有机氯农药内分泌干扰效应研究
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摘要
DDT和BHC等有机氯农药(OCPs)曾作为杀虫剂在世界各国被广泛而大量生产与使用,但由于其具有难降解、高残留、脂溶性,可通过食物链生物富集及放大等特征,对环境生态、动植物与人类产生了极大的危害而已被禁用二十多年。大量研究表明,DDT和BHC及其代谢产物在当前环境和生物体内仍可检出,具有地域性差异,在某些局部地区环境和人体内(特别是脂肪组织)的检出率和检出水平还比较高。近年研究提示,OCPs作为持久性有机污染物(POPs)具有内分泌干扰作用,可能与男性精子数减少、精子活力下降、男性不育症患者增加、睾丸癌和前列腺癌发病率增高等,以及女性性早熟、子宫内膜异位症、子宫癌、卵巢癌和乳腺癌等发生率增加有关。因此,DDT和BHC等有机氯农药在体内的残留对人体健康的危害,特别是对生殖系统的危害日益受到人们的广泛关注,其生殖与发育毒性成为目前的研究热点。本课题人群研究部分特选择1985年女性居民脂肪样品调查DDT残留水平为全国之冠的湖北省天门市(曾经的棉产区)作为调查点,检测当地人群中有机氯农药的残留水平,分组研究其对体内相关生殖激素(FSH、LH、E2和P)和基因及蛋白(α-ER、β-EP和GnRH)表达水平的影响,结合整体动物染毒实验,以期探索有机氯农药的内分泌干扰效应。
第一部分p,p'-DDE和B-BHC联合作用对
孕小鼠生殖及其胎仔发育的影响
目的:研究p,p'-DDE和B-BHC联合作用对孕小鼠生殖及其胎仔发育的影响。
方法:以p,p'-DDE和B-BHC作为受试物,用不同浓度(p,p'-DDE和β-BHC分别为10 mg/kg/次+10 mg/kg/次;5 mg/kg/次+5 mg/kg/次;1 mg/kg/次+1 mg/kg/次;对照组灌胃同体积大豆油),于昆明种小鼠(清洁级)妊娠第12～14d期间每天给动物染毒1次。从动物妊娠0天至第18天(动物被处死之日),每天称量小鼠体重,观察其生长变化。于妊娠第18d断头处死孕小鼠,收集血液37℃分离血清,-20℃保存,用于孕鼠血清雌二醇(E2)和孕酮(P)测定(磁性分离酶联免疫法)。常规剖检母鼠,取心、肝、肾、脾、垂体、卵巢、子宫、胎盘等称重,计算各脏器系数和子宫腔内液重;计数卵巢中的黄体,检查子宫着床数,记录活胎数、死胎、吸收胎数,外观畸形胎数;记录每窝胎仔数,测定胎仔的体重、身长、尾长、腹围、肛殖距(AD)、性别比。采集胎盘组织样本,于无菌生理盐水中漂洗后,迅速置于液氮中速冻,然后转入-80℃冰箱保存,用于胎盘组织中α-ER、GnRH和β-EP mRNA表达水平测定(RT-PCR法)。用Spearman方法分析胎盘组织基因表达水平与血中激素含量之间、胎盘组织基因表达水平与胎仔肛殖距及雌雄比之间、血中激素含量与胎仔肛殖距及雌雄比之间的相关关系。结果:①对母鼠的影响:随着受试物剂量的加大,孕小鼠体重和增重下降,孕鼠肝脏重量和脏体比增加,p,p'-DDE和B-BHC联合染毒可使孕鼠子宫增重,脏/体比值上升,子宫腔内液增多,着床数减少,血清E2和P的含量增高(P<0.05)。②对胎仔发育的影响:p,p'-DDE和B-BHC联合染毒,可使活胎数减少,死胎、吸收胎、畸形胎仔数增加,胎仔肛殖距和雌雄比增加,组间差异比较有显著性(P<0.05),胎盘组织α-ER和GnRH mRNA表达上调,而β-EP表达下调,组间差异比较有显著性(P<0.05)。③相关性分析表明,血清E2、P的含量与胎盘组织中α-ER、GnRH呈正相关,而与β-EP mRNA的表达水平呈负相关。胎仔肛殖距、雌雄比与胎盘组织中α-ER、GnRH呈正相关,而与β-EP mRNA的表达水平呈负相关。孕鼠血清P含量与胎仔雌雄比之间表现为正相关关系(P<0.05)。
结论:p,p'-DDE和B-BHC联合作用在雌(女)性表现为类雌激素效应,可干扰生殖过程,导致发育障碍,可致后代雄性雌性化。
第二部分有机氯农药污染区产妇静脉血清中DDT和BHC残留水平测定
目的:测定有机氯农药污染区产妇静脉血清中DDT和BHC残留水平,以了解目前人群的农药残留情况。
方法:抽取2004年1月1日至4月30日在湖北省天门市妇幼保健院住院分娩的71例产妇的静脉血,应用气相色谱法(GC)检测血清中DDT和BHC的8种异构体的残留水平。
结果:①该测定方法的平均加标回收率和相对标准偏差分别为87.3%～94.6%,1.8%～6.8%;最低检测限为0.0005μg/L。②8种异构体的检出率为7.04%～47.89%,检出范围为0.0～147.7μg/L;平均检出量以γ-BHC(11.88±27.65μg/L)和o,p'-DDT(8.47±19.33μg/L)为最高。③本次共检测71例产妇血清,总有机氯检出率为87.32%(62/71),检出水平为37.48151.24μg/L(0.0～248.1μg/L)。其中9例均未检出目标成分作为对照组(9/71),26例总有机氯含量在2.1～9.7μg/L之间作为低残留组(26/71),17例总有机氯含量在12.6～39.6μg/L之间作为中残留组(17/71),19例总有机氯含量在54.5～248.1之间作为高残留组(19/71),以便对相关生物学效应指标进行对比分析。
结论:DDT和BHC等有机氯农药在我国目前某些人群中残留水平还比较高,有些产品(如林丹和三氯杀螨醇)可能仍在局部地区非法使用,继续监测有机氯农药在环境和人体内的残留很有必要。
第三部分抽样人群流行病学调查
目的:为了解有机氯农药的生殖和发育毒性作用,分析其内分泌干扰效应的影响因素,排除混杂因素的干扰,增加组间各检测指标的可比性。方法:采用问卷调查的方法,对被抽样的孕妇于住院分娩后2天内由经过培训的调查员按照《孕(产)妇健康情况调查表》的要求逐项询问和检查。
结果:①问卷调查的合格率为100%(71/71)。②孕妇体内有机氯农药残留水平的增加可导致既往不良妊娠结局次数的上升(P<0.05)。③孕妇体内有机氯农药残留水平可能与婴儿平均出生体重的改变有关(P<0.05)。④体内不同有机氯农药残留水平的孕妇及其配偶在年龄、职业分布、接触有害物理和化学因素、孕期用药、吸烟和饮酒、孕期营养和睡眠、家族史等方面未见显著性差异(P>0.05)。
结论:通过人群流行病学调查,增强了其他实验结果解释的可靠性。同时说明体内有机氯农药残留可能与生殖及发育障碍有关。
第四部分产妇体内有机氯农药残留对血中4种生殖激素的影响
目的:研究产妇体内有机氯农药残留对孕妇静脉血和脐带血中FSH、LH、E2和
P水平的影响。
方法:采集2004年1月1日至4月30日在湖北省天门市妇幼保健院住院分娩的71例产妇的静脉血和脐带血,采用磁性分离酶联免疫法测定产妇静脉血和脐带血FSH、LH、E2和P的含量。用Spearman法分析血中总有机氯残留水平与产妇血及脐带血中4种生殖激素之间、产妇血与脐带血中FSH、LH、E2和P的含量之间的相关关系。
结果:①随着产妇体内有机氯农药残留水平的升高,产妇静脉血FSH、E2、P和脐带血FSH、LH、E2含量呈上升趋势(产妇血:FSH从未检出组0.83 mIU/ml增加到高残留组2.27 mIU/ml,P从264.04 ng/ml增加到327.22 ng/ml,E2从41.80ng/ml增加到中残留组54.99 ng/ml;脐带血:FSH从未检出组1.41 mIU/ml上升到高残留组2.91 mIU/ml,LH从0.60 mIU/ml上升到2.07 mIU/ml,E2从12.53ng/ml上升到中残留组24.03 ng/ml),而静脉血LH和脐带血中P呈下降趋势(产妇血LH从未检出组1.47 mIU/ml下降到高残留组0.63 mIU/ml,脐带血P从804.47 ng/ml下降到604.70 ng/ml),均有剂量依赖性关系(P<0.05)。②相关性分析表明,高残留组农药残留水平与产妇血E2、P呈负相关(r=-0.5158,P=0.0238;r=-0.6491,P=0.0026)。产妇血FSH与脐带血FSH、LH、E2,产妇血LH与脐带血P,产妇血P与脐带血LH、E2之间呈正相关;而产妇血FSH与脐带血P,产妇血LH与脐带血FSH、LH,产妇血E2与脐带血FSH,产妇血P与脐带血P之间呈负相关(P<0.05)。
结论:人体内有机氯农药残留可显著干扰血中生殖激素水平。
第五部分产妇体内有机氯农药残留对胎盘和脐带组织
α-ER、β-EP、GnRH mRNA表达水平的影响
目的:研究产妇体内有机氯农药残留对胎盘和脐带组织α-ER、β-EP、GnRHmRNA表达水平的影响。
方法:采集2004年1月1日至4月30日在湖北省天门市妇幼保健院住院分娩的71例产妇的胎盘和脐带组织样,采用RT-PCR检测胎盘和脐带组织α-ER、β-EP、GnRH mRNA的表达水平,用Spearman法分析血中农药残留含量与组织基因表达水平、血中激素含量与组织基因表达水平、以及胎盘和脐带组织基因表达水平之间的相关关系。
结果:①体内有机氯农药残留可诱导胎盘与脐带组织α-ER和β-EP基因表达上调(胎盘组织:α-ER mRNA表达从未检出组1.62递增到高残留组2.42,β-EP从0.36递增到0.68;脐带组织:α-ER从1.49上升到2.14,β-EP从0.24上升到0.46),有剂量依赖性关系(P<0.05)。胎盘GnRH mRNA的表达虽也有随体内残留水平的升高而加强的趋势,但组间差异无统计学意义(P>0.05)。在脐带组织未检测到GnRH mRNA的表达。②相关性分析表明,低残留组产妇静脉血中总有机氯残留水平与胎盘及脐带组织α-ER mRNA的表达水平呈负相关(r=-0.4874,P=0.0116;r:-0.4815,P=0.0127),而与胎盘组织GnRH mRNA的表达呈正相关(r=0.4870,P=0.0116)。胎盘与脐带组织α-ER和β-EP相互之间呈正相关,而胎盘GnRH与脐带α-ER、β-EP呈负相关。胎盘组织α-ER与脐带血E2,胎盘组织β-EP与产妇血FSH及脐带血FSH、E2,脐带组织α-ER与脐带血E2,脐带组织β-EP与产妇血FSH、P及脐带血E2之间呈正相关;而脐带血P与胎盘和脐带组织α-ER、β-EP之间呈负相关(P<0.05)。
结论:产妇体内有机氯农药残留可干扰胎盘和脐带组织某些环境应答基因的表达。
第六部分产妇体内有机氯农药残留对胎盘组织
α-ER、β-EP、GnRH蛋白表达水平的影响
目的:探讨产妇体内有机氯农药残留对胎盘组织α-ER、β-EP、GnRH蛋白表达水平的影响。
方法:采集2004年1月1日至4月30日在湖北省天门市妇幼保健院住院分娩的71例产妇的胎盘组织样,运用SABC免疫组化方法检测胎盘组织α-ER、β-EP、GnRH蛋白的表达水平。用Spearman法分析血中农药残留含量与组织蛋白表达水平、组织蛋白与基因表达水平、组织蛋白表达水平与血中激素含量之间的相关关系。
结果:①产妇体内有机氯农药残留可诱导胎盘组织α-ER、β-EP、GnRH蛋白的表达(α-ER从未检出组128.80递增到高残留组149.70,β-EP从102.98递增到121.17,GnRH从127.75递增到153.95),但只有后者(GnRH)组间差异有显著性(P<0.05)。②相关性分析表明,低残留组血中T-OCPs(总有机氯)残留水平与胎盘组织中α-ER蛋白的表达呈负相关(r=-0.5326,P=0.0124);而与GnRH蛋白的表达呈正相关(r=0.6210,P=0.01 03)。胎盘组织α-ER、β-EP
mRNA与胎盘组织α-ER、β-EP蛋白,胎盘GnRH蛋白与GnRH mRNA表达水平之间呈正相关;而胎盘GnRH蛋白与胎盘α-ER、β-EP mRNA,胎盘GnRH
mRNA与胎盘α-ER、β-EP蛋白呈负相关。胎盘组织α-ER蛋白表达水平与产妇血P及脐带血E2含量,胎盘β-EP蛋白与产妇血FSH、脐带血FSH、E2含量之间呈正相关;而脐带血P与胎盘α-ER、β-EP蛋白之间呈负相关(P<0.05)。
结论:产妇体内有机氯农药残留可干扰胎盘组织α-ER、β-EP、GnRH蛋白的表达。
综上所述,DDT和BHC及其代谢产物在本研究目标人群中的残留水平还比较高,且o,p-DDT与γ-BHC是产妇血中最主要的残留成分,推测某些有机氯农药(如林丹和三氯杀螨醇)可能仍在该地区使用。p,p'-DDE和B-BHC联合作用在雌(女)性表现为类雌激素效应,可致后代雄性雌性化。产妇体内有机氯农药残留可干扰血中生殖激素水平,诱导胎盘和脐带组织某些环境应答基因(如α-ER、β-EP、GnRH)的表达,干扰生殖过程,导致发育障碍。但具体机制有待于进一步研究。
本研究的创新点有:①将动物实验与人群研究有机地结合,并通过流行病学调查,排除了影响有机氯农药致内分泌干扰的混杂因素,增强了实验结果的可比性。研究表明,体内有机氯农药的残留可干扰血中生殖激素水平,导致产妇静脉血FSH、E2、P和脐带血FSH、LH、E2含量增高,而静脉血LH和脐带血中P水平降低;可诱导人胎盘和脐带组织α-ER、β-EP及GnRH基因与蛋白的表达。②率先进行p,p'-DDE和B-BHC联合染毒孕期小鼠的研究,观察其生殖和发育毒性。结果显示,p,p'-DDE和B-BHC联合作用可使孕鼠子宫增重,腔内液增多,着床数减少,血中E2和P含量上升,诱导胎盘组织α-ER与GnRH基因的表达,而抑制β-EP基因的表达;可使活胎数减少,而死胎、吸收胎、畸形胎仔数增多;导致胎仔肛殖距与雌雄比上升。
Organochlorine pesticides(OCPs) such as DDT and BHC had ever used extensively and massively in worldwide. They have been banned to produce and use for more than twenty years, however, because of their hard degradation, high residue, iposolubility, and their biological amplification through food chain, which had made great harms to environmental ecosystem, animals, plants and human being. A great number of studies have indicated that DDT, BHC and their metabolites can still be detected in various environmental and biological samples. Their detected percents and concentrations were high in certain environments and population, especially in fatty tissue. Recent studies suggested that OCPs, as a type of persistent organic pollutants (POPs), possess endocrine dirupting effects. They may be concerned with decrease of sperm count and vitality, and increase of incidences of male infertility, carcinoma of testis and prostate. They may also be related to increase of incidences of prematuration, endometriosis, carcinoma of uterus, ovary and mammary gland. For these reasons, hazards of OCPs to human, especially to genital system, have caused great attention, and their reproductive and developmental toxicity have become a focus in recent studies. We selected the people as our studied objects who came from Tianmen city in Hubei province, because their average concentration of DDT residues in the fat samples of female residents was the highest in China in 1985. In the present study we determined residual levels of OCPs in sera of the local population, concentrations of FSH、LH、E_2 and P in blood, and expressional abundance of the genes and proteins such as α-ER、β-EP and GnRH in the samples. Population survey and animal experiment were integrated to explore endocrine dirupting effects of OCPs.
Part Ⅰ Effects of p,p'-DDE and beta-BHC on reproduction
and development in pregnant mice and their foetus Objective: To explore effects of reproduction and development in pregnant mice and their foetus co-incubated by p,p'-DDE and beta-BHC.
Methods: The pregnant mice were randomly divided into four groups, which were provided with plant oil, 1 mg/kg + 1 mg/kg, 5 mg/kg + 5 mg/kg, 10 mg/kg +10 mg/kg of p,p'-DDE and beta-BHC, respectively, from the 12th day to 14th after pregnancy and were treated one times per day. From P0 to P18, the pregnant mice were observed and weightened per day. When the animals were killed (P18), their blood was collected to determine concentration of estradiol and progestone by Immunoenzymetric assay (magnetic solid phase), and their placentae were collected to detect expressional abundance of α-estrogen receptor(α-ER), β-endorphin (β-EP) and gonadotropin releasing hormone (GnRH) mRNA by RT-PCR. The organ coefficients of heart, liver, kidney, spleen, pituitary, ovary, uterus, intraluminal fluid and placenta were determined, respectively. Corepus luteums, nidations, live foetus, dead foetus, absorbed foetus and featus deformities were counted, respectively. Weight, body length, tail length, abdominal circumference, anogenital distance (AD) and ratio of female to male (F/M) in the foetus were determined, respectively. The Spearman method was employed to analyse correlativity between expressional abundances of the genes and concentrations of the hormones, between AD and ratio of F/M and genes and hormones, respectively.
Results: a) Effects on the pregnant mice: The pregnant mice were poisoned by p,p'-DDE and beta-BHC, which have decreased their weights and gained weights, increased organ coefficient of liver, uterus and intramminal fluid, decreased nidation, increased concentrations of estradiol and progestone in sera (P<0.05). b) Effcets on the foetus: with increase of p,p'-DDE and beta-BHC, the number of live foetus lessened while dead foetus, absorbed foetus and featus deformities increased, AD and ratio of F/M in F1 generation increased. Significances were found among the control, low-, mid-, high-dose groups. Expressional abundances α-ER and GnRH mRNA increased while β-EP decreased in placenta. There were significant differences among the four groups (P<0.05). c) Correlation analysis indicated that positive correlatons were found between concentrations of estradiol, progestone in sera and expressional abundances of α-ER, GnRH in placenta, between AD of foetus, ratio of F/M and α-ER, GnRH, between progestone and ratio of F/M, that negative correlation existed between estradiol, progestone and β-EP mRNA, between AD of foetus, ratio of F/M and β-EP mRNA. Conclusions: p,p'-DDE and beta-BHC possess estragenicity in female, which may disrupt reproduction and development, thereby lead to feminization in their offsprings.
Part Ⅱ Determination of residues of DDT and BHC
in sera of pregnant women at delivery
Objective: To detect concentrations of the eight isomers of DDT and BHC in sera of pregnant women so as to reveal current residual levels of OCPs in population. Methods: Sera of the 71 women who delivered their babies at term in Tianmen hospital for maternal and child care in Hubei province during Jan 1st to Apr 30 in 2004 were collected. Capillary gas chromatography (CGC) was employed to determine concentrations of residues of DDT and BHC in sera.
Results: a) The average recoveries of the three spiked levels were 87.3%～94.6%. The coefficient of variation (CV) were 1.8%～6.8%. The minimum detection limit was 0.0005 μg/L. b) The detected percent and range of detection of the eight metabolites were 7.04%～47.89% and 0.0～147.7 μg/L, respectively. The average concentration of γ-BHC among the BHCs and o,p'-DDT among the DDTs were the highest in the samples, respectively. c) The average detected percent and concentration of T-OCPs were 87.32% and 37.48±51.24 μg/L in sera of the 71 women, respectively. 9 of whom were taken as control because no metabolite was found, 26, 17, 19 of whom were divided into the low-, mid-, and high-residue groups because their average levels of T-OCPs were failed into 2.1～9.7 μg/L, 12.6～39.6 μg/L, and 54.5～248.1 μg/L, respectively.
Conclusions: High residual levels of DDT and BHC are still detected in some people in China. Some products such as lindane and dicofol are probably used illegally in certain areas. It is very necessary to continue to determine residues of OCPs in environment and population.
Part Ⅲ Epidemiologic survey on the sampled population
Objective: To explore reproductive and developmental toxicity of OCPs, to rule out confounding factors effecting its endocrine disrupting effects, thereby increase reliability of the gained data.
Methods: According to 《questionnaire on pregnant women's health》 , the sampled women were surveyed by the trained investigator in two days after they delivered their babys. Results: a) The responsivity to questionnaire was 100% (71/71). b) With increase of residues of OCPs in the pregnant women, the mean of previous adverse pregnancy outcomes (PAPO) went up (P < 0.05) . c) The change of mean of weight in neonates were probably related to residues of OCPs in the pregnant women. d) No significance was found on age, occupation, expose to harmful physical and chemical factors, drug use during pregnancy, smoking and drinking, nutrition and sleep quality during pregnancy, family medical history (FMH) and so on in the sampled women and their spouses (P>0.05).
Conclusions: Epidemiological survey on population increases reliability of the other experimental data. Meanwhile, it indicates that residues of OCPs in body are probably concerned with reproduction dysfunction and maldevelopment.
Part IV Effects of residues of OCPs on the four reproductive hormones in pregnant women
Objective: To explore effects of residues of OCPs in pregnant women on concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E_2) and progesterone (P) in the sera of venous blood and blood from umbilical cord.
Methods: The 71 pregnant women who delivered at term in Hubei Tianmen Hospital for Maternal and Child Care during Jan 1st to Apr 30th in 2004 were recruited to participate in the present study. 10 ml venous blood samples respectively from the studied individuals and umbilical cords at delivery were collected and analyzed by adopting Enzyme Immunoassay (Magnetic Solid Phase) to determine concentrations of FSH, LH, E_2 and P. Spearman method was employed to analyze correlation between concentrations of T-OCPs and the four hormones, between levels of FSH, LH, E_2 and P in sera and in blood from cord.
Results: a) with increase of residual level of T-OCPs in the women, concentrations of FSH, E_2, P in sera and FSH, LH, E_2 in cord bood increased, respectively. In the puerperant sera, FSH increased from 0.83 mIU/ml in the control group to 2.27 mIU/ml in the high residual group, P from 264.04 ng/ml to 327.22 ng/ml, E_2 increased from 41.80 ng/ml in the control to 54.99 ng/ml in the mid-residual group, respectively. In the cord blood, FSH increased from 1.41 mIU/ml in the control to 2.91 mIU/ml in the high residual group, LH from 0.60 mIU/ml to 2.07 mIU/ml, E_2 increased from 12.53 ng/ml in the control to 24.03 ng/ml in the mid-residual group, respectively. Concentrations of LH in the venous sera and P in the cord blood, however, decreased from 1.47 mIU/ml to 0.63 mIU/ml, and from 804.47 ng/ml in the control group to 604.70 ng/ml in the high residual group, respectively. Significant differences were found among them (P < 0.05). b) Correlation analysis indicated that negative correlations were found between concentrations of T-OCPs in the high-residual group and E_2, P in sera (r = -0.5158, P = 0.0238; r = -0.6491, P = 0.0026) . Positive correlation existed between FSH in sera and FSH, LH, E_2 in cord blood, between LH in sera and P in cord, between P in sera and LH, E_2 in cord. But there were negative correlations between FSH in sera and LH in cord blood , between LH in sera and FSH, LH in cord blood, between E_2 in sera and FSH in cord blood, between P in sera and P in cord blood (P<0.05) .
Conclusions: Residues of OCPs in body may disrupt concentrations of reproductive hormones in blood.
Part V Effects of residues of OCPs in pregnant women on expressional abundances of α-ER、β-EP and GnRH mRNA
in placenta and umbilical tissues
Objective: To study effects on expressional abundances of α-ER、β-EP and GnRH mRNA in placenta and umbilical tissues by DDT and BHC and their metabolites in puerperants.
Methods: The studied individuals were the same in the Part Four. 71 tissue samples came from placenta and umbilical cord, respectively. Expressional abundances of α-ER、β-EP and GnRH mRNA in placenta and cord were determined by RT-PCR . Correlations by Spearman were analyzed between residue levels of T-OCPs in blood and the genes' expressional abundances in tissues, between concentrations of the hormones in blood and expressional abundances of the genes in tissues, and between expressional abundances of the genes in placenta and in cord.
Results: a) Residues of OCPs in pregnant women could up-regulate expression of α-ER and β-EP mRNA. In placenta, expression of α-ER mRNA increased from 1.62 in the control to 2.42 in the high residual group, and β-EP from 0.36 to 0.68. In umbilical cord, α-ER improved from 1.49 to 2.14, and β-EP from 0.24 to 0.46. There were significant differences among the control, low-, mid-, high-residual groups (P < 0.05 ) . GnRH mRNA expressions in placenta were also up-regulated, but no dose-dependent effect was found. Expressional abundance of GnRH mRNA in cord was not determined in the present study. b) Correlation analysis indicated that there were negative correlation between residual levels of OCPs in blood in the low-group and expression of α-ER mRNA in placenta and cord (r= -0.4874, P = 0.0116; r = -0.4815, P = 0.0127) , respectively. And positive correlation was found between residual levels of OCPs and expression of GnRH mRNA (r = 0.4870, P = 0.0116) . It also suggested that α-ER and β-EP expressions were positive correlation in placenta and cord, while GnRH expression in placenta was negatively related to α-ER、β-EP in cord. There were positive correlations between α-ER in placenta and E_2 in cord blood, between β-EP in placenta and FSH in puerperant blood, and FSH, E2 in cord blood, between α-ER in cord tissues and E_2 in cord blood, between β-EP in cord tissues and FSH, P in puerperant blood, and E2 in cord blood. But negative correlation existed between P in cord blood and α-ER, β-EP in placenta and cord tissues, respectively (P<0.05) .
Conclusions: Residues of OCPs in pregnant women may disrupt expression of some environmental response genes in placenta and umbilical cord.
Part VI Effects of residues of OCPs in pregnant women
on expression of the 3 proteins in placenta
Objective: To explore effects of residues of OCPs in puerperants on expressional abundances of α-ER, β-EP and GnRH protein in placenta.
Methods: The studied individuals were the same in the Part Four. 71 placenta samples were collected to determine expressional abundances of α-ER, β-EP and GnRH protein by SABC immunohistochemistry. Correlations by Spearman were analysed between T-OCPs' residual concentrations in blood and the proteins' expressional levels in placenta, between the proteins and the genes mRNA expression in tissues, between expressional abundances of the proteins in placenta and concentrations of the hormones in blood.
Results: a) Residues of OCPs in the women could induce expression of α-ER, β-EP and GnRH protein in placenta. Expressional abundances of α-ER increased from 128.80 in the control group to 149.70 in the high residual group, β-EP from 102.98 to 121.17, GnRH from 127.75 to 153.95, respectively. But there was only significant difference on GnRH expression among the control, low-, mid- and high-residual group (P < 0.05) . b) Correlation analysis indicated that T-OCPs level in blood in the low-residual group was negatively related to α-ER protein expression in placenta (r = -0.5326, P = 0.0124), but was positively related to GnRH protein expression (r = 0.6210, P = 0.0103) . Positive correlations were found between α-ER, β-EP mRNA and α-ER, β-EP protein, between GnRH protein and GnRH mRNA in placenta, respectively. However, negative correlation existed between GnRH protein and α-ER mRNA, β-EP mRNA in placenta, respectively, between GnRH mRNA and α-ER, β-EP protein in placenta. There were positive correlations between α-ER protein expression in placenta and concentration of P in sera, E2 in cord blood, between β-EP protein in placenta and FSH in sera, FSH and E_2 in cord blood, respectively. But there were negative correlation between P in cord blood and α-ER, β-EP protein in placenta, respectively (P < 0.05 ) .
Conclusions: Residues of OCPs in pregnant women may disrupt expression of α-ER, β-EP and GnRH protein in placenta.
To sum up, concentrations of DDT, BHC and their metabolites were still high in the targeted population in the present study. Furthermore, o,p-DDT and γ-BHC were the main components in the puerperant blood. Therefore, we suppose that certain OCPs such as lindane and dicofol were still illegally used in this region. The joint action of p,p-DDE and β-BHC on the pregnant mice have shown estrogenicity in female, which could lead to feminination in their offsprings. Residues of OCPs in pregnant women could disrupt levels of reproductive hormones in blood, induce expression of certain enviromental respone genes such as α-ER、β-EP and GnRH in placenta and umbilical cord. Therefore, they may result in reproductive dysfunction and maldevelopment. However, its detailed mechanisms deserve further studies.
This study possesses some new ideas as follow: a) we combined organically population study with animal experiment. Through epidemiological survey, the confounding factors effecting endocrine dirupting action of OCPs were ruled out, which improved reliability of the other expremental results. The present study indicated that residues of OCPs in pregnant women were probably concerned with increase of concentrations of FSH, E2, P in puerperant sera and FSH, LH, E2 in cord blood, and with decrease of levels of LH in sera and P in cord blood. At the same time, they could induce expression of α-ER, β-EP and GnRH gene (protein) in placenta and umbilical cord. b) For the first time, pregnant mice were co-incubated by p,p'-DDE and β-BHC to explore their reproductive and developmental toxicity. The results suggested that p,p'-DDE and β-BHC could decrease weights of the pregnant mice, increased of organ coefficient of uterus and intraluminal fluid, decreased nidation, increased concentrations of estradiol and progestone in sera in pregnant mice. Meanwhile, they could lessen the number of live foetus while increase dead foetus, absorbed foetus and featus deformities, increase AD and ratio of F/M in F1 generation, and induce expression of α-ER and GnRH mRNA while suppress β-EP in placenta.
第一部分p,p'-DDE和B-BHC联合作用对
孕小鼠生殖及其胎仔发育的影响
目的:研究p,p'-DDE和B-BHC联合作用对孕小鼠生殖及其胎仔发育的影响。
方法:以p,p'-DDE和B-BHC作为受试物,用不同浓度(p,p'-DDE和β-BHC分别为10 mg/kg/次+10 mg/kg/次;5 mg/kg/次+5 mg/kg/次;1 mg/kg/次+1 mg/kg/次;对照组灌胃同体积大豆油),于昆明种小鼠(清洁级)妊娠第12～14d期间每天给动物染毒1次。从动物妊娠0天至第18天(动物被处死之日),每天称量小鼠体重,观察其生长变化。于妊娠第18d断头处死孕小鼠,收集血液37℃分离血清,-20℃保存,用于孕鼠血清雌二醇(E2)和孕酮(P)测定(磁性分离酶联免疫法)。常规剖检母鼠,取心、肝、肾、脾、垂体、卵巢、子宫、胎盘等称重,计算各脏器系数和子宫腔内液重;计数卵巢中的黄体,检查子宫着床数,记录活胎数、死胎、吸收胎数,外观畸形胎数;记录每窝胎仔数,测定胎仔的体重、身长、尾长、腹围、肛殖距(AD)、性别比。采集胎盘组织样本,于无菌生理盐水中漂洗后,迅速置于液氮中速冻,然后转入-80℃冰箱保存,用于胎盘组织中α-ER、GnRH和β-EP mRNA表达水平测定(RT-PCR法)。用Spearman方法分析胎盘组织基因表达水平与血中激素含量之间、胎盘组织基因表达水平与胎仔肛殖距及雌雄比之间、血中激素含量与胎仔肛殖距及雌雄比之间的相关关系。结果:①对母鼠的影响:随着受试物剂量的加大,孕小鼠体重和增重下降,孕鼠肝脏重量和脏体比增加,p,p'-DDE和B-BHC联合染毒可使孕鼠子宫增重,脏/体比值上升,子宫腔内液增多,着床数减少,血清E2和P的含量增高(P<0.05)。②对胎仔发育的影响:p,p'-DDE和B-BHC联合染毒,可使活胎数减少,死胎、吸收胎、畸形胎仔数增加,胎仔肛殖距和雌雄比增加,组间差异比较有显著性(P<0.05),胎盘组织α-ER和GnRH mRNA表达上调,而β-EP表达下调,组间差异比较有显著性(P<0.05)。③相关性分析表明,血清E2、P的含量与胎盘组织中α-ER、GnRH呈正相关,而与β-EP mRNA的表达水平呈负相关。胎仔肛殖距、雌雄比与胎盘组织中α-ER、GnRH呈正相关,而与β-EP mRNA的表达水平呈负相关。孕鼠血清P含量与胎仔雌雄比之间表现为正相关关系(P<0.05)。
结论:p,p'-DDE和B-BHC联合作用在雌(女)性表现为类雌激素效应,可干扰生殖过程,导致发育障碍,可致后代雄性雌性化。
第二部分有机氯农药污染区产妇静脉血清中DDT和BHC残留水平测定
目的:测定有机氯农药污染区产妇静脉血清中DDT和BHC残留水平,以了解目前人群的农药残留情况。
方法:抽取2004年1月1日至4月30日在湖北省天门市妇幼保健院住院分娩的71例产妇的静脉血,应用气相色谱法(GC)检测血清中DDT和BHC的8种异构体的残留水平。
结果:①该测定方法的平均加标回收率和相对标准偏差分别为87.3%～94.6%,1.8%～6.8%;最低检测限为0.0005μg/L。②8种异构体的检出率为7.04%～47.89%,检出范围为0.0～147.7μg/L;平均检出量以γ-BHC(11.88±27.65μg/L)和o,p'-DDT(8.47±19.33μg/L)为最高。③本次共检测71例产妇血清,总有机氯检出率为87.32%(62/71),检出水平为37.48151.24μg/L(0.0～248.1μg/L)。其中9例均未检出目标成分作为对照组(9/71),26例总有机氯含量在2.1～9.7μg/L之间作为低残留组(26/71),17例总有机氯含量在12.6～39.6μg/L之间作为中残留组(17/71),19例总有机氯含量在54.5～248.1之间作为高残留组(19/71),以便对相关生物学效应指标进行对比分析。
结论:DDT和BHC等有机氯农药在我国目前某些人群中残留水平还比较高,有些产品(如林丹和三氯杀螨醇)可能仍在局部地区非法使用,继续监测有机氯农药在环境和人体内的残留很有必要。
第三部分抽样人群流行病学调查
目的:为了解有机氯农药的生殖和发育毒性作用,分析其内分泌干扰效应的影响因素,排除混杂因素的干扰,增加组间各检测指标的可比性。方法:采用问卷调查的方法,对被抽样的孕妇于住院分娩后2天内由经过培训的调查员按照《孕(产)妇健康情况调查表》的要求逐项询问和检查。
结果:①问卷调查的合格率为100%(71/71)。②孕妇体内有机氯农药残留水平的增加可导致既往不良妊娠结局次数的上升(P<0.05)。③孕妇体内有机氯农药残留水平可能与婴儿平均出生体重的改变有关(P<0.05)。④体内不同有机氯农药残留水平的孕妇及其配偶在年龄、职业分布、接触有害物理和化学因素、孕期用药、吸烟和饮酒、孕期营养和睡眠、家族史等方面未见显著性差异(P>0.05)。
结论:通过人群流行病学调查,增强了其他实验结果解释的可靠性。同时说明体内有机氯农药残留可能与生殖及发育障碍有关。
第四部分产妇体内有机氯农药残留对血中4种生殖激素的影响
目的:研究产妇体内有机氯农药残留对孕妇静脉血和脐带血中FSH、LH、E2和
P水平的影响。
方法:采集2004年1月1日至4月30日在湖北省天门市妇幼保健院住院分娩的71例产妇的静脉血和脐带血,采用磁性分离酶联免疫法测定产妇静脉血和脐带血FSH、LH、E2和P的含量。用Spearman法分析血中总有机氯残留水平与产妇血及脐带血中4种生殖激素之间、产妇血与脐带血中FSH、LH、E2和P的含量之间的相关关系。
结果:①随着产妇体内有机氯农药残留水平的升高,产妇静脉血FSH、E2、P和脐带血FSH、LH、E2含量呈上升趋势(产妇血:FSH从未检出组0.83 mIU/ml增加到高残留组2.27 mIU/ml,P从264.04 ng/ml增加到327.22 ng/ml,E2从41.80ng/ml增加到中残留组54.99 ng/ml;脐带血:FSH从未检出组1.41 mIU/ml上升到高残留组2.91 mIU/ml,LH从0.60 mIU/ml上升到2.07 mIU/ml,E2从12.53ng/ml上升到中残留组24.03 ng/ml),而静脉血LH和脐带血中P呈下降趋势(产妇血LH从未检出组1.47 mIU/ml下降到高残留组0.63 mIU/ml,脐带血P从804.47 ng/ml下降到604.70 ng/ml),均有剂量依赖性关系(P<0.05)。②相关性分析表明,高残留组农药残留水平与产妇血E2、P呈负相关(r=-0.5158,P=0.0238;r=-0.6491,P=0.0026)。产妇血FSH与脐带血FSH、LH、E2,产妇血LH与脐带血P,产妇血P与脐带血LH、E2之间呈正相关;而产妇血FSH与脐带血P,产妇血LH与脐带血FSH、LH,产妇血E2与脐带血FSH,产妇血P与脐带血P之间呈负相关(P<0.05)。
结论:人体内有机氯农药残留可显著干扰血中生殖激素水平。
第五部分产妇体内有机氯农药残留对胎盘和脐带组织
α-ER、β-EP、GnRH mRNA表达水平的影响
目的:研究产妇体内有机氯农药残留对胎盘和脐带组织α-ER、β-EP、GnRHmRNA表达水平的影响。
方法:采集2004年1月1日至4月30日在湖北省天门市妇幼保健院住院分娩的71例产妇的胎盘和脐带组织样,采用RT-PCR检测胎盘和脐带组织α-ER、β-EP、GnRH mRNA的表达水平,用Spearman法分析血中农药残留含量与组织基因表达水平、血中激素含量与组织基因表达水平、以及胎盘和脐带组织基因表达水平之间的相关关系。
结果:①体内有机氯农药残留可诱导胎盘与脐带组织α-ER和β-EP基因表达上调(胎盘组织:α-ER mRNA表达从未检出组1.62递增到高残留组2.42,β-EP从0.36递增到0.68;脐带组织:α-ER从1.49上升到2.14,β-EP从0.24上升到0.46),有剂量依赖性关系(P<0.05)。胎盘GnRH mRNA的表达虽也有随体内残留水平的升高而加强的趋势,但组间差异无统计学意义(P>0.05)。在脐带组织未检测到GnRH mRNA的表达。②相关性分析表明,低残留组产妇静脉血中总有机氯残留水平与胎盘及脐带组织α-ER mRNA的表达水平呈负相关(r=-0.4874,P=0.0116;r:-0.4815,P=0.0127),而与胎盘组织GnRH mRNA的表达呈正相关(r=0.4870,P=0.0116)。胎盘与脐带组织α-ER和β-EP相互之间呈正相关,而胎盘GnRH与脐带α-ER、β-EP呈负相关。胎盘组织α-ER与脐带血E2,胎盘组织β-EP与产妇血FSH及脐带血FSH、E2,脐带组织α-ER与脐带血E2,脐带组织β-EP与产妇血FSH、P及脐带血E2之间呈正相关;而脐带血P与胎盘和脐带组织α-ER、β-EP之间呈负相关(P<0.05)。
结论:产妇体内有机氯农药残留可干扰胎盘和脐带组织某些环境应答基因的表达。
第六部分产妇体内有机氯农药残留对胎盘组织
α-ER、β-EP、GnRH蛋白表达水平的影响
目的:探讨产妇体内有机氯农药残留对胎盘组织α-ER、β-EP、GnRH蛋白表达水平的影响。
方法:采集2004年1月1日至4月30日在湖北省天门市妇幼保健院住院分娩的71例产妇的胎盘组织样,运用SABC免疫组化方法检测胎盘组织α-ER、β-EP、GnRH蛋白的表达水平。用Spearman法分析血中农药残留含量与组织蛋白表达水平、组织蛋白与基因表达水平、组织蛋白表达水平与血中激素含量之间的相关关系。
结果:①产妇体内有机氯农药残留可诱导胎盘组织α-ER、β-EP、GnRH蛋白的表达(α-ER从未检出组128.80递增到高残留组149.70,β-EP从102.98递增到121.17,GnRH从127.75递增到153.95),但只有后者(GnRH)组间差异有显著性(P<0.05)。②相关性分析表明,低残留组血中T-OCPs(总有机氯)残留水平与胎盘组织中α-ER蛋白的表达呈负相关(r=-0.5326,P=0.0124);而与GnRH蛋白的表达呈正相关(r=0.6210,P=0.01 03)。胎盘组织α-ER、β-EP
mRNA与胎盘组织α-ER、β-EP蛋白,胎盘GnRH蛋白与GnRH mRNA表达水平之间呈正相关;而胎盘GnRH蛋白与胎盘α-ER、β-EP mRNA,胎盘GnRH
mRNA与胎盘α-ER、β-EP蛋白呈负相关。胎盘组织α-ER蛋白表达水平与产妇血P及脐带血E2含量,胎盘β-EP蛋白与产妇血FSH、脐带血FSH、E2含量之间呈正相关;而脐带血P与胎盘α-ER、β-EP蛋白之间呈负相关(P<0.05)。
结论:产妇体内有机氯农药残留可干扰胎盘组织α-ER、β-EP、GnRH蛋白的表达。
综上所述,DDT和BHC及其代谢产物在本研究目标人群中的残留水平还比较高,且o,p-DDT与γ-BHC是产妇血中最主要的残留成分,推测某些有机氯农药(如林丹和三氯杀螨醇)可能仍在该地区使用。p,p'-DDE和B-BHC联合作用在雌(女)性表现为类雌激素效应,可致后代雄性雌性化。产妇体内有机氯农药残留可干扰血中生殖激素水平,诱导胎盘和脐带组织某些环境应答基因(如α-ER、β-EP、GnRH)的表达,干扰生殖过程,导致发育障碍。但具体机制有待于进一步研究。
本研究的创新点有:①将动物实验与人群研究有机地结合,并通过流行病学调查,排除了影响有机氯农药致内分泌干扰的混杂因素,增强了实验结果的可比性。研究表明,体内有机氯农药的残留可干扰血中生殖激素水平,导致产妇静脉血FSH、E2、P和脐带血FSH、LH、E2含量增高,而静脉血LH和脐带血中P水平降低;可诱导人胎盘和脐带组织α-ER、β-EP及GnRH基因与蛋白的表达。②率先进行p,p'-DDE和B-BHC联合染毒孕期小鼠的研究,观察其生殖和发育毒性。结果显示,p,p'-DDE和B-BHC联合作用可使孕鼠子宫增重,腔内液增多,着床数减少,血中E2和P含量上升,诱导胎盘组织α-ER与GnRH基因的表达,而抑制β-EP基因的表达;可使活胎数减少,而死胎、吸收胎、畸形胎仔数增多;导致胎仔肛殖距与雌雄比上升。
Organochlorine pesticides(OCPs) such as DDT and BHC had ever used extensively and massively in worldwide. They have been banned to produce and use for more than twenty years, however, because of their hard degradation, high residue, iposolubility, and their biological amplification through food chain, which had made great harms to environmental ecosystem, animals, plants and human being. A great number of studies have indicated that DDT, BHC and their metabolites can still be detected in various environmental and biological samples. Their detected percents and concentrations were high in certain environments and population, especially in fatty tissue. Recent studies suggested that OCPs, as a type of persistent organic pollutants (POPs), possess endocrine dirupting effects. They may be concerned with decrease of sperm count and vitality, and increase of incidences of male infertility, carcinoma of testis and prostate. They may also be related to increase of incidences of prematuration, endometriosis, carcinoma of uterus, ovary and mammary gland. For these reasons, hazards of OCPs to human, especially to genital system, have caused great attention, and their reproductive and developmental toxicity have become a focus in recent studies. We selected the people as our studied objects who came from Tianmen city in Hubei province, because their average concentration of DDT residues in the fat samples of female residents was the highest in China in 1985. In the present study we determined residual levels of OCPs in sera of the local population, concentrations of FSH、LH、E_2 and P in blood, and expressional abundance of the genes and proteins such as α-ER、β-EP and GnRH in the samples. Population survey and animal experiment were integrated to explore endocrine dirupting effects of OCPs.
Part Ⅰ Effects of p,p'-DDE and beta-BHC on reproduction
and development in pregnant mice and their foetus Objective: To explore effects of reproduction and development in pregnant mice and their foetus co-incubated by p,p'-DDE and beta-BHC.
Methods: The pregnant mice were randomly divided into four groups, which were provided with plant oil, 1 mg/kg + 1 mg/kg, 5 mg/kg + 5 mg/kg, 10 mg/kg +10 mg/kg of p,p'-DDE and beta-BHC, respectively, from the 12th day to 14th after pregnancy and were treated one times per day. From P0 to P18, the pregnant mice were observed and weightened per day. When the animals were killed (P18), their blood was collected to determine concentration of estradiol and progestone by Immunoenzymetric assay (magnetic solid phase), and their placentae were collected to detect expressional abundance of α-estrogen receptor(α-ER), β-endorphin (β-EP) and gonadotropin releasing hormone (GnRH) mRNA by RT-PCR. The organ coefficients of heart, liver, kidney, spleen, pituitary, ovary, uterus, intraluminal fluid and placenta were determined, respectively. Corepus luteums, nidations, live foetus, dead foetus, absorbed foetus and featus deformities were counted, respectively. Weight, body length, tail length, abdominal circumference, anogenital distance (AD) and ratio of female to male (F/M) in the foetus were determined, respectively. The Spearman method was employed to analyse correlativity between expressional abundances of the genes and concentrations of the hormones, between AD and ratio of F/M and genes and hormones, respectively.
Results: a) Effects on the pregnant mice: The pregnant mice were poisoned by p,p'-DDE and beta-BHC, which have decreased their weights and gained weights, increased organ coefficient of liver, uterus and intramminal fluid, decreased nidation, increased concentrations of estradiol and progestone in sera (P<0.05). b) Effcets on the foetus: with increase of p,p'-DDE and beta-BHC, the number of live foetus lessened while dead foetus, absorbed foetus and featus deformities increased, AD and ratio of F/M in F1 generation increased. Significances were found among the control, low-, mid-, high-dose groups. Expressional abundances α-ER and GnRH mRNA increased while β-EP decreased in placenta. There were significant differences among the four groups (P<0.05). c) Correlation analysis indicated that positive correlatons were found between concentrations of estradiol, progestone in sera and expressional abundances of α-ER, GnRH in placenta, between AD of foetus, ratio of F/M and α-ER, GnRH, between progestone and ratio of F/M, that negative correlation existed between estradiol, progestone and β-EP mRNA, between AD of foetus, ratio of F/M and β-EP mRNA. Conclusions: p,p'-DDE and beta-BHC possess estragenicity in female, which may disrupt reproduction and development, thereby lead to feminization in their offsprings.
Part Ⅱ Determination of residues of DDT and BHC
in sera of pregnant women at delivery
Objective: To detect concentrations of the eight isomers of DDT and BHC in sera of pregnant women so as to reveal current residual levels of OCPs in population. Methods: Sera of the 71 women who delivered their babies at term in Tianmen hospital for maternal and child care in Hubei province during Jan 1st to Apr 30 in 2004 were collected. Capillary gas chromatography (CGC) was employed to determine concentrations of residues of DDT and BHC in sera.
Results: a) The average recoveries of the three spiked levels were 87.3%～94.6%. The coefficient of variation (CV) were 1.8%～6.8%. The minimum detection limit was 0.0005 μg/L. b) The detected percent and range of detection of the eight metabolites were 7.04%～47.89% and 0.0～147.7 μg/L, respectively. The average concentration of γ-BHC among the BHCs and o,p'-DDT among the DDTs were the highest in the samples, respectively. c) The average detected percent and concentration of T-OCPs were 87.32% and 37.48±51.24 μg/L in sera of the 71 women, respectively. 9 of whom were taken as control because no metabolite was found, 26, 17, 19 of whom were divided into the low-, mid-, and high-residue groups because their average levels of T-OCPs were failed into 2.1～9.7 μg/L, 12.6～39.6 μg/L, and 54.5～248.1 μg/L, respectively.
Conclusions: High residual levels of DDT and BHC are still detected in some people in China. Some products such as lindane and dicofol are probably used illegally in certain areas. It is very necessary to continue to determine residues of OCPs in environment and population.
Part Ⅲ Epidemiologic survey on the sampled population
Objective: To explore reproductive and developmental toxicity of OCPs, to rule out confounding factors effecting its endocrine disrupting effects, thereby increase reliability of the gained data.
Methods: According to 《questionnaire on pregnant women's health》 , the sampled women were surveyed by the trained investigator in two days after they delivered their babys. Results: a) The responsivity to questionnaire was 100% (71/71). b) With increase of residues of OCPs in the pregnant women, the mean of previous adverse pregnancy outcomes (PAPO) went up (P < 0.05) . c) The change of mean of weight in neonates were probably related to residues of OCPs in the pregnant women. d) No significance was found on age, occupation, expose to harmful physical and chemical factors, drug use during pregnancy, smoking and drinking, nutrition and sleep quality during pregnancy, family medical history (FMH) and so on in the sampled women and their spouses (P>0.05).
Conclusions: Epidemiological survey on population increases reliability of the other experimental data. Meanwhile, it indicates that residues of OCPs in body are probably concerned with reproduction dysfunction and maldevelopment.
Part IV Effects of residues of OCPs on the four reproductive hormones in pregnant women
Objective: To explore effects of residues of OCPs in pregnant women on concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E_2) and progesterone (P) in the sera of venous blood and blood from umbilical cord.
Methods: The 71 pregnant women who delivered at term in Hubei Tianmen Hospital for Maternal and Child Care during Jan 1st to Apr 30th in 2004 were recruited to participate in the present study. 10 ml venous blood samples respectively from the studied individuals and umbilical cords at delivery were collected and analyzed by adopting Enzyme Immunoassay (Magnetic Solid Phase) to determine concentrations of FSH, LH, E_2 and P. Spearman method was employed to analyze correlation between concentrations of T-OCPs and the four hormones, between levels of FSH, LH, E_2 and P in sera and in blood from cord.
Results: a) with increase of residual level of T-OCPs in the women, concentrations of FSH, E_2, P in sera and FSH, LH, E_2 in cord bood increased, respectively. In the puerperant sera, FSH increased from 0.83 mIU/ml in the control group to 2.27 mIU/ml in the high residual group, P from 264.04 ng/ml to 327.22 ng/ml, E_2 increased from 41.80 ng/ml in the control to 54.99 ng/ml in the mid-residual group, respectively. In the cord blood, FSH increased from 1.41 mIU/ml in the control to 2.91 mIU/ml in the high residual group, LH from 0.60 mIU/ml to 2.07 mIU/ml, E_2 increased from 12.53 ng/ml in the control to 24.03 ng/ml in the mid-residual group, respectively. Concentrations of LH in the venous sera and P in the cord blood, however, decreased from 1.47 mIU/ml to 0.63 mIU/ml, and from 804.47 ng/ml in the control group to 604.70 ng/ml in the high residual group, respectively. Significant differences were found among them (P < 0.05). b) Correlation analysis indicated that negative correlations were found between concentrations of T-OCPs in the high-residual group and E_2, P in sera (r = -0.5158, P = 0.0238; r = -0.6491, P = 0.0026) . Positive correlation existed between FSH in sera and FSH, LH, E_2 in cord blood, between LH in sera and P in cord, between P in sera and LH, E_2 in cord. But there were negative correlations between FSH in sera and LH in cord blood , between LH in sera and FSH, LH in cord blood, between E_2 in sera and FSH in cord blood, between P in sera and P in cord blood (P<0.05) .
Conclusions: Residues of OCPs in body may disrupt concentrations of reproductive hormones in blood.
Part V Effects of residues of OCPs in pregnant women on expressional abundances of α-ER、β-EP and GnRH mRNA
in placenta and umbilical tissues
Objective: To study effects on expressional abundances of α-ER、β-EP and GnRH mRNA in placenta and umbilical tissues by DDT and BHC and their metabolites in puerperants.
Methods: The studied individuals were the same in the Part Four. 71 tissue samples came from placenta and umbilical cord, respectively. Expressional abundances of α-ER、β-EP and GnRH mRNA in placenta and cord were determined by RT-PCR . Correlations by Spearman were analyzed between residue levels of T-OCPs in blood and the genes' expressional abundances in tissues, between concentrations of the hormones in blood and expressional abundances of the genes in tissues, and between expressional abundances of the genes in placenta and in cord.
Results: a) Residues of OCPs in pregnant women could up-regulate expression of α-ER and β-EP mRNA. In placenta, expression of α-ER mRNA increased from 1.62 in the control to 2.42 in the high residual group, and β-EP from 0.36 to 0.68. In umbilical cord, α-ER improved from 1.49 to 2.14, and β-EP from 0.24 to 0.46. There were significant differences among the control, low-, mid-, high-residual groups (P < 0.05 ) . GnRH mRNA expressions in placenta were also up-regulated, but no dose-dependent effect was found. Expressional abundance of GnRH mRNA in cord was not determined in the present study. b) Correlation analysis indicated that there were negative correlation between residual levels of OCPs in blood in the low-group and expression of α-ER mRNA in placenta and cord (r= -0.4874, P = 0.0116; r = -0.4815, P = 0.0127) , respectively. And positive correlation was found between residual levels of OCPs and expression of GnRH mRNA (r = 0.4870, P = 0.0116) . It also suggested that α-ER and β-EP expressions were positive correlation in placenta and cord, while GnRH expression in placenta was negatively related to α-ER、β-EP in cord. There were positive correlations between α-ER in placenta and E_2 in cord blood, between β-EP in placenta and FSH in puerperant blood, and FSH, E2 in cord blood, between α-ER in cord tissues and E_2 in cord blood, between β-EP in cord tissues and FSH, P in puerperant blood, and E2 in cord blood. But negative correlation existed between P in cord blood and α-ER, β-EP in placenta and cord tissues, respectively (P<0.05) .
Conclusions: Residues of OCPs in pregnant women may disrupt expression of some environmental response genes in placenta and umbilical cord.
Part VI Effects of residues of OCPs in pregnant women
on expression of the 3 proteins in placenta
Objective: To explore effects of residues of OCPs in puerperants on expressional abundances of α-ER, β-EP and GnRH protein in placenta.
Methods: The studied individuals were the same in the Part Four. 71 placenta samples were collected to determine expressional abundances of α-ER, β-EP and GnRH protein by SABC immunohistochemistry. Correlations by Spearman were analysed between T-OCPs' residual concentrations in blood and the proteins' expressional levels in placenta, between the proteins and the genes mRNA expression in tissues, between expressional abundances of the proteins in placenta and concentrations of the hormones in blood.
Results: a) Residues of OCPs in the women could induce expression of α-ER, β-EP and GnRH protein in placenta. Expressional abundances of α-ER increased from 128.80 in the control group to 149.70 in the high residual group, β-EP from 102.98 to 121.17, GnRH from 127.75 to 153.95, respectively. But there was only significant difference on GnRH expression among the control, low-, mid- and high-residual group (P < 0.05) . b) Correlation analysis indicated that T-OCPs level in blood in the low-residual group was negatively related to α-ER protein expression in placenta (r = -0.5326, P = 0.0124), but was positively related to GnRH protein expression (r = 0.6210, P = 0.0103) . Positive correlations were found between α-ER, β-EP mRNA and α-ER, β-EP protein, between GnRH protein and GnRH mRNA in placenta, respectively. However, negative correlation existed between GnRH protein and α-ER mRNA, β-EP mRNA in placenta, respectively, between GnRH mRNA and α-ER, β-EP protein in placenta. There were positive correlations between α-ER protein expression in placenta and concentration of P in sera, E2 in cord blood, between β-EP protein in placenta and FSH in sera, FSH and E_2 in cord blood, respectively. But there were negative correlation between P in cord blood and α-ER, β-EP protein in placenta, respectively (P < 0.05 ) .
Conclusions: Residues of OCPs in pregnant women may disrupt expression of α-ER, β-EP and GnRH protein in placenta.
To sum up, concentrations of DDT, BHC and their metabolites were still high in the targeted population in the present study. Furthermore, o,p-DDT and γ-BHC were the main components in the puerperant blood. Therefore, we suppose that certain OCPs such as lindane and dicofol were still illegally used in this region. The joint action of p,p-DDE and β-BHC on the pregnant mice have shown estrogenicity in female, which could lead to feminination in their offsprings. Residues of OCPs in pregnant women could disrupt levels of reproductive hormones in blood, induce expression of certain enviromental respone genes such as α-ER、β-EP and GnRH in placenta and umbilical cord. Therefore, they may result in reproductive dysfunction and maldevelopment. However, its detailed mechanisms deserve further studies.
This study possesses some new ideas as follow: a) we combined organically population study with animal experiment. Through epidemiological survey, the confounding factors effecting endocrine dirupting action of OCPs were ruled out, which improved reliability of the other expremental results. The present study indicated that residues of OCPs in pregnant women were probably concerned with increase of concentrations of FSH, E2, P in puerperant sera and FSH, LH, E2 in cord blood, and with decrease of levels of LH in sera and P in cord blood. At the same time, they could induce expression of α-ER, β-EP and GnRH gene (protein) in placenta and umbilical cord. b) For the first time, pregnant mice were co-incubated by p,p'-DDE and β-BHC to explore their reproductive and developmental toxicity. The results suggested that p,p'-DDE and β-BHC could decrease weights of the pregnant mice, increased of organ coefficient of uterus and intraluminal fluid, decreased nidation, increased concentrations of estradiol and progestone in sera in pregnant mice. Meanwhile, they could lessen the number of live foetus while increase dead foetus, absorbed foetus and featus deformities, increase AD and ratio of F/M in F1 generation, and induce expression of α-ER and GnRH mRNA while suppress β-EP in placenta.
引文
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