线粒体损伤和细胞凋亡在甲氧滴滴涕卵巢毒性中的作用
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摘要
环境内分泌干扰物(Endocrine Disrupting Chemicals,EDCs)被定义为对维持自身平衡、生殖、发育和行为的体内激素的合成、传输、键合、作用或清除有干扰作用的外源性物质,这些物质能够模拟、强化或抑制激素合成的作用,在某些情况下,可能引发组织或器官功能异常和肿瘤发生。由于职业和环境因素使人类越来越多地暴露于这类干扰物中,严重影响人类的生殖功能和身体健康。
作为环境内分泌干扰物之一的甲氧滴滴涕(methoxychlor,MXC),是近年来被广泛应用的、代替滴滴涕的有机氯杀虫剂,与滴滴涕相比具有在哺乳动物体内代谢快,易排泄、毒性低等特点。然而,甲氧滴滴涕被证实可引起雌性大鼠下丘脑-垂体-卵巢性腺轴紊乱,合成、分泌甾体激素减少、动情期延长、雄性生殖系统异常,等一系列毒性损害,因此研究甲氧滴滴涕对卵巢组织的毒性作用及其作用机制具有重要意义。本研究通过构建雌性小鼠甲氧滴滴涕染毒模型,观察其对雌鼠卵巢组织的毒性损害作用,探讨参与这一过程的细胞凋亡途径及线粒体损伤机制。
本实验分三部分:
第一部分:甲氧滴滴涕染毒雌性小鼠模型的构建及其对卵巢的毒性作用
将40只32日龄雌性昆明小鼠适应性饲养7日后,随机分为溶剂芝麻油组(对照组)及MXC16,32,64mg/(kg·d)组,连续20天经腹腔注射染毒MXC,染毒结束后于动情期处死小鼠,观察指标有:体重、卵巢脏器指数;苏木素-伊红染色(Hematoxylin and eosin,HE)光镜下计数各剂量组卵泡闭锁数目,计算卵泡闭锁百分率;放射免疫法测定血清中E2、P、FSH和LH的水平。结果:①各剂量组小鼠体重无显著性差异,中高剂量组卵巢质量逐渐下降,脏器指数显著降低;②中高剂量组闭锁卵泡百分率随剂量增加而升高;③中、高剂量组血清FSH和E2水平显著降低,P和LH与对照组比较无显著性差异。结论:①MXC可以降低卵巢质量,增加卵泡闭锁;②中高剂量的MXC可以引起实验剂量的甲氧滴滴涕可以引起下丘脑-垂体-卵巢轴紊乱,导致FSH和E2水平降低;③低剂量组对卵巢组织未产生明显的影响。
第二部分:甲氧滴滴涕染毒对颗粒细胞凋亡机制的研究
以实验一中石蜡包埋卵巢组织为标本,观察指标有:脱氧核糖核苷酸末端转移酶介导的缺口末端标记技术(TUNEL法)染色,荧光显微镜下观察、计数各剂量组卵巢组织中颗粒细胞凋亡的情况;透射电镜观察卵巢颗粒细胞超微结构改变;免疫组化SP法观察各剂量组卵巢组织Bax、Bcl-2蛋白表达水平。结果:①TUNEL法显示随染毒剂量增加,中高剂量组凋亡细胞数较低剂量组及对照组增加;②透射电镜见中高剂量组颗粒细胞内出现凋亡小体、胞浆空泡等典型凋亡形态学改变③中高剂量组Bax蛋白在卵巢中的表达明显高于对照组,Bcl-2蛋白的表达各组间无显著性差异。结论:①中高剂量的MXC可以引起明显的颗粒细胞凋亡;②中高剂量的MXC可提高小鼠卵巢组织促凋亡蛋白Bax的表达,发挥其诱导颗粒细胞凋亡的作用。
第三部分:甲氧滴滴涕对卵巢组织线粒体损伤机制的研究
动物染毒途径及方法同实验一,处死各组小鼠后迅速取出双侧卵巢制备组织匀浆,经多次低温高速离心提取出卵巢组织线粒体后,荧光分光光度计测各剂量组卵巢线粒体活性氧簇(reactive oxygen species,ROS)、膜电势的变化;紫外分光光度法检测线粒体呼吸链复合物Ⅰ活性变化。结果:卵巢组织线粒体膜电势,线粒体呼吸链复合物Ⅰ活性在中高剂量组低于对照组,线粒体ROS水平则高于对照组。结论:中高剂量的MXC可以通过降低线粒体膜电势、抑制线粒体复合物I活性及增加活性氧的产生诱导线粒体发生氧化应激,从而促进颗粒细胞凋亡、卵泡闭锁。
There are many exogenous chemicals which can interfere the synthesis, transportation, binding, function or elimination of hormones in vivo, which maitain balance , reproduction, development and behavior in human beings.These chemicals can mimic, strengthen or inhibiti the synthesis of hormones in vivo, in some conditions, they may result in abnormality of tissues and organs as well as tumor. These kinds of chemicals are defined as endocrine disrupting chemicals. More and more evidence indicate that the exposure of these chemicals through occupation and enviorment would influence and change the generation function of human beings.
Methoxychlor(MXC) is an organochlorine pesticide, which is widely used to be an alternative to dichloro-diphenyl-trichloroethane (DDT) for the past few years,Its advantages over DDT are that it is more rapidly metabolized excreted in mammals, it is acutely less toxic than DDT and it is biodegradable. It has been reported methoxychlor can affect reproduction of male mice, induce the disorder of hypothalamic-pituitary-ovarian axis, decrease secretion and synthesis of hormones, prolong estruation circle of female rats. For this reason, it is necessary to investigate the toxic effects as well as the mechanisms of MXC on mice ovary. The study was designed to analyze the effects of MXC on ovary, also to make clear whether the mitochondria exert the effects.
The study were divided into three parts:
Part 1. Construction of methoxychlor poisoned mice model and effects of methoxychlor on mice ovary.
MXC were administratede to forty female 39-day-mice at doses of 0 (control), 16, 32, 64mg/(kg·day) via intraperitoneal injection for 20d, then mice were euthanized in estrous. Body weights, organ coefficients of ovary were observed, a quantitive analysis of corpora atretica were conducted,. Serum follicle stimulating hormone(FSH), leteinizing hormone(LH), estradiol(E2) and progestereone(P) were detected with the radio immunoassays Results:①Increasing of body weights was not different between 4 groups after treatment.②Organ weights and organ coefficients of ovaries in mice treated with MXC 32 and 64 mg groups were significantly different from the control group.③Serum 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. .Conclusion:①MXC could decrease ovary weights and increase number of aatresic follicle.②MXC in experimental dose may induce the disorder of hypothalamic-pituitary-ovarian axis,which induce the decrease of E2 and FSH;③No significant influence on female gonads toxicities was found in low-dose group.
Part 2. Research of methoxychlor on the apoptosis of granulosa cell.
We used the ovary tissue embeded with paraffin just from the first experiment.Then the apoptosis of granulosa cell were observed by TUNEL and transmission electron microscope ;Bax and Bcl-2 in ovaries were examined with the SP immunohisochemical method. Results:①The number of apoptosis cells in 32,64 mg/ ( kg·d)groups was obviously higherthan that in 16 mg/ ( kg·d)and control groups;②The transmission electron microscope showed the apoptosis body and in 32,64mg/ ( kg·d)group; The expression of bax in 32,64 mg/ ( kg·d)group were significantly increased ,while these dose does not change the expression of bcl-2. Conclusion:①MXC in 32,64 mg/ ( kg·d)group could result in apoptosis of granulosa cell.②MXC in 32,64 mg/ ( kg·d) could increase the expression of bax in ovary ,which cause follicular atrsia.
Part 3.The research of methoxychlor on the mitochondria damage of ovary.
We erected the model on intraperitoneal injection MXC just like the first experiment. Then Mice were euthanized, their ovaries collected. After the preparation of mitochondria, the generation of ROS and the membrane potential of mice ovary mitochondria were detected by Fluoscence spectrophotometer, the activity of complex of mitochondria was measured by UV spectrophotomete. Results: The activity of complexⅠand the membrane potential of mitochondria were significantly lower in 32 and 64 mg/ ( kg·d) groups when compared to 16 and control groups(P<0.01),While the ROS were higher in 32 and 64 mg/ ( kg·d)groups than 16 and control groups(P<0.01). Conclusion: MXC could cause oxidative stress in mitochondria of mice ovary which may induce the apoptosis of granulosa cells, cause follicular atrsia.
作为环境内分泌干扰物之一的甲氧滴滴涕(methoxychlor,MXC),是近年来被广泛应用的、代替滴滴涕的有机氯杀虫剂,与滴滴涕相比具有在哺乳动物体内代谢快,易排泄、毒性低等特点。然而,甲氧滴滴涕被证实可引起雌性大鼠下丘脑-垂体-卵巢性腺轴紊乱,合成、分泌甾体激素减少、动情期延长、雄性生殖系统异常,等一系列毒性损害,因此研究甲氧滴滴涕对卵巢组织的毒性作用及其作用机制具有重要意义。本研究通过构建雌性小鼠甲氧滴滴涕染毒模型,观察其对雌鼠卵巢组织的毒性损害作用,探讨参与这一过程的细胞凋亡途径及线粒体损伤机制。
本实验分三部分:
第一部分:甲氧滴滴涕染毒雌性小鼠模型的构建及其对卵巢的毒性作用
将40只32日龄雌性昆明小鼠适应性饲养7日后,随机分为溶剂芝麻油组(对照组)及MXC16,32,64mg/(kg·d)组,连续20天经腹腔注射染毒MXC,染毒结束后于动情期处死小鼠,观察指标有:体重、卵巢脏器指数;苏木素-伊红染色(Hematoxylin and eosin,HE)光镜下计数各剂量组卵泡闭锁数目,计算卵泡闭锁百分率;放射免疫法测定血清中E2、P、FSH和LH的水平。结果:①各剂量组小鼠体重无显著性差异,中高剂量组卵巢质量逐渐下降,脏器指数显著降低;②中高剂量组闭锁卵泡百分率随剂量增加而升高;③中、高剂量组血清FSH和E2水平显著降低,P和LH与对照组比较无显著性差异。结论:①MXC可以降低卵巢质量,增加卵泡闭锁;②中高剂量的MXC可以引起实验剂量的甲氧滴滴涕可以引起下丘脑-垂体-卵巢轴紊乱,导致FSH和E2水平降低;③低剂量组对卵巢组织未产生明显的影响。
第二部分:甲氧滴滴涕染毒对颗粒细胞凋亡机制的研究
以实验一中石蜡包埋卵巢组织为标本,观察指标有:脱氧核糖核苷酸末端转移酶介导的缺口末端标记技术(TUNEL法)染色,荧光显微镜下观察、计数各剂量组卵巢组织中颗粒细胞凋亡的情况;透射电镜观察卵巢颗粒细胞超微结构改变;免疫组化SP法观察各剂量组卵巢组织Bax、Bcl-2蛋白表达水平。结果:①TUNEL法显示随染毒剂量增加,中高剂量组凋亡细胞数较低剂量组及对照组增加;②透射电镜见中高剂量组颗粒细胞内出现凋亡小体、胞浆空泡等典型凋亡形态学改变③中高剂量组Bax蛋白在卵巢中的表达明显高于对照组,Bcl-2蛋白的表达各组间无显著性差异。结论:①中高剂量的MXC可以引起明显的颗粒细胞凋亡;②中高剂量的MXC可提高小鼠卵巢组织促凋亡蛋白Bax的表达,发挥其诱导颗粒细胞凋亡的作用。
第三部分:甲氧滴滴涕对卵巢组织线粒体损伤机制的研究
动物染毒途径及方法同实验一,处死各组小鼠后迅速取出双侧卵巢制备组织匀浆,经多次低温高速离心提取出卵巢组织线粒体后,荧光分光光度计测各剂量组卵巢线粒体活性氧簇(reactive oxygen species,ROS)、膜电势的变化;紫外分光光度法检测线粒体呼吸链复合物Ⅰ活性变化。结果:卵巢组织线粒体膜电势,线粒体呼吸链复合物Ⅰ活性在中高剂量组低于对照组,线粒体ROS水平则高于对照组。结论:中高剂量的MXC可以通过降低线粒体膜电势、抑制线粒体复合物I活性及增加活性氧的产生诱导线粒体发生氧化应激,从而促进颗粒细胞凋亡、卵泡闭锁。
There are many exogenous chemicals which can interfere the synthesis, transportation, binding, function or elimination of hormones in vivo, which maitain balance , reproduction, development and behavior in human beings.These chemicals can mimic, strengthen or inhibiti the synthesis of hormones in vivo, in some conditions, they may result in abnormality of tissues and organs as well as tumor. These kinds of chemicals are defined as endocrine disrupting chemicals. More and more evidence indicate that the exposure of these chemicals through occupation and enviorment would influence and change the generation function of human beings.
Methoxychlor(MXC) is an organochlorine pesticide, which is widely used to be an alternative to dichloro-diphenyl-trichloroethane (DDT) for the past few years,Its advantages over DDT are that it is more rapidly metabolized excreted in mammals, it is acutely less toxic than DDT and it is biodegradable. It has been reported methoxychlor can affect reproduction of male mice, induce the disorder of hypothalamic-pituitary-ovarian axis, decrease secretion and synthesis of hormones, prolong estruation circle of female rats. For this reason, it is necessary to investigate the toxic effects as well as the mechanisms of MXC on mice ovary. The study was designed to analyze the effects of MXC on ovary, also to make clear whether the mitochondria exert the effects.
The study were divided into three parts:
Part 1. Construction of methoxychlor poisoned mice model and effects of methoxychlor on mice ovary.
MXC were administratede to forty female 39-day-mice at doses of 0 (control), 16, 32, 64mg/(kg·day) via intraperitoneal injection for 20d, then mice were euthanized in estrous. Body weights, organ coefficients of ovary were observed, a quantitive analysis of corpora atretica were conducted,. Serum follicle stimulating hormone(FSH), leteinizing hormone(LH), estradiol(E2) and progestereone(P) were detected with the radio immunoassays Results:①Increasing of body weights was not different between 4 groups after treatment.②Organ weights and organ coefficients of ovaries in mice treated with MXC 32 and 64 mg groups were significantly different from the control group.③Serum 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. .Conclusion:①MXC could decrease ovary weights and increase number of aatresic follicle.②MXC in experimental dose may induce the disorder of hypothalamic-pituitary-ovarian axis,which induce the decrease of E2 and FSH;③No significant influence on female gonads toxicities was found in low-dose group.
Part 2. Research of methoxychlor on the apoptosis of granulosa cell.
We used the ovary tissue embeded with paraffin just from the first experiment.Then the apoptosis of granulosa cell were observed by TUNEL and transmission electron microscope ;Bax and Bcl-2 in ovaries were examined with the SP immunohisochemical method. Results:①The number of apoptosis cells in 32,64 mg/ ( kg·d)groups was obviously higherthan that in 16 mg/ ( kg·d)and control groups;②The transmission electron microscope showed the apoptosis body and in 32,64mg/ ( kg·d)group; The expression of bax in 32,64 mg/ ( kg·d)group were significantly increased ,while these dose does not change the expression of bcl-2. Conclusion:①MXC in 32,64 mg/ ( kg·d)group could result in apoptosis of granulosa cell.②MXC in 32,64 mg/ ( kg·d) could increase the expression of bax in ovary ,which cause follicular atrsia.
Part 3.The research of methoxychlor on the mitochondria damage of ovary.
We erected the model on intraperitoneal injection MXC just like the first experiment. Then Mice were euthanized, their ovaries collected. After the preparation of mitochondria, the generation of ROS and the membrane potential of mice ovary mitochondria were detected by Fluoscence spectrophotometer, the activity of complex of mitochondria was measured by UV spectrophotomete. Results: The activity of complexⅠand the membrane potential of mitochondria were significantly lower in 32 and 64 mg/ ( kg·d) groups when compared to 16 and control groups(P<0.01),While the ROS were higher in 32 and 64 mg/ ( kg·d)groups than 16 and control groups(P<0.01). Conclusion: MXC could cause oxidative stress in mitochondria of mice ovary which may induce the apoptosis of granulosa cells, cause follicular atrsia.
引文
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35 Starek A. Estrogens and organochlorine xenoestrogens and breast cancer risk[J]. Occup Med Environ Health, 2003, 16 (2) :113–124.
36 Frigo DE, Tang Y, Beckman BS,et al. Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway[J]. Carcinogenesis,2004,25:249–261.
37 Lewis JS, Thomas TJ, Richard G,et al. Differential effects of 16-hydroxyestrone and 2-methoxyestradiol on cyclin D1 involving the transcription factor ATF-2 in MCF-7 breast cancer cells [J]. Mol Endocrinol, 2005,34:91–105.
38 Roy D , Palangal M , Chen CW, et al. Biochemical and molecular changes at the cellular level in response to exposure to environmental strogen-like chemicals [J].Toxicol Environ Health ,1997 ,50(1):1-29.
39 Miles Dean Engell, John Godwin, Young Larry J,et al. Perinatal exposure to endocrine disrupting compounds alters behavior and brain in the female pine vole[J].Neurotoxicol Teratol,2006,28(1):103-110.
40 Ropero Ana B, Paloma Alonso-Magdalena, Cristina Ripoll, et al. Rapid endocrinedisruption: Environmental estrogen actions triggered outside the nucleus[J].Steroid Biochem Mol Biol,2006,102(1-5):163-169.
41吕东阳,李文兰.环境激素作用机制的研究[J ].哈尔滨商业大学学报,2003,19(1):20-23.
42 Rob Zachowa,b, Mehmet Uzumcua.The methoxychlor metabolite, 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane, inhibits steroidogenesis in rat ovarian granulosa cells in vitro[J].Repro Toxicol,2006,22:659–665
43 R.K. Gupta , R.A. Schuh , G. Fiskum ,et al.Methoxychlor causes mitochondrial dysfunction and oxidative damage in the mouse ovary [J]. Toxicology and Applied Pharmacology,2006,216:436–445.
44 Martinez EM, Swartz WJ. Effects of methoxychlor on the reproductive system of the adult female mouse.1.Gross and histologic observations[J]. Reprod Toxicol,1991,5(2):139-47.
45 Martinez EM, Swartz WJ. Effects of methoxychlor on the reproductive system of the adult female mouse: 2. Ultrastructural observations[J].Reprod Toxicol,1992;6(1):93-8.
46 Cummings AM, Laskey J.Effect of methoxychlor on ovaria steroidogenesis: role in early pregnancy loss[J]. Reprod Toxicol,1993;7(1):17-23.
47 Tiemann U, Pohland R, Schneider F.Influence of organochlorine pesticides on physiological potency of cultured granulosa cells from bovine preovulatory follicles[J]. Theriogenology,1996; 46(2):253-65.
48 Uzumcu M,Kuhn PE,Marano JE,et al.Early postnatal methoxychlor exposure inhibits folliculogenesis and stimulates anti-Mullerian hormone production in the rat ovary[J]. Endocrinol,2006,191(3):549-58.
49 Miller KP, Gupta RK, Flaws JA. Methoxychlor metabolites may cause ovarian toxicity through estrogen-regulated pathways[J].Toxicol Sci. 2006 ; 93(1):180-8.
50 Tomic D, Frech MS, Babus JK,et al.Methoxychlor induces atresia of antral follicles in ERalpha-overexpressing mice[J].Toxicol Sci. 2006 ; 93(1):196-204.
51 Borgeest C,Symonds D,Mayer LP,et al.Methoxychlor may cause ovarian follicular atresia and proliferation of the ovarian epithelium in the mouse[J]. Toxicol Sci, 2002,68(2):473-8.
52 Symonds DA,Tomic D,Miller KP,et al.Methoxychlor induces proliferation of the mouse ovarian surface epithelium[J]. Toxicol Sci, 2005,83(2):355-62.
53 Hironori Takagi, Makoto Shibutani, Kyoung-Youl Le. Impact of maternal dietary exposure to endocrine-acting chemicals on progesterone receptor expression in microdissected hypothalamic medial preoptic areas of rat offspring[J]. Toxicology and Applied Pharmacology,2005,208:127–136
54 Suzuki M, Lee H C, Chiba S, et al. Effects of methoxychlor exposure during perinatal period on reproductive function after maturation in rats [J]. Reproductive and Development, 2004,50(4):455-61.
55 Sergei Y A, Elena A K, Alevtina N G, et al. Preimplantation exposures of murine embryos to estradiol or methoxychlor change postnatal development[J]. Reproductive Toxicology,2004,18:103–108
56 M.A. Ottinger, M.J. Quinn Jr, E. Lavoie, et al. Consequences of endocrine disrupting chemicals on reproductive endocrine function in birds:Establishing reliable end points of exposure[J].Domestic Animal Endocrinology, 2005, 29: 414-419
57 Wang XJ, Bartolucci-Page E, Fenton SE, et al. Altered mammary gland development in male rats exposed to genistein and methoxychlor[J]. Toxicological Science,2006,91(1):93-103.
58 Yukiko Takeuchi, Tadashi Kosaka, Koichi Hayashi,et al. Thymic atrophy induced by methoxychlor in rat pups[J]. Toxicol letters,2002,135(3):199-207
59 Guo TL, Germolec DR, Musgrove DL, et al.Myelotoxicity in genistein-,nonylphenol-, methoxychlor-,vinclozolin- or ethinyl estradiol-exposed F1 generations of Sprague–Dawley rats following developmental and adult exposures[J].Toxicology,2005,211:207–219.
60 Eroschenko VP.Ultrastructure of vagina and uterus in young mice after methoxychlor exposure[J].Reprod Toxicol. 1991;5(5):427-35.
61 Rourke AW, Eroschenko VP, Washburn LJ. Protein secretions in mouse uterus after methoxychlor or estradiol exposure[J].Reprod Toxicol. 1991;5(5):437-42.
62 Cummings AM, Metcalf JL. Effects of estrogen, progesterone, and methoxychlor on surgically induced endometriosis in rats[J].Fundam Appl Toxicol. 1995 ;27(2):287-90.
63 Tiemann U, Schneider F, Tuchscherer A. Effects of organochlorine pesticides on DNA synthesis of cultured oviductal and uterine cells and on estrogen receptor of uterine tissue from heifers[J].Arch Toxicol. 1996;70(8):490-6.64
64 Tiemann U, Kuchenmeister U. Influence of organochlorine pesticides on ATPase activities of microsomal fractions of bovine oviductal and endometrial cells[J].Toxicol Lett. 1999; 104(1-2):75-81.
65 Eroschenko VP, Johnson TJ, Rourke AW. Estradiol and pesticide methoxychlor do not exhibit additivity or synergism in the reproductive tract of adult ovariectomized mice[J].Toxicol Environ Health A. 2000; 60(6): 407-21.
66 Hodges LC, Bergerson JS, Hunter DS, Walker CL. Estrogenic effects of organochlorine pesticides on uterine leiomyoma cells in vitro[J].Toxicol Sci.2000,54(2):355-64.
67 Kiberstis PA.Mitochondria make a comeback[J].Sciencel,1999,283:1475.
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34 McDuffie HH. Host factors and genetic susceptibility: a paradigm of the conundrum of pesticide exposure and cancer associations[J].Rev Environ Health,2005, 20 (2) :77–101.
35 Starek A. Estrogens and organochlorine xenoestrogens and breast cancer risk[J]. Occup Med Environ Health, 2003, 16 (2) :113–124.
36 Frigo DE, Tang Y, Beckman BS,et al. Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway[J]. Carcinogenesis,2004,25:249–261.
37 Lewis JS, Thomas TJ, Richard G,et al. Differential effects of 16-hydroxyestrone and 2-methoxyestradiol on cyclin D1 involving the transcription factor ATF-2 in MCF-7 breast cancer cells [J]. Mol Endocrinol, 2005,34:91–105.
38 Roy D , Palangal M , Chen CW, et al. Biochemical and molecular changes at the cellular level in response to exposure to environmental strogen-like chemicals [J].Toxicol Environ Health ,1997 ,50(1):1-29.
39 Miles Dean Engell, John Godwin, Young Larry J,et al. Perinatal exposure to endocrine disrupting compounds alters behavior and brain in the female pine vole[J].Neurotoxicol Teratol,2006,28(1):103-110.
40 Ropero Ana B, Paloma Alonso-Magdalena, Cristina Ripoll, et al. Rapid endocrinedisruption: Environmental estrogen actions triggered outside the nucleus[J].Steroid Biochem Mol Biol,2006,102(1-5):163-169.
41吕东阳,李文兰.环境激素作用机制的研究[J ].哈尔滨商业大学学报,2003,19(1):20-23.
42 Rob Zachowa,b, Mehmet Uzumcua.The methoxychlor metabolite, 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane, inhibits steroidogenesis in rat ovarian granulosa cells in vitro[J].Repro Toxicol,2006,22:659–665
43 R.K. Gupta , R.A. Schuh , G. Fiskum ,et al.Methoxychlor causes mitochondrial dysfunction and oxidative damage in the mouse ovary [J]. Toxicology and Applied Pharmacology,2006,216:436–445.
44 Martinez EM, Swartz WJ. Effects of methoxychlor on the reproductive system of the adult female mouse.1.Gross and histologic observations[J]. Reprod Toxicol,1991,5(2):139-47.
45 Martinez EM, Swartz WJ. Effects of methoxychlor on the reproductive system of the adult female mouse: 2. Ultrastructural observations[J].Reprod Toxicol,1992;6(1):93-8.
46 Cummings AM, Laskey J.Effect of methoxychlor on ovaria steroidogenesis: role in early pregnancy loss[J]. Reprod Toxicol,1993;7(1):17-23.
47 Tiemann U, Pohland R, Schneider F.Influence of organochlorine pesticides on physiological potency of cultured granulosa cells from bovine preovulatory follicles[J]. Theriogenology,1996; 46(2):253-65.
48 Uzumcu M,Kuhn PE,Marano JE,et al.Early postnatal methoxychlor exposure inhibits folliculogenesis and stimulates anti-Mullerian hormone production in the rat ovary[J]. Endocrinol,2006,191(3):549-58.
49 Miller KP, Gupta RK, Flaws JA. Methoxychlor metabolites may cause ovarian toxicity through estrogen-regulated pathways[J].Toxicol Sci. 2006 ; 93(1):180-8.
50 Tomic D, Frech MS, Babus JK,et al.Methoxychlor induces atresia of antral follicles in ERalpha-overexpressing mice[J].Toxicol Sci. 2006 ; 93(1):196-204.
51 Borgeest C,Symonds D,Mayer LP,et al.Methoxychlor may cause ovarian follicular atresia and proliferation of the ovarian epithelium in the mouse[J]. Toxicol Sci, 2002,68(2):473-8.
52 Symonds DA,Tomic D,Miller KP,et al.Methoxychlor induces proliferation of the mouse ovarian surface epithelium[J]. Toxicol Sci, 2005,83(2):355-62.
53 Hironori Takagi, Makoto Shibutani, Kyoung-Youl Le. Impact of maternal dietary exposure to endocrine-acting chemicals on progesterone receptor expression in microdissected hypothalamic medial preoptic areas of rat offspring[J]. Toxicology and Applied Pharmacology,2005,208:127–136
54 Suzuki M, Lee H C, Chiba S, et al. Effects of methoxychlor exposure during perinatal period on reproductive function after maturation in rats [J]. Reproductive and Development, 2004,50(4):455-61.
55 Sergei Y A, Elena A K, Alevtina N G, et al. Preimplantation exposures of murine embryos to estradiol or methoxychlor change postnatal development[J]. Reproductive Toxicology,2004,18:103–108
56 M.A. Ottinger, M.J. Quinn Jr, E. Lavoie, et al. Consequences of endocrine disrupting chemicals on reproductive endocrine function in birds:Establishing reliable end points of exposure[J].Domestic Animal Endocrinology, 2005, 29: 414-419
57 Wang XJ, Bartolucci-Page E, Fenton SE, et al. Altered mammary gland development in male rats exposed to genistein and methoxychlor[J]. Toxicological Science,2006,91(1):93-103.
58 Yukiko Takeuchi, Tadashi Kosaka, Koichi Hayashi,et al. Thymic atrophy induced by methoxychlor in rat pups[J]. Toxicol letters,2002,135(3):199-207
59 Guo TL, Germolec DR, Musgrove DL, et al.Myelotoxicity in genistein-,nonylphenol-, methoxychlor-,vinclozolin- or ethinyl estradiol-exposed F1 generations of Sprague–Dawley rats following developmental and adult exposures[J].Toxicology,2005,211:207–219.
60 Eroschenko VP.Ultrastructure of vagina and uterus in young mice after methoxychlor exposure[J].Reprod Toxicol. 1991;5(5):427-35.
61 Rourke AW, Eroschenko VP, Washburn LJ. Protein secretions in mouse uterus after methoxychlor or estradiol exposure[J].Reprod Toxicol. 1991;5(5):437-42.
62 Cummings AM, Metcalf JL. Effects of estrogen, progesterone, and methoxychlor on surgically induced endometriosis in rats[J].Fundam Appl Toxicol. 1995 ;27(2):287-90.
63 Tiemann U, Schneider F, Tuchscherer A. Effects of organochlorine pesticides on DNA synthesis of cultured oviductal and uterine cells and on estrogen receptor of uterine tissue from heifers[J].Arch Toxicol. 1996;70(8):490-6.64
64 Tiemann U, Kuchenmeister U. Influence of organochlorine pesticides on ATPase activities of microsomal fractions of bovine oviductal and endometrial cells[J].Toxicol Lett. 1999; 104(1-2):75-81.
65 Eroschenko VP, Johnson TJ, Rourke AW. Estradiol and pesticide methoxychlor do not exhibit additivity or synergism in the reproductive tract of adult ovariectomized mice[J].Toxicol Environ Health A. 2000; 60(6): 407-21.
66 Hodges LC, Bergerson JS, Hunter DS, Walker CL. Estrogenic effects of organochlorine pesticides on uterine leiomyoma cells in vitro[J].Toxicol Sci.2000,54(2):355-64.
67 Kiberstis PA.Mitochondria make a comeback[J].Sciencel,1999,283:1475.
68刘树森.线粒体学与生物医学新前沿[J].世界科技研究与发展,2001,23:35-43.
69 Gunter TE,Gunter KK,Sheu SS,et al. Mitochondrial calcium transport: physiological and pathological relevance[ J]. Am J Physiol, 1994, 267: 313- 339.
70 Gunter TE, Buntinas L, Sparagna GC, et al. The Ca2+ transport mechanisms of mitochondria and Ca2+ uptake from physiological-type Ca2+ transients[J]. BBA, 1998, 1366(1-2): 5-17
71潘丙珍.线粒体在细胞凋亡中的作用.美国中华临床医学杂志[ J]. 2006, 8(2):218-220.
72陈慧利,李建华,王树庆.线粒体跨膜电位和细胞凋亡相关性的研究[J].分子生物学,2007,13:1041-1043.
73 Ischiropoulos H, Beckman JS. Oxidative stress and nitration in Neurodegeneration: cause , effect ,or association[J].Clin Invest , 2003 , 111(2) : 163 - 169.
74 Voeikov VL. Biological oxidation: over a century of hardship for the concept of active oxygen [J]. Cell Mol Biol, 2005 , 517 :663 - 675.
75 Magder S. Reactiveoxygen species: toxic moleculesor sparkof life[J].Crit Care , 2006 , 101:208.
76 Hsu SY,Hsueh AJ.Tissue-specific Bcl-2 protein partners in apoptosis:An ovarian paradigmJ [J]. Physiol Rev,2000 ,80(2):593-614.
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