Sen N, Tripathi G, et al. Lipid peroxidation associated cardiolipin loss and membrane depolarization in rat brain mitochondria [J]. Neurochem Int, 2006, 49: 20-27
[3] Niki E, Yoshida Y, Saito Y, et al. Lipid peroxidation: mechanism, inhibition, and biological effects [J]. Biochem Biophys Res Commun, 2005, 336: 1-9
[4] Uchida K. 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress [J]. Prog Lipid Res, 2003, 42: 318-343
[5] Luo J, Shi R. Acroline induced oxidative stress in brain mitochondria [J]. Neurochem Int, 2005, 46: 243-252
[6] Pathak N, Khandelwal S. Influence of cadmium on murine thymocytes: potentiation of apoptosis and oxidative stress [J]. Toxicol Lett, 2006, 165: 121-132
[7] Scaduto RC, Grotyohann LW. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives [J]. Biophys J, 1999, 76: 469-477
[8] Dimri U, Ranjan R, Kumar N, et al. Changes in oxidative stress indices, zinc and copper concentrations in blood in canine demodicosis [J]. Vet Parasitol, 2008, 154: 98-102
[9] Huxtable RJ. Physiological action of taurine [J]. J Physiol Revi, 1992, 72: 101-142
[10] Sieg DJ, Billings RE. Lead/cytokine-mediated oxidative DNA damage in cultured mouse hepatocytes [J]. Toxicol Appl Pharmacol, 1997, 142: 106-115
[11] Kelly SA, Havrilla CM, Brady TC, et al. Oxidative stress in toxicology: established mammalian and emerging piscine model systems [J]. Environ Health Perspect, 1998, 106: 375-384
[12] Findel T, Holbrook NJ. Oxidants, oxidative stress and the bilolgy of aging [J]. Nature, 2000, 408: 239-247
[13] Gurer H, Ozgunes H, Neal R, et al. Antioxidant effects of N-acetyl cysteine and succimer in red blood cells from lead exposed rats [J]. Toxicology, 1998, 128: 181-189
[14] Pari L, Murugavel P. Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats [J]. Toxicology, 2007, 234: 44-50
[15] Thévenod F. Nephrotoxicity and the proximal tubule [J]. Insights from cadmium. Nephron Physiol, 2003, 93: 87-93
[16] Sies H, Akerboom TP. Glutathione disulfide (GSSG) efflux from cells and tissues [J]. Methods Enzymol, 1984, 105: 445-451
[17] Leelank BN, Bansal MP. Effect of selenium supplementation on the glutathione redox system in the kidney of mice after chronic cadmium exposures [J]. J Appl Toxicol, 1996, 17: 81-84
[18] Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple [J]. Free Radic Biol Med, 2001, 30: 1191-1212
[19] Nigam D, Shukla GS, Agarwal AK. Glutathione depletion and oxidative damage in mitochondria following exposure to cadmium in rat liver and kidney [J]. Toxicol Lett, 1999, 106: 151-157
[20] Higuchi Y. Chromosomal DNA fragmentation in apoptosis and necrosis induced by oxidative stress [J]. Biochem Pharmacol, 2003, 66: 1527-1535
[21]孔繁翔.环境生物学[M].北京:高教出版社,2000,68
[22] Fang YZ, Yang S, Wu G. Free radical, antioxidants and nutrition [J]. Nutrition, 2002, 18: 872-879
[23] Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine [M]. Clarendon Press, 1989, Oxford
[24] Januel C, Fay LB, Ruggiero D, et al. Covalent coupling of reduced glutathione with ribose: loss of cosubstrate ability to glutathione peroxidase [J]. Biochim Biophys Acta, 2003, 1620: 125-132
[25] Foster KA, Galeffi F, Gerich FJ, et al. Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration [J]. Prog Neurobiol, 2006, 79: 136-171
[26] Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications [J]. Drug Resist Updat, 2004, 7: 97-110
[27] Ye JL, Mao WP, Wu AL, et al. Cadmium-induced apoptosis in human normal liver L-02 cellsby acting on mitochondria and regulating Ca2+ signals [J]. Environ Toxicol Pharmacol, 2007, 24: 45-54
[28] Pham TND, Marion M, Denizeau F, et al. Cadmium-induced apoptosis in rat hepatocytes does not necessarily involve caspase-dependent pathways [J]. Toxicol in Vitro, 2006, 20: 1331-1342
[29] Turrens JF. Mitochondrial formation of reactive oxygen species [J]. J Physiol, 2003, 552: 335-344
[30] Djavaheri-Mergny M, Wietzerbin J, Besancon F, et al. 2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production [J]. Oncogene, 2003, 22: 2558-2567
[31] Chen F, Vallyathan V, Castranova V, et al. Cell apoptosis induced by carcinogenic metals [J]. Mol Cell Biochem, 2001, 222: 183-188
[32] Alvarez-Barrientos A, O’Connor JE, Nieto Castillo R, et al. Use of flow cytometry and confocal microscopy techniques to investigate early CdCl2-induced nephrotoxicity in vitro [J]. Toxicol in Vitro, 2001, 15: 407-412
[33] Kim MS, Kim BJ, Woo HN, et al. Cadmium induces caspase-mediated cell death: suppression by Bcl-2 [J]. Toxicology, 2000, 145: 27-37
[34] Li M, Kondo T, Zhao QL, et al. Apoptosis induced by cadmium in human lymphoma U937 cells through Ca2+-calpain and caspase-mitochondria-dependent pathways [J]. J Biol Chem, 2000, 275: 39702-39709
[35] Chen L, Yang X, Jiao H, et al. Tea catechins protect against lead-induced ROS formation, mitochondrial dysfunction, and calcium dysregulation in PC12 cells [J]. Chem Res Toxicol, 2003, 16: 1155-1161
[1] Vasiliev JM, Gelfand IM. Surface changes disturbing intracellular homeostasis as a factor inducing cell growth and division [J]. Curr Mod Biol, 1968, 2: 43-55
[2] Missiaen L, Robberecht W, Bosch LV, et al. Abnormal intracellular Ca2+ homeostasis and disease [J]. Cell calcium, 2000, 28: 1-21
[3] Monti DM, Gesualdi NM, Matou?ek J, et al. The cytosolic ribonuclease inhibitor contributes to intracellular redox homeostasis [J]. FEBS Lett, 2007, 581: 930-934
[4] Dearborn DG, Waller RL, Brattin WJ. Intracellular Ca2+ homeostasis in lymphocytes from patients with mucoviscidosis [J].Cell calcium, 1984, 5: 306
[5] Lange Y, Steck TL. The role of intracellular cholesterol transport in cholesterol homeostasis [J]. Trends Cell Biol, 1996, 6: 205-208
[6] Silver IA, Deas J, Erecinska M. Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells [J]. Neuroscience, 1997, 78: 589-601
[7] Wang L, Cao J, Chen D, et al. Role of oxidative stress, apoptosis, and intracellular homeostasis in primary cultures of rat proximal tubular cells exposed to cadmium [J]. Biol Trace Elem Res, 2009, 127: 53-68
[8] Dyatlov VA, Dyatlova OM, Parsons PJ, et al. Lipopolysaccharide and interleukin-6 enhance lead entry into cerebellar neurons: application of a new and sensitive flow cytometric technique to measure intracellular lead and calcium concentrations [J]. Neurotoxicology, 1998, 19: 293-302
[9] Hirpara JL, Clément MV, Pervaiz S. Intracellular acidification triggered by mitochondrial-derived hydrogen peroxide is an effector mechanism for drug-induced apoptosis in tumor cells [J]. J Biol Chem, 2001, 276: 514-521
[10] Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with the Folin phenol reagent [J]. J Biol Chem, 1951, 193: 265-275
[11]厉为良.细胞内pH、钙离子与细胞凋亡[J].国外医学·生理、病理科学与临床分册,1998,18(2):131-134
[12] Voehringer DW. Bcl-2 and glutathione: alterations in cellular redox state that regulate apoptosis sensitivity [J]. Free Radic Biol Med, 1999, 27: 945-950
[13] Moran LK, Guteridge JM, Quinlan GJ. Thiols in cellular redox signaling and control [J]. Curr Med Chem, 2001, 8: 763-772
[14] Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple [J]. Free Radic Biol Med, 2001, 30: 1191-1212
[15] Masella R, Benedetto R, VarìR, et al. Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes [J]. J Nutr Biochem, 2005, 16: 577-586
[16] Lavrentiadou SN, Chan C, Kawcak T, et al. Ceramide-mediated apoptosis in lung epithelial cells is regulated by glutathione [J]. Am J Respir Cell Mol Biol, 2001, 25: 676-684
[17] Nigam D, Shukla GS, Agarwal AK. Glutathione depletion and oxidative damage in mitochondria following exposure to cadmium in rat liver and kidney [J]. Toxicol Lett, 1999, 106: 151-157
[18] Valko M, Morris H, Cronin MTD. Metals, toxicity and oxidative stress [J]. Curr Med Chem, 2005, 12: 1161-1208
[19] Gaido ML, Cidlowski JA. Identification, purification and characterization of a calcium- dependent endonuclease (NUC18) from apoptotic rat thymocytes [J]. J Biol Chem, 1991, 266: 18580-18585
[20] Orrenius S, Mccabe MJ, Nicotera P. Ca2+-dependent mechanisms of cytotoxicity and programmed cell death [J]. Toxicol Lett, 1992, 64: 357-364
[21] McConkey DJ, Orrenius S. The Role of Calcium in the Regulation of Apoptosis [J]. BiochemBiophys Res Commun, 1997, 239: 357-366
[22] Hu Q, Chang J, Tao L, et al. Endoplasmic reticulum mediated necrosis-like apoptosis of HeLa cells induced by Ca2+ oscillation [J]. J Biochem Mol Biol, 2005, 38: 709-716
[23] Rekasi Z, Czompoly T, Schally AV, et al. Antagonist of growth hormone releasing hormone induces apoptosis in LNCaP human prostate cancer cells through a Ca2+-dependent pathway [J]. Proc Natl Acad Sci, 2005, 102: 3435-3440
[24] Foster KA, Galeffi F, Gerich FJ, et al. Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration [J]. Prog Neurobiol, 2006, 79: 136-171
[25] Grammatopoulos TN, Johnson V, Moore SA, et al. Angiotensin type 2 receptor neuroprotection against chemical hypoxia is dependent on the delayed rectifier K+ channel, Na+/Ca2+ exchanger and Na+/K+ ATPase in primary cortical cultures [J]. Neurosci Res, 2004, 50: 299-306
[26] Altschuld RA. Intracellular calcium regulatory system during ischemia and reperfusion [J]. EXS, 1996, 76: 87-97
[27] Doliba NM, Doliba NM, Chang Q, et al. Mitochondrial oxidative phosphorylation in heart from stressed cardiomyopathic hamsters [J]. J Mol Cell Cardiol, 1999, 31: 543-553
[28] Blaustein MP. Sodium ions, calcium ions, blood pressure regulation and hypertension: a reassessment and a hypothesis [J]. Am J Physiol Cell Physiol, 1977, 232: C165-C173
[29] Fujita T, Inoue H, Kitamura T, et al. Senescence marker protein-30 (SMP30) rescues cell death by enhancing plasma membrane Ca2+-pumping activity in HepG2 cells [J]. Biochem Biophys Res Commun, 1998, 250: 374-380
[30] Qin XJ, Li YN, Liang X, et al. The dysfunction of ATPases due to impaired mitochondrial respiration in phosgene-induced pulmonary edema [J]. Biochem Biophys Res Commun, 2008, 367: 150-155
[31] Wang XQ, Xiao AY, Sheline C, et al. Apoptotic insults impair Na+/K+-ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress [J]. J Cell Sci, 2003, 116: 2099-2110
[32]边肖海,霍静,郑曙民.细胞内酸化对宫颈癌Hela细胞凋亡的影响[J].长治医学院学报,2005, 19(2):81-83
[33] Matsuyama S, Llopis J, Deveraux QL, et al. Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis [J]. Nat Cell Biol, 2000, 2: 318-325
[34] Clément MV, Ponton A, Pervaiz S. Apoptosis induced by hydrogen peroxide is mediated by decreased superoxide anion concentration and reduction of intracellular milieu [J]. FEBS Lett, 1998, 440: 13-18