甲氧滴滴涕染毒对雌性SD大鼠的性腺毒性及其机制研究
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摘要
外环境中存在许多能模拟或干扰机体内分泌功能的化学物,影响体内激素的合成、分泌、运输、结合、作用、代谢或消除等环节,从而对个体的生殖、发育以及生物行为产生影响,表现出拟天然激素或抗天然激素的作用,这一类化合物统称为环境内分泌干扰物(Endocrine Disruptor Chemicals,EDCs),可以对人体的生殖健康产生严重的影响。生殖健康包括了男女两个方面,由于女性的生殖过程远较男性复杂,但在有关生殖健康的研究中,有关环境污染物对女性健康影响的资料与男性相比相对较少。而女性在人类生殖的过程中,不仅提供繁衍生命的生殖细胞,还提供孕育生命的母体环境,因此保护女性的生殖健康对人类的繁衍具有重要意义。
甲氧滴滴涕(methoxychlor,MXC)是一种替代滴滴涕的有机氯杀虫剂,其杀虫效果明显,生物毒性相对较低,在许多国家得到广泛应用。然而,近几年的研究表明,甲氧滴滴涕是确定的环境内分泌干扰物,可对雌性和雄性生殖内分泌产生影响。
很多研究表明MXC对雄性生殖系统有破坏作用,但是对于雌性研究的较少。本课题通过构建雌性SD大鼠染毒模型,研究MXC对雌性大鼠性腺的毒性作用及卵巢抗氧化功能的影响,并观察了MXC对卵巢和子宫ER蛋白表达及垂体FSH表达的调节机制,为深入阐明MXC对雌性动物生殖功能的影响提供理论和实验依据。
第一部分:甲氧滴滴涕染毒雌性SD大鼠模型的构建及对生殖内分泌的干扰作用
使用雌性SD大鼠作为实验动物,3月龄,随机分为4组,每组10只,染毒剂量分别为0(对照)、16(低剂量)、32(中剂量)、64(高剂量)mg/(kg?d),对照组给予等剂量芝麻油,所有实验大鼠均通过腹腔注射染毒,连续20d。每天用阴道脱落细胞涂片法连续观察并记录动情周期。染毒结束后于动情期将大鼠处死,观察指标包括体重,卵巢、子宫的脏器系数;放射免疫法测定血清中E2、P、FSH和LH的水平。免疫组化SP法观察雌激素受体(ER)在子宫和卵巢组织中的表达,免疫荧光染色观察FSH在垂体的表达;运用光镜和电镜观察卵巢组织和细胞超微结构的变化,计数各级卵泡及黄体数目。结果表明:①染毒前后各组体质量增加未见显著差异;②中高剂量染毒组动情期延长,周期数减少;③中高剂量组卵巢体质量及卵巢指数显著降低;④中、高剂量染毒组血清FSH和E2水平显著降低,P和LH与对照组比较无显著性差异;⑤中高剂量组闭锁卵泡显著增加,且次级卵泡闭锁率显著升高;⑥各组子宫内膜和卵巢ER蛋白的表达无显著性差异;⑦中高剂量组垂体FSH表达水平显著降低。结论:①甲氧滴滴涕可以使动情周期延长,卵泡闭锁增加,对雌性性腺产生毒性;②实验剂量的甲氧滴滴涕可以引起下丘脑-垂体-卵巢轴紊乱,降低垂体FSH表达水平,但并不是通过改变卵巢和子宫ER蛋白表达水平引起雌性性腺毒性的;③低剂量组未对雌性性腺产生明显的影响。
第二部分:甲氧滴滴涕染毒对SD大鼠卵巢抗氧化系统功能的影响
实验动物染毒模型构建同实验一,将雌性SD大鼠随机分为MXC 0、32、64mg/(kg?d)及MXC 64 mg+维生素E 20 mg/(kg?d)组。20 d后处死大鼠,用分光光度法测定其卵巢中超氧化物歧化酶(SOD)、还原型谷胱甘肽(GSH)的活力以及丙二醛(MDA)的含量;用RT-PCR法观察卵巢组织中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)以及过氧化氢酶(CAT)等抗氧化酶mRNA的表达。结果表明:①中高剂量MXC组SOD、GSH活性显著下降,MDA含量升高,MXC64mg+维生素E20mg组SOD、GSH活性及MDA含量与对照组比较无显著性差异;②RT-PCR结果显示MXC中高剂量组卵巢中抗氧化酶(SOD、GSH-Px、CAT)mRNA表达均显著降低,MXC64mg+维生素E20mg组抗氧化酶mRNA表达与对照组比较无显著性差异。结论:①MXC可以对卵巢抗氧化系统产生影响,造成抗氧化酶活性降低,脂质过氧化增强;②维生素E可以对MXC引起的氧化应激损伤产生拮抗作用;③中高剂量组MXC引起卵泡闭锁可能是通过氧化应激产生。
There are many kinds of chemicals which can simulate or interfere endocrine function of human beings in nature environment, such as synthesis, secretion, transportation, binding, action and so on. Metabolism or elimination of natural blood-borne hormones in the body were influenced, which resulted in changes in multiple aspects incluing reproduction, growth and behaveior. These kinds of conpounds are defined as endocrine disruptor chemicals (DECs) which can cause serious influence to generateon health of mankind. Because the process of female’s generation prodedure is more complicate than male’s, there are much more research documents based on the influences caused by EDCs in male than female. women provides not only reproductive cells but also environment of foetus growth. For these reasons, it is very important to protect women’s generational health.
Methoxychlor (MXC) is an organochlorine pesticide, which is widely sprayed on fruits, vegetables, forage crops, and home gardens to prevent insects from attacking them. MXC is considered to be an alternative to dichloro-diphenyl-trichloroethane (DDT). Although MXC has been considered as a potent environmental toxicant for several years, it was not until recently that MXC had been considered to be a reproductive toxicant.
Until rencently, numerous researches have found that MXC could cause damage to male rat’s reproductive system. However, there is little information regarding influence of MXC on female reproductive activity. Consequently, the present study was designed to investigate the adverse effect of MXC on various reproductive parameters of female rat. The study was designed to analyze the effects of MXC on ovary and as well as expression of hormone receptor in both ovary and uterus. We also studied whether vitminE can reduce the reproductive toxicity of organic pollutants of MXC to female SD rats.
Part 1. Construction of methoxychlor poisoned rats model and effects of methoxychlor on reproduction and endocrine system.
Forty female SD rats were randomly divided into 4 groups, 4 different dose levels (0, 16, 32 and 64 mg/(kg?d) MXC ) were injected intraperitoneally accordingly for 20 d. Vaginal smears of rats were performed to determine estrous cycle. The rats were sacrificed on the day of estrus stage. Body weights, estrus stage, organ weights and organ coefficients of ovary were observed. Uterine tissue and ovary were prosessed for histologic examination. Serum follicle stimulating hormone(FSH), leteinizing hormone(LH), estradiol(E2) and progestereone(P) were detected with the radio immunoassays. Estrogen receptor in the uterine and ovary were examined with the SP immunohisochemical method. Expression of FSH in pituitary gland was detected with immunofluorescence. Ultrastruction changes of folliciles was observed by electron microscope. A quantitative analysis of different stage follicles, atretic follicles and corporaluteum were conducted. Results:①Increasing of body weight was not different between 4 groups after treatment.②E struation was prolonged in MXC 32 and 64 mg groups, periodicity decresed accordingly.③Organ weights and organ coefficients of ovaries in rats treated with MXC 32 and 64 mg groups were significantly different from the control group.④Serum follicle stimulating hormone (FSH) and estradiol (E2) were significantly decreased in 32, 64 MXC group. There were no significant differences on both serum progestereone (P) and leteinizing hormone (LH) in the 4 groups.⑤Numbers of atresic follicle were significantly increased in both the MXC 32 and 64 mg groups, the atresic rate of secondary follicle was significantly increasd.⑥There were no significant differences on the positive percentage of ER in both endometria of uterus and ovaries in the 4 groups.⑦The positive percentage of FSH in pituitary gland were desreased in rats treated with MXC 32 and 64 mg/(kg?d). Conclusion:①MXC could result in prolonged estruation circle and increased number of atresic follicle.②Hypothalamic-pituitary-ovarian axis function and expression of FSH level in pituitary gland were changed at the dose we used, that’s why female gonads toxicities was caused. MXC in experimental dose may induce the disorder of hypothalamic-pituitary-ovarian axis and decrease the expression level of FSH, however, this dose can not change the expression level of ER secreted from ovarian and uterus, and increase the toxicities of female gonad.③N o significant influence on female gonads toxicities was found in low-dose group.
Part 2. Effects of methoxychlor on the function of ovarian antioxidant system in rats
We erected the model on intraperitoneal injection MXC just like the first experiment. Forty SD rats were randomly divided into 4 groups treated with MXC 0, 32,64 mg/(kg?d) and MXC 64 mg +VitE 20 mg/(kg?d) )for 20d. The activities of superoxide dismutase (SOD), reduced glutathione hormone (GSH) and the level of malondialdehyde (MDA) were measured by spectrophotometry. The method of reverse transcription polymerase chain reaction (RT-PCR) was used to detect the presence of antioxidase(SOD、GSH-Px、CAT) in rat ovaries, which may be helpful to elucidate the mechanism of endocrine disruption of MXC. Results:The activities of GSH and SOD in the MXC 32 and 64mg groups were decreased significantly as compared with those in the control group (P<0.05), but the level of MDA was raised in comparison with the control group (P<0.01). The expression levels of antioxidase(SOD、GSH-Px、CAT)in MXC 32, 64mg groups were lower than that in control group. The activities of GSH, SOD and MDA and the mRNA expression levels of antioxidase were no significant difference between the 64mg MXC + Vit E 20 mg and the control group in ovary. Conclusion: MXC could increase the number of atresic follicle by disturbing the function of ovarian antioxidant system in female SD rats.The adverse effect was blocked by Vitamin E.
甲氧滴滴涕(methoxychlor,MXC)是一种替代滴滴涕的有机氯杀虫剂,其杀虫效果明显,生物毒性相对较低,在许多国家得到广泛应用。然而,近几年的研究表明,甲氧滴滴涕是确定的环境内分泌干扰物,可对雌性和雄性生殖内分泌产生影响。
很多研究表明MXC对雄性生殖系统有破坏作用,但是对于雌性研究的较少。本课题通过构建雌性SD大鼠染毒模型,研究MXC对雌性大鼠性腺的毒性作用及卵巢抗氧化功能的影响,并观察了MXC对卵巢和子宫ER蛋白表达及垂体FSH表达的调节机制,为深入阐明MXC对雌性动物生殖功能的影响提供理论和实验依据。
第一部分:甲氧滴滴涕染毒雌性SD大鼠模型的构建及对生殖内分泌的干扰作用
使用雌性SD大鼠作为实验动物,3月龄,随机分为4组,每组10只,染毒剂量分别为0(对照)、16(低剂量)、32(中剂量)、64(高剂量)mg/(kg?d),对照组给予等剂量芝麻油,所有实验大鼠均通过腹腔注射染毒,连续20d。每天用阴道脱落细胞涂片法连续观察并记录动情周期。染毒结束后于动情期将大鼠处死,观察指标包括体重,卵巢、子宫的脏器系数;放射免疫法测定血清中E2、P、FSH和LH的水平。免疫组化SP法观察雌激素受体(ER)在子宫和卵巢组织中的表达,免疫荧光染色观察FSH在垂体的表达;运用光镜和电镜观察卵巢组织和细胞超微结构的变化,计数各级卵泡及黄体数目。结果表明:①染毒前后各组体质量增加未见显著差异;②中高剂量染毒组动情期延长,周期数减少;③中高剂量组卵巢体质量及卵巢指数显著降低;④中、高剂量染毒组血清FSH和E2水平显著降低,P和LH与对照组比较无显著性差异;⑤中高剂量组闭锁卵泡显著增加,且次级卵泡闭锁率显著升高;⑥各组子宫内膜和卵巢ER蛋白的表达无显著性差异;⑦中高剂量组垂体FSH表达水平显著降低。结论:①甲氧滴滴涕可以使动情周期延长,卵泡闭锁增加,对雌性性腺产生毒性;②实验剂量的甲氧滴滴涕可以引起下丘脑-垂体-卵巢轴紊乱,降低垂体FSH表达水平,但并不是通过改变卵巢和子宫ER蛋白表达水平引起雌性性腺毒性的;③低剂量组未对雌性性腺产生明显的影响。
第二部分:甲氧滴滴涕染毒对SD大鼠卵巢抗氧化系统功能的影响
实验动物染毒模型构建同实验一,将雌性SD大鼠随机分为MXC 0、32、64mg/(kg?d)及MXC 64 mg+维生素E 20 mg/(kg?d)组。20 d后处死大鼠,用分光光度法测定其卵巢中超氧化物歧化酶(SOD)、还原型谷胱甘肽(GSH)的活力以及丙二醛(MDA)的含量;用RT-PCR法观察卵巢组织中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)以及过氧化氢酶(CAT)等抗氧化酶mRNA的表达。结果表明:①中高剂量MXC组SOD、GSH活性显著下降,MDA含量升高,MXC64mg+维生素E20mg组SOD、GSH活性及MDA含量与对照组比较无显著性差异;②RT-PCR结果显示MXC中高剂量组卵巢中抗氧化酶(SOD、GSH-Px、CAT)mRNA表达均显著降低,MXC64mg+维生素E20mg组抗氧化酶mRNA表达与对照组比较无显著性差异。结论:①MXC可以对卵巢抗氧化系统产生影响,造成抗氧化酶活性降低,脂质过氧化增强;②维生素E可以对MXC引起的氧化应激损伤产生拮抗作用;③中高剂量组MXC引起卵泡闭锁可能是通过氧化应激产生。
There are many kinds of chemicals which can simulate or interfere endocrine function of human beings in nature environment, such as synthesis, secretion, transportation, binding, action and so on. Metabolism or elimination of natural blood-borne hormones in the body were influenced, which resulted in changes in multiple aspects incluing reproduction, growth and behaveior. These kinds of conpounds are defined as endocrine disruptor chemicals (DECs) which can cause serious influence to generateon health of mankind. Because the process of female’s generation prodedure is more complicate than male’s, there are much more research documents based on the influences caused by EDCs in male than female. women provides not only reproductive cells but also environment of foetus growth. For these reasons, it is very important to protect women’s generational health.
Methoxychlor (MXC) is an organochlorine pesticide, which is widely sprayed on fruits, vegetables, forage crops, and home gardens to prevent insects from attacking them. MXC is considered to be an alternative to dichloro-diphenyl-trichloroethane (DDT). Although MXC has been considered as a potent environmental toxicant for several years, it was not until recently that MXC had been considered to be a reproductive toxicant.
Until rencently, numerous researches have found that MXC could cause damage to male rat’s reproductive system. However, there is little information regarding influence of MXC on female reproductive activity. Consequently, the present study was designed to investigate the adverse effect of MXC on various reproductive parameters of female rat. The study was designed to analyze the effects of MXC on ovary and as well as expression of hormone receptor in both ovary and uterus. We also studied whether vitminE can reduce the reproductive toxicity of organic pollutants of MXC to female SD rats.
Part 1. Construction of methoxychlor poisoned rats model and effects of methoxychlor on reproduction and endocrine system.
Forty female SD rats were randomly divided into 4 groups, 4 different dose levels (0, 16, 32 and 64 mg/(kg?d) MXC ) were injected intraperitoneally accordingly for 20 d. Vaginal smears of rats were performed to determine estrous cycle. The rats were sacrificed on the day of estrus stage. Body weights, estrus stage, organ weights and organ coefficients of ovary were observed. Uterine tissue and ovary were prosessed for histologic examination. Serum follicle stimulating hormone(FSH), leteinizing hormone(LH), estradiol(E2) and progestereone(P) were detected with the radio immunoassays. Estrogen receptor in the uterine and ovary were examined with the SP immunohisochemical method. Expression of FSH in pituitary gland was detected with immunofluorescence. Ultrastruction changes of folliciles was observed by electron microscope. A quantitative analysis of different stage follicles, atretic follicles and corporaluteum were conducted. Results:①Increasing of body weight was not different between 4 groups after treatment.②E struation was prolonged in MXC 32 and 64 mg groups, periodicity decresed accordingly.③Organ weights and organ coefficients of ovaries in rats treated with MXC 32 and 64 mg groups were significantly different from the control group.④Serum follicle stimulating hormone (FSH) and estradiol (E2) were significantly decreased in 32, 64 MXC group. There were no significant differences on both serum progestereone (P) and leteinizing hormone (LH) in the 4 groups.⑤Numbers of atresic follicle were significantly increased in both the MXC 32 and 64 mg groups, the atresic rate of secondary follicle was significantly increasd.⑥There were no significant differences on the positive percentage of ER in both endometria of uterus and ovaries in the 4 groups.⑦The positive percentage of FSH in pituitary gland were desreased in rats treated with MXC 32 and 64 mg/(kg?d). Conclusion:①MXC could result in prolonged estruation circle and increased number of atresic follicle.②Hypothalamic-pituitary-ovarian axis function and expression of FSH level in pituitary gland were changed at the dose we used, that’s why female gonads toxicities was caused. MXC in experimental dose may induce the disorder of hypothalamic-pituitary-ovarian axis and decrease the expression level of FSH, however, this dose can not change the expression level of ER secreted from ovarian and uterus, and increase the toxicities of female gonad.③N o significant influence on female gonads toxicities was found in low-dose group.
Part 2. Effects of methoxychlor on the function of ovarian antioxidant system in rats
We erected the model on intraperitoneal injection MXC just like the first experiment. Forty SD rats were randomly divided into 4 groups treated with MXC 0, 32,64 mg/(kg?d) and MXC 64 mg +VitE 20 mg/(kg?d) )for 20d. The activities of superoxide dismutase (SOD), reduced glutathione hormone (GSH) and the level of malondialdehyde (MDA) were measured by spectrophotometry. The method of reverse transcription polymerase chain reaction (RT-PCR) was used to detect the presence of antioxidase(SOD、GSH-Px、CAT) in rat ovaries, which may be helpful to elucidate the mechanism of endocrine disruption of MXC. Results:The activities of GSH and SOD in the MXC 32 and 64mg groups were decreased significantly as compared with those in the control group (P<0.05), but the level of MDA was raised in comparison with the control group (P<0.01). The expression levels of antioxidase(SOD、GSH-Px、CAT)in MXC 32, 64mg groups were lower than that in control group. The activities of GSH, SOD and MDA and the mRNA expression levels of antioxidase were no significant difference between the 64mg MXC + Vit E 20 mg and the control group in ovary. Conclusion: MXC could increase the number of atresic follicle by disturbing the function of ovarian antioxidant system in female SD rats.The adverse effect was blocked by Vitamin E.
引文
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24. Pauwels A, Schepens PJ, D'Hooghe T.et al. The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: a case-control study of infertile women. Hum Reprod. 2001;16(10):2050-2055.
25. Eskenazi B, Mocarelli P, Warner M.et al. Serum dioxin concentrations andendometriosis: a cohort study in Seveso, Italy. Environ Health Perspect. 2002;110(7):629-634.
26. Matikainen T, Perez GI, Jurisicova A.et al. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet. 2001;28(4):355-360.
27. Gerhard I, Daniel V, Link S.et al. Chlorinated hydrocarbons in women with repeated miscarriages. Environ Health Perspect. 1998;106(10):675-681.
28. Berry M, Bove F. Birth weight reduction associated with residence near a hazardous waste landfill. Environ Health Perspect. 1997;105(8):856-861.
29. Garry VF, Schreinemachers D, Harkins ME.et al. Pesticide appliers, biocides, and birth defects in rural Minnesota. Environ Health Perspect. 1996;104(4):394-399.
30. Korrick SA, Altshul L. High breast milk levels of polychlorinated biphenyls (PCBs) among four women living adjacent to a PCB-contaminated waste site. Environ Health Perspect. 1998;106(8):513-518.
31. 李永红. 农药的发展与人类的健康. 生物学通报 2001;36(5):12-14.
32. 宋宏宇, 王捷. 环境内分泌干扰物与农药. 农药科学与管理 2001;22(2):23-25.
33. Cummings AM. Methoxychlor as a model for environmental estrogens. Crit Rev Toxicol . 1997;27(4):367-379.
34. Nimrod AC, Benson WH. Xenobiotic interaction with and alteration of channel catfish estrogen receptor. Toxicol Appl Pharmacol. 1997;147(2):381-390.
35. Gaido KW, Maness SC, McDonnell DP.et al. Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies. Mol Pharmacol. 2000;58(4):852-858.
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39. Latchoumycandane C, Mathur PP. Effect of methoxychlor on the antioxidant system in mitochondrial and microsome-rich fractions of rat testis. Toxicology. 2002;176(1-2):67-75.
40. Cupp AS, Skinner MK. Actions of the endocrine disruptor methoxychlor and its estrogenic metabolite on in vitro embryonic rat seminiferous cord formation and perinatal testis growth. Reprod Toxicol. 2001;15(3):317-326.
41. Gray LE Jr, Ostby J, Monosson E.et al. Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat. Toxicol Ind Health . 1999;15(1-2):48-64.
42. Latchoumycandane C, Mathur PP. Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor. Arch Toxicol. 2002;76(12):692-698.
43. Ankley GT, Jensen KM, Kahl MD.et al. Description and evaluation of a short-term reproduction test with the fathead minnow (Pimephales promelas). Environ Toxicol Chem . 2001;20(6):1276-1290.
44. Borgeest C, Symonds D, Mayer LP.et al. Methoxychlor may cause ovarian follicular atresia and proliferation of the ovarian epithelium in the mouse. Toxicol Sci. 2002;68(2):473-478.
45. Pickford DB, Morris ID. Inhibition of gonadotropin-induced oviposition and ovarian steroidogenesis in the African clawed frog (Xenopus laevis) by the pesticide methoxychlor. Aquat Toxicol. 2003;62(3):179-194.
46. Fort DJ, Guiney PD, Weeks JA.et al. Effect of methoxychlor on various life stages of Xenopus laevis. Toxicol Sci. 2004;81(2):454-466.
47. Amstislavsky SY, Kizilova EA, Golubitsa AN.et al. Preimplantation exposures of murine embryos to estradiol or methoxychlor change postnatal development. Reprod Toxicol. 2004;18(1):103-108.
48. Suzuki M, Lee HC, Chiba S.et al. Effects of methoxychlor exposure during perinatalperiod on reproductive function after maturation in rats. Reprod Dev. 2004;50(4):455-461.
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52. Hazai E, Gagne PV, Kupfer D. Glucuronidation of the oxidative cytochrome P450-mediated phenolic metabolites of the endocrine disruptor pesticide: methoxychlor by human hepatic UDP-glucuronosyl transferases. Drug Metab Dispos.2004;32(7):742-751.
53. Murono EP, Derk RC, Akgul Y. In vivo exposure of young adult male rats to methoxychlor reduces serum testosterone levels and ex vivo Leydig cell testosterone formation and cholesterol side-chain cleavage activity. Reprod Toxicol. 2006;21(2):148-153.
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22. Daniels JL, Olshan AF, Savitz DA. Pesticides and childhood cancers. Environ Health Perspect. 1997;105(10):1068-1077.
23. 朱珠, 刘嘉. 环境内分泌干扰物对女性生殖健康影响的研究进展. 国外医学:妇产科学分册 2004;31(3):179-182.
24. Pauwels A, Schepens PJ, D'Hooghe T.et al. The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: a case-control study of infertile women. Hum Reprod. 2001;16(10):2050-2055.
25. Eskenazi B, Mocarelli P, Warner M.et al. Serum dioxin concentrations andendometriosis: a cohort study in Seveso, Italy. Environ Health Perspect. 2002;110(7):629-634.
26. Matikainen T, Perez GI, Jurisicova A.et al. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet. 2001;28(4):355-360.
27. Gerhard I, Daniel V, Link S.et al. Chlorinated hydrocarbons in women with repeated miscarriages. Environ Health Perspect. 1998;106(10):675-681.
28. Berry M, Bove F. Birth weight reduction associated with residence near a hazardous waste landfill. Environ Health Perspect. 1997;105(8):856-861.
29. Garry VF, Schreinemachers D, Harkins ME.et al. Pesticide appliers, biocides, and birth defects in rural Minnesota. Environ Health Perspect. 1996;104(4):394-399.
30. Korrick SA, Altshul L. High breast milk levels of polychlorinated biphenyls (PCBs) among four women living adjacent to a PCB-contaminated waste site. Environ Health Perspect. 1998;106(8):513-518.
31. 李永红. 农药的发展与人类的健康. 生物学通报 2001;36(5):12-14.
32. 宋宏宇, 王捷. 环境内分泌干扰物与农药. 农药科学与管理 2001;22(2):23-25.
33. Cummings AM. Methoxychlor as a model for environmental estrogens. Crit Rev Toxicol . 1997;27(4):367-379.
34. Nimrod AC, Benson WH. Xenobiotic interaction with and alteration of channel catfish estrogen receptor. Toxicol Appl Pharmacol. 1997;147(2):381-390.
35. Gaido KW, Maness SC, McDonnell DP.et al. Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies. Mol Pharmacol. 2000;58(4):852-858.
36. Duggan RE, Corneliussen PE, Duggan MB.et al. Pesticide residue levels in foods in the United States from July 1, 1969, to June 30, 1976: Summary. Assoc Off Anal Chem. 1983;66(6):1534-1535.
37. Badach H, Nazimek T, Kaminski R.et al. Organochlorine pesticides concentration in the drinking water from regions of extensive agriculture in Poland. Ann Agric Environ Med . 2000;7(1):25-28.
38. Larsen GL, Beskid C, Shirname-More L. Environmental air toxics: role in asthma occurrence?. Environ Health Perspect. 2002;110 Suppl 4:501-504.
39. Latchoumycandane C, Mathur PP. Effect of methoxychlor on the antioxidant system in mitochondrial and microsome-rich fractions of rat testis. Toxicology. 2002;176(1-2):67-75.
40. Cupp AS, Skinner MK. Actions of the endocrine disruptor methoxychlor and its estrogenic metabolite on in vitro embryonic rat seminiferous cord formation and perinatal testis growth. Reprod Toxicol. 2001;15(3):317-326.
41. Gray LE Jr, Ostby J, Monosson E.et al. Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat. Toxicol Ind Health . 1999;15(1-2):48-64.
42. Latchoumycandane C, Mathur PP. Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor. Arch Toxicol. 2002;76(12):692-698.
43. Ankley GT, Jensen KM, Kahl MD.et al. Description and evaluation of a short-term reproduction test with the fathead minnow (Pimephales promelas). Environ Toxicol Chem . 2001;20(6):1276-1290.
44. Borgeest C, Symonds D, Mayer LP.et al. Methoxychlor may cause ovarian follicular atresia and proliferation of the ovarian epithelium in the mouse. Toxicol Sci. 2002;68(2):473-478.
45. Pickford DB, Morris ID. Inhibition of gonadotropin-induced oviposition and ovarian steroidogenesis in the African clawed frog (Xenopus laevis) by the pesticide methoxychlor. Aquat Toxicol. 2003;62(3):179-194.
46. Fort DJ, Guiney PD, Weeks JA.et al. Effect of methoxychlor on various life stages of Xenopus laevis. Toxicol Sci. 2004;81(2):454-466.
47. Amstislavsky SY, Kizilova EA, Golubitsa AN.et al. Preimplantation exposures of murine embryos to estradiol or methoxychlor change postnatal development. Reprod Toxicol. 2004;18(1):103-108.
48. Suzuki M, Lee HC, Chiba S.et al. Effects of methoxychlor exposure during perinatalperiod on reproductive function after maturation in rats. Reprod Dev. 2004;50(4):455-461.
49. Chapin RE, Harris MW, Davis BJ.et al. The effects of perinatal/juvenile methoxychlor exposure on adult rat nervous, immune, and reproductive system function. Fundam Appl Toxicol. 1997;40(1):138-157.
50. Gangadharan B, Murugan MA, Mathur PP. Effect of methoxychlor on antioxidant system of goat epididymal sperm in vitro. Asian J Androl. 2001;3(4):285-288.
51. Schuh RA, Kristian T, Gupta RK.et al. Methoxychlor inhibits brain mitochondrial respiration and increases hydrogen peroxide production and CREB phosphorylation. Toxicol Sci. 2005;88(2):495-504.
52. Hazai E, Gagne PV, Kupfer D. Glucuronidation of the oxidative cytochrome P450-mediated phenolic metabolites of the endocrine disruptor pesticide: methoxychlor by human hepatic UDP-glucuronosyl transferases. Drug Metab Dispos.2004;32(7):742-751.
53. Murono EP, Derk RC, Akgul Y. In vivo exposure of young adult male rats to methoxychlor reduces serum testosterone levels and ex vivo Leydig cell testosterone formation and cholesterol side-chain cleavage activity. Reprod Toxicol. 2006;21(2):148-153.
54. Masutomi N, Shibutani M, Takagi H.et al. Alteration of pituitary hormone-immunoreactive cell populations in rat offspring after maternal dietary exposure to endocrine-active chemicals. Arch Toxicol. 2004;78(4):232-240.
55. Danzo BJ. Environmental xenobiotics may disrupt normal endocrine function by interfering with the binding of physiological ligands to steroid receptors and binding proteins. Environ Health Perspect. 1997;105(3):294-301.
56. Dechaud H, Ravard C, Claustrat F.et al. Xenoestrogen interaction with human sex hormone-binding globulin (hSHBG). Steroids. 1999;64(5):328-334.
57. McLachlan JA. Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals. Endocr Rev. 2001;22(3):319-341.
58. Waters KM, Safe S, Gaido KW. Differential gene expression in response tomethoxychlor and estradiol through ERalpha, ERbeta, and AR in reproductive tissues of female mice. Toxicol Sci. 2001;63(1):47-56.
59. Tomic D, Frech MS, Babus JK.et al. Methoxychlor induces atresia of antral follicles in ERalpha-overexpressing mice. Toxicol Sci. 2006;93(1):196-204.
60. Symonds DA, Miller KP, Tomic D.et al. Effect of methoxychlor and estradiol on cytochrome p450 enzymes in the mouse ovarian surface epithelium. Toxicol Sci. 2006;89(2):510-514.
61. Oropeza-Hernandez LF, Lopez-Romero R, Albores A. Hepatic CYP1A, 2B, 2C, 2E and 3A regulation by methoxychlor in male and female rats. Toxicol Lett. 2003;144(1):93-103.
62. Amstislavsky SY, Amstislavskaya TG, Amstislavsky VS.et al. Reproductive abnormalities in adult male mice following preimplantation exposures to estradiol or pesticide methoxychlor. Reprod Toxicol. 2006;21(2):154-159.
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