ENDOCRINE DISRUPTORS EFFECTS ON OFFSPRING

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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.