亚慢性镉暴露致五指山猪肾脏损伤研究
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摘要
镉是一种人体非必需且普遍存在于环境中的有毒有害重金属。长期低剂量镉接触会对机体多种器官造成损伤。肾脏是低剂量镉暴露最主要的受损器官。前期很多学者研究了镉对啮齿类大鼠、小鼠所产生的肾脏毒性,但啮齿类动物与人类差异较大,不能很好的反映镉对人体所造成的损伤。随着流行病学研究的深入,人们发现镉导致肾脏毒性的阈值浓度被远远高估。本试验使用与人类亲缘关系较近的五指山猪作为试验动物,研究镉的肾脏毒性,为镉肾脏毒性的预防和监测提供进一步的理论依据。
将20头近交系五指山猪随机分成5组,每组4头,分别饲喂添加0.0、0.5、2.0、8.0、32.0 mg/kg镉的基础饲料对其进行100 d攻毒饲养试验。试验期间,每20 d称重、采血、采尿一次。饲喂结束后屠宰全部试验动物,取其心脏、肝脏、脾脏、肺脏、肾脏、臀股二头肌、大肠、小肠、十二指肠、胃、膀胱、股骨、肋骨、大脑、小脑、耳朵、皮肤、尾巴、舌肌。微波消解-原子吸收法测定血液、尿液及组织器官中的镉含量;采集猪肾脏,测定肾脏指数并制作病理切片;采集肾脏皮质,分光光度计法测定其中SOD、CAT、GSH-Px活力和MDA含量;ELISA法测定尿液中Cd-MT, NAG,β2-MG, RBP,α1-MG;BMD法计算镉性肾损伤阈值浓度。主要结论如下:
1)亚慢性镉暴露条件下,猪体内的镉主要富集在肾脏、肝脏、十二指肠、脾脏,其中,肾脏皮质是镉富集的最主要部位;
2)低于32.0 mg/kg的亚慢性镉暴露不能抑制五指山猪的生长,也不会对五指山猪肾脏造成脂质过氧化损伤。高于0.5 mg/kg的亚慢性镉暴露可导致肾小管上皮细胞肿胀,肾小管管腔狭窄,肾脏损伤程度随着镉暴露剂量的增加而加剧;
3)血镉含量与镉暴露剂量呈剂量-效应关系,是反映机体近期镉接触的有效指标;尿镉含量与镉暴露剂量及镉性肾损伤效应标志物含量呈显著正相关,尿镉能较好地反应镉接触情况及肾脏损伤程度,是镉性肾损伤有效的暴露标志物。
4)亚慢性镉暴露可导致肾脏功能紊乱,出现低分子蛋白尿。UCd-MT, UNAG, Uβ2-MG, URBP作为镉性肾损伤效应标志物时存在较好的一致性,通过BMD法计算所得各标志物异常时的镉暴露剂量BMDL值分别为1.00、0.88、3.08、0.67mg/kg。URBP是镉性肾损伤早期检测较敏感效应标志物。
5)亚慢性镉暴露导致肾脏损伤的阈值浓度为0.67 mg/kg,以此为参考点得出的健康指导值ADI为0.2μg/kg·BW。
Cadmium is a non-essential and toxic heavy metal for human, ubiquitous in the environment. Kidney is the critical target organ for subchronic exposure to cadmium. Many scholars studied the kidney toxicity of the cadmium in rodents such as rats and mice previously. However, there are great differences between rodents and human in size and genes, so those experimental results couldn’t well reflect the degree of possible injuries of cadmium to human body. In addition, many recent epidemiological studies showed that the critical concentrations of cadmium toxicity had been overestimated. This research was to study the kidney toxicity of cadmium with pigs as experimental animal, it could provide further theoretical data for prevention and monitoring of cadmium renal toxicity for their genetic relationship is closer to human.
20 inbred strain pigs were randomly divided into five groups, each for four, and they were fed for 100 days with normal feeds and feeds added with the cadmium with the content of 0.5、2.0、8.0、32.0 mg/kg, respectively. The body weight was measured, the urine and blood was collected every 20 days. After continuously feeding for 100 days, the pigs were killed and their hearts, livers, spleens, lungs, kidneys, muscle, duodenums, large intestines, small intestines, stomachs, bladders, femurs, ribs, brains, cerebellas, ears, derma, tails and tongues were collected to determine the cadmium content by microwave digestion-AAS. Kidney was collected to determine its kidney index, and observe its pathological changes with pathological sections by H·E staining method. Kidney cortical was collected to determine the activity of SOD, CAT, GSH-Px and content of MDA by spectrophotometer. Uβ2-MG, Uα1-MG, UNAG, Cd-MT and URBP were measured by means of enzyme linked immunoabsorbent assay (ELISA). Threshold dose of kidney damage was calculated by benchmark dose method. The main conclusions were as follows:
1) Under the conditions of subchronic cadmium exposure, cadmium in pigs mainly distributed in kidney, liver, duodenum, spleen. Kidney cortex is the most important part for cadmium accumulation;
2) Cadmium exposure less than 32.0 mg/kg could not significantly inhibit the growth of Wuzhishan pigs, or cause lipid peroxidation damage. Cadmium exposure higher than 0.5 mg/kg could cause renal tubular epithelial cell swelling, and tubular stenosis. The degree of damage of kidney pathological damage aggravate with the increasment of cadmium exposure dose;
3) Blood cadmium levels showed a dose-response relationship with cadmium exposure, which suggests that blood cadmium levels is effective indicator for recent cadmium exposure. Urine cadmium concentration can reflect both the cadmium exposure dose and the kidney dysfunction. Urine cadmium concentration is a reliable biomarker of cadmium exposure.
4) Subchronic cadmium exposure gave rise to renal tubular dysfunction, which was reflected by low-molecular-weight proteinuria. There were good consistencies when UCd-MT, UNAG, Uβ2-MG, URBP were used as effect biomarkers of cadmium induced renal damage. The estimated BMDL were 1.00, 0.88, 3.08, 0.67 mg Cd/kg for UCd-MT, UNAG, Uβ2-MG and URBP, respectively. URBP was a sensitive effect biomarker for early renal damage.
5) The threshold dose of subchronic cadmium exposure induce renal damage was 0.67 mg/kg, and when it was used as a reference point for the health guideline value derived ADI was 0.2μg/kg·BW.
将20头近交系五指山猪随机分成5组,每组4头,分别饲喂添加0.0、0.5、2.0、8.0、32.0 mg/kg镉的基础饲料对其进行100 d攻毒饲养试验。试验期间,每20 d称重、采血、采尿一次。饲喂结束后屠宰全部试验动物,取其心脏、肝脏、脾脏、肺脏、肾脏、臀股二头肌、大肠、小肠、十二指肠、胃、膀胱、股骨、肋骨、大脑、小脑、耳朵、皮肤、尾巴、舌肌。微波消解-原子吸收法测定血液、尿液及组织器官中的镉含量;采集猪肾脏,测定肾脏指数并制作病理切片;采集肾脏皮质,分光光度计法测定其中SOD、CAT、GSH-Px活力和MDA含量;ELISA法测定尿液中Cd-MT, NAG,β2-MG, RBP,α1-MG;BMD法计算镉性肾损伤阈值浓度。主要结论如下:
1)亚慢性镉暴露条件下,猪体内的镉主要富集在肾脏、肝脏、十二指肠、脾脏,其中,肾脏皮质是镉富集的最主要部位;
2)低于32.0 mg/kg的亚慢性镉暴露不能抑制五指山猪的生长,也不会对五指山猪肾脏造成脂质过氧化损伤。高于0.5 mg/kg的亚慢性镉暴露可导致肾小管上皮细胞肿胀,肾小管管腔狭窄,肾脏损伤程度随着镉暴露剂量的增加而加剧;
3)血镉含量与镉暴露剂量呈剂量-效应关系,是反映机体近期镉接触的有效指标;尿镉含量与镉暴露剂量及镉性肾损伤效应标志物含量呈显著正相关,尿镉能较好地反应镉接触情况及肾脏损伤程度,是镉性肾损伤有效的暴露标志物。
4)亚慢性镉暴露可导致肾脏功能紊乱,出现低分子蛋白尿。UCd-MT, UNAG, Uβ2-MG, URBP作为镉性肾损伤效应标志物时存在较好的一致性,通过BMD法计算所得各标志物异常时的镉暴露剂量BMDL值分别为1.00、0.88、3.08、0.67mg/kg。URBP是镉性肾损伤早期检测较敏感效应标志物。
5)亚慢性镉暴露导致肾脏损伤的阈值浓度为0.67 mg/kg,以此为参考点得出的健康指导值ADI为0.2μg/kg·BW。
Cadmium is a non-essential and toxic heavy metal for human, ubiquitous in the environment. Kidney is the critical target organ for subchronic exposure to cadmium. Many scholars studied the kidney toxicity of the cadmium in rodents such as rats and mice previously. However, there are great differences between rodents and human in size and genes, so those experimental results couldn’t well reflect the degree of possible injuries of cadmium to human body. In addition, many recent epidemiological studies showed that the critical concentrations of cadmium toxicity had been overestimated. This research was to study the kidney toxicity of cadmium with pigs as experimental animal, it could provide further theoretical data for prevention and monitoring of cadmium renal toxicity for their genetic relationship is closer to human.
20 inbred strain pigs were randomly divided into five groups, each for four, and they were fed for 100 days with normal feeds and feeds added with the cadmium with the content of 0.5、2.0、8.0、32.0 mg/kg, respectively. The body weight was measured, the urine and blood was collected every 20 days. After continuously feeding for 100 days, the pigs were killed and their hearts, livers, spleens, lungs, kidneys, muscle, duodenums, large intestines, small intestines, stomachs, bladders, femurs, ribs, brains, cerebellas, ears, derma, tails and tongues were collected to determine the cadmium content by microwave digestion-AAS. Kidney was collected to determine its kidney index, and observe its pathological changes with pathological sections by H·E staining method. Kidney cortical was collected to determine the activity of SOD, CAT, GSH-Px and content of MDA by spectrophotometer. Uβ2-MG, Uα1-MG, UNAG, Cd-MT and URBP were measured by means of enzyme linked immunoabsorbent assay (ELISA). Threshold dose of kidney damage was calculated by benchmark dose method. The main conclusions were as follows:
1) Under the conditions of subchronic cadmium exposure, cadmium in pigs mainly distributed in kidney, liver, duodenum, spleen. Kidney cortex is the most important part for cadmium accumulation;
2) Cadmium exposure less than 32.0 mg/kg could not significantly inhibit the growth of Wuzhishan pigs, or cause lipid peroxidation damage. Cadmium exposure higher than 0.5 mg/kg could cause renal tubular epithelial cell swelling, and tubular stenosis. The degree of damage of kidney pathological damage aggravate with the increasment of cadmium exposure dose;
3) Blood cadmium levels showed a dose-response relationship with cadmium exposure, which suggests that blood cadmium levels is effective indicator for recent cadmium exposure. Urine cadmium concentration can reflect both the cadmium exposure dose and the kidney dysfunction. Urine cadmium concentration is a reliable biomarker of cadmium exposure.
4) Subchronic cadmium exposure gave rise to renal tubular dysfunction, which was reflected by low-molecular-weight proteinuria. There were good consistencies when UCd-MT, UNAG, Uβ2-MG, URBP were used as effect biomarkers of cadmium induced renal damage. The estimated BMDL were 1.00, 0.88, 3.08, 0.67 mg Cd/kg for UCd-MT, UNAG, Uβ2-MG and URBP, respectively. URBP was a sensitive effect biomarker for early renal damage.
5) The threshold dose of subchronic cadmium exposure induce renal damage was 0.67 mg/kg, and when it was used as a reference point for the health guideline value derived ADI was 0.2μg/kg·BW.
引文
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Roels H, Lauwerys R, Materne D. 1994. Study on cadmium proteinuria. Glomerular dysfunction: an early sign of renal impairment. Proceedings, Recent Advances in the Assessment of the Health Effects of Environmental Pollution, 2: 631-641.
Satarug S, Baker JR, Urbenjapol S, Haswell-Elkins M, Reily PE, Williams DJ, Moore MR. 2003. A global perspective on cadmium pollution and toxicity in non-occupationally exposed population. Toxicol Lett, 137: 65-83.
Savolainen H. 1995. Cadmium-Associated renal disease. Renal Failure, 17(5): 485.
Shaikh Z. 1982. Urinary metallothiothionein: a specific test for monitoring occupational cadmium exposure. Vet Hum Toxic, 24: 276.
Shaikh ZA, Ellis KJ, Subramanian KS, Greenberg A. 1990. Biological monitoring for occupational cadmium exposure: the urinary metallotheionein. Toxicology, 63: 53-62.
Shaikh ZA, Smith LM. 1984. Biological indicators of cadmium exposure and toxicity. Cellular and Molecular Life Sciences, 40: 36-43.
Shaikh ZA, Vu TT, Zaman K. 1999. Oxidative stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants. Toxicol Appl Pharmacol, 154: 256-263.
Shiroishi K. 1997. Urine analysis for detection of cadmium-induced renal changes with special reference toβ2-microglobulin. Envir Res, 13: 407-424.
Sidhu M, Prasad R, Gill KD. 1997. Alterations in isoforms of glutathione S-transferase in liver and kidney of cadmium exposed rhesus monkeys: purification and kinetic characterization. Mol Cell Biochem, 166(2): 55-63.
Skoczyn A, Joanna W, Andrzejak R. 2001. Lead-cadmium interaction effect on the responsiveness of ratmesenteric vessels to norepinephrine and angiotensinⅡ. Toxicology, 162: 157-170.
Satarug S, Baker JR, Urbenjapol S, Haswell-Elkins M, Reily EB, Eilliams DJ, Moore MR. 2003. A global perspective on cadmium pollution and toxicity in non-occupationally exposed population. Toxicology Letters, 137: 65-83.
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Staessen JA, Lauwerys RR, Geert I, Roels HA, Vyncke G, Amery A. 1994. Renal function and historical environmental cadmium pollution from zinc smelters. Lancet, 343: 1523-1527.
Sidney S, Debasis B, Ezdihar H, Manashi B. 2000. Oxidative mechanisms in the toxicity of chromium and cadmium ions. Environ Pathol Toxicol Oncol, 19(3): 201-213
Sugihira N, Sagai M, Suzuki KT. 1987. Renal damage induced by cadmium-metallothionein: effects on biochemical indicators. Toxicology, 44(1): 1-11.
Suwazono Y, Uetani M, ?kesson A, Vahter M. 2010. Recent applications of benchmark dose method for estimation of reference cadmium exposure for renal effects in man. Toxicology Letters, 198, 40-43.
Takenaka S, Oldiges H, Konig H. 1983. Carcinogenicity of cadmium chloride aerosols in wistar rats. J Natl Cancer Inst, 70: 367-373.
Thijssen S, Maringwa J, Faes C, Lambrichts I, Kerhove EV. 2007. Chronic exposure of mice to environmentally relavant, low doses of cadmium leads to early renal damage, not predicted by blood or urine cadmium levels. Toxicology, 229, 145-156.
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Trzcinka-Ochocka M, Jakubowski M, Razniewska G, Halatek T, Gazewski A. 2004. The effect of environmental cadmium exposure on kidney function: the possible influence of age. Environ Res, 95: 143-150.
Tsuchiya K, Iwao S. 1999. Increased urinaryβ2-microglobulin in cadmium exposure: dose-effect relationship and biological significance ofβ2-microglobulin. Envir Hlth Perspect, 28: 147-153.
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Verschoor M, Herber R, Van Hennen J, Wibowo A, Zielhuis R. 1999. Renal function of workers with low-level cadmium exposure. Scand J Work Enviro Health, 13: 232-238.
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Yamagami T, Suna T, Fukui Y, Ohashi F, Takada S, Sakurai H, Aoshima K, Ikeda M. 2008. Biological variations in cadmium, Alpha 1-microglobulin, Beta 2-microglobulin and N-acetyl-beta-D- glucosaminidase in adult women in a non-polluted area. Int Arch Occup Environ Health, 81: 263-271.
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Roels H, Bernard A M, Cardenas A, Buchet JP, Lauwerys RR, Hotter G, Ramis I, Mutti A, Franchini I, Bundschuh I. 1993. Markers of early renal changes induced by industrial pollutants.ⅢApplication to workers exposed to cadmium. British Journal of Medicine, 50: 37-38.
Roels H, Lauwerys R, Materne D. 1994. Study on cadmium proteinuria. Glomerular dysfunction: an early sign of renal impairment. Proceedings, Recent Advances in the Assessment of the Health Effects of Environmental Pollution, 2: 631-641.
Satarug S, Baker JR, Urbenjapol S, Haswell-Elkins M, Reily PE, Williams DJ, Moore MR. 2003. A global perspective on cadmium pollution and toxicity in non-occupationally exposed population. Toxicol Lett, 137: 65-83.
Savolainen H. 1995. Cadmium-Associated renal disease. Renal Failure, 17(5): 485.
Shaikh Z. 1982. Urinary metallothiothionein: a specific test for monitoring occupational cadmium exposure. Vet Hum Toxic, 24: 276.
Shaikh ZA, Ellis KJ, Subramanian KS, Greenberg A. 1990. Biological monitoring for occupational cadmium exposure: the urinary metallotheionein. Toxicology, 63: 53-62.
Shaikh ZA, Smith LM. 1984. Biological indicators of cadmium exposure and toxicity. Cellular and Molecular Life Sciences, 40: 36-43.
Shaikh ZA, Vu TT, Zaman K. 1999. Oxidative stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants. Toxicol Appl Pharmacol, 154: 256-263.
Shiroishi K. 1997. Urine analysis for detection of cadmium-induced renal changes with special reference toβ2-microglobulin. Envir Res, 13: 407-424.
Sidhu M, Prasad R, Gill KD. 1997. Alterations in isoforms of glutathione S-transferase in liver and kidney of cadmium exposed rhesus monkeys: purification and kinetic characterization. Mol Cell Biochem, 166(2): 55-63.
Skoczyn A, Joanna W, Andrzejak R. 2001. Lead-cadmium interaction effect on the responsiveness of ratmesenteric vessels to norepinephrine and angiotensinⅡ. Toxicology, 162: 157-170.
Satarug S, Baker JR, Urbenjapol S, Haswell-Elkins M, Reily EB, Eilliams DJ, Moore MR. 2003. A global perspective on cadmium pollution and toxicity in non-occupationally exposed population. Toxicology Letters, 137: 65-83.
Satarug S, Nishijo M, Ujjin P, Vanavanitkun Y, Baker JR, Moore MR. 2004. Effects of chronic exposure to low-level cadmium on renal tubular function and CYP2A6-mediated coumarin metabolism in healthy human subjects. Toxicology Letters, 148: 187-197.
Staessen JA, Lauwerys RR, Geert I, Roels HA, Vyncke G, Amery A. 1994. Renal function and historical environmental cadmium pollution from zinc smelters. Lancet, 343: 1523-1527.
Sidney S, Debasis B, Ezdihar H, Manashi B. 2000. Oxidative mechanisms in the toxicity of chromium and cadmium ions. Environ Pathol Toxicol Oncol, 19(3): 201-213
Sugihira N, Sagai M, Suzuki KT. 1987. Renal damage induced by cadmium-metallothionein: effects on biochemical indicators. Toxicology, 44(1): 1-11.
Suwazono Y, Uetani M, ?kesson A, Vahter M. 2010. Recent applications of benchmark dose method for estimation of reference cadmium exposure for renal effects in man. Toxicology Letters, 198, 40-43.
Takenaka S, Oldiges H, Konig H. 1983. Carcinogenicity of cadmium chloride aerosols in wistar rats. J Natl Cancer Inst, 70: 367-373.
Thijssen S, Maringwa J, Faes C, Lambrichts I, Kerhove EV. 2007. Chronic exposure of mice to environmentally relavant, low doses of cadmium leads to early renal damage, not predicted by blood or urine cadmium levels. Toxicology, 229, 145-156.
Tohyama C. 1981. Metallothionein excretion in urine upon cadmium exposure: its relationship with liver and kidney cadmium. Toxicology, 22: 181-191.
Trzcinka-Ochocka M, Jakubowski M, Razniewska G, Halatek T, Gazewski A. 2004. The effect of environmental cadmium exposure on kidney function: the possible influence of age. Environ Res, 95: 143-150.
Tsuchiya K, Iwao S. 1999. Increased urinaryβ2-microglobulin in cadmium exposure: dose-effect relationship and biological significance ofβ2-microglobulin. Envir Hlth Perspect, 28: 147-153.
Uchida M, Teranishi H, Aoshima K, Katoh T, Kasuya M, Inadera H. 2007. Elevated urinary levels of vitamin D-binding protein in the inhabitants of a cadmium pollute area, Jinzu River basin, Japan. Tohoku J Exp Med, 211(3): 269-274.
Verschoor M, Herber R, Van Hennen J, Wibowo A, Zielhuis R. 1999. Renal function of workers with low-level cadmium exposure. Scand J Work Enviro Health, 13: 232-238.
Weise M, Prufer D, Jaques G. 1981. Beta2-microglobulin and other proteins as parameters for tubular function. Contrib Nephrol, 24: 88~98.
Yamagami T, Suna T, Fukui Y, Ohashi F, Takada S, Sakurai H, Aoshima K, Ikeda M. 2008. Biological variations in cadmium, Alpha 1-microglobulin, Beta 2-microglobulin and N-acetyl-beta-D- glucosaminidase in adult women in a non-polluted area. Int Arch Occup Environ Health, 81: 263-271.
Zahir A. 1984. Urinary metallothionein as indicator of cadmium body burden and of cadmium-induced nephrotoxity. Envir Health Kerspeltives, 54: 171-174.
Zhou T. 1998. Cadmium induced apoptosis and related changes in expression of p53, c-jun and MT-Igenes in testes and ventral prostate of rats. Licentiate Thesis in Medical Science in Umea University. Umea. Sweden, 24: 123-128.