ENDOCRINE DISRUPTORS EFFECTS ON OFFSPRING

描述：（改编自申请人的描述）该项目审查 对男性和女性生殖器官发育的影响 与母体摄入环境雌激素有关的后代， 双酚A，在怀孕和哺乳期。 超过10亿磅的 双酚A每年用于制造树脂涂料， 食品和饮料罐以及聚碳酸酯食品和饮料容器。 双酚A在消毒过程中会进入食物。 一 初步研究中，怀孕小鼠摄入了一定剂量的双酚A， 可以被食用罐头食品的人消耗，表明双酚A是 仅比口服己烯雌酚的效力低10- 100倍 (DES)这两种化学物质都永久性地改变了男性的前列腺 后代 主要目的是确定暴露期间的影响， 开发低，环境相关剂量的双酚A; DES将 作为雌激素作用的阳性对照给药。 携带a 将雌激素受体（ER）基因的突变与野生型进行比较 小鼠（表达正常雌激素受体）和纯合子ER敲除小鼠 小鼠（对雌激素无反应）在同一窝内生产。 急诊室- 小鼠将允许确定雌激素化学物质的影响是否 对生殖器官发育的影响是通过与雌激素结合来介导的 受体或通过替代反应途径。 生殖器官将会 在胎儿期（性分化期间）、婴儿期 （性分化几乎完成）和成年期。 器官要 检查包括女性的子宫和卵巢，以及前列腺、附睾 和雄性睾丸中进行了多种测定。 章节编写自 将使用以下方法检查前列腺和子宫：1）定量形态测定法，2） 原位杂交组织化学（ISHH），以测量编码 雌激素和雄激素受体，3）雌激素和雄激素的数量 受体（通过交换测定），和4）细胞增殖速率（通过 免疫染色）。 还将确定基因差异是否 活性由于差异甲基化的启动子区域内的 雌激素和雄激素受体基因介导先前观察到的效应 雌激素对子宫雌激素和雄激素受体数量的影响 和前列腺。 卵泡数量和类型在卵巢和日常 将确定睾丸中的精子产量以及细菌的比例 睾丸中的支持细胞和附睾中的精子数量。

DESCRIPTION: (adapted from applicant's description) This project examines the consequences on reproductive organ development in male and female offspring associated with maternal ingestion of the environmental estrogen, bisphenol A, during pregnancy and lactation. Over one-billion pounds of bisphenol A are used annually in the manufacture of the resin coating of food and beverage cans and in polycarbonate food and drink containers. Bisphenol A migrates into food during the sterilization process. A preliminary study in which pregnant mice ingested a dose of bisphenol A that could be consumed by people eating canned foods showed that bisphenol A was only 10- 100-times less potent than orally ingested diethylstilbestrol (DES),and both chemicals permanently altered the prostate gland in male offspring. The primary objective is to determine effects of exposure during development to low, environmentally relevant doses of bisphenol A; DES will be administered as a positive control for estrogen action. Mice carrying a mutation for the estrogen receptor (ER) gene will be compared to wild type mice (that express normal estrogen receptors) and homozygous ER-knockout mice (unresponsive to estrogen) produced within the same litter. The ER- mouse will allow a determination of whether effects of estrogenic chemicals on reproductive organ development are mediated via binding to estrogen receptors or via alternative response pathways. Reproductive organs will be collected during fetal life (during sexual differentiation), during infancy (sexual differentiation is almost completed) and in adulthood. Organs to be examined include uteri and ovaries in females, and prostate, epididymides and testes in males using a variety of assays. Sections prepared from prostates and uteri will be examined using: 1) quantitative morphometry, 2) in situ hybridization histochemistry (ISHH) to measure mRNAs encoding estrogen and androgen receptors, 3) numbers of estrogen and androgen receptors (by exchange assays), and 4) rates of cell proliferation (by immunostaining). It will also be determined whether differences in gene activity due to differential methylation within the promoter region of the estrogen and androgen receptor gene mediate the previously observed effects of estrogenic chemicals on estrogen and androgen receptor numbers in uterus and prostate, respectively. Follicle numbers and types in ovaries and daily sperm production in testes will be determined, as will the ratio of germ cells to Sertoli cells in testes and sperm numbers in epididymides.