Different environmental chemicals can affect the reproductive capability of a variety of organisms, depending on the timing and dose of exposure, and are thought to impact human reproduction as well. One example is the phytoestrogen, genistein, which when given to neonatal female mice has long-term effects on their ability to reproduce. The underlying causes of their infertility, however, are not known. A second example is diethylstilbestrol, which causes reproductive tract malformations when given prenatally (before birth) and reproductive tract dysfunction and cancer when given neonatally (around the time of birth). We are using both neonatal genistein and DES treatments to determine how estrogenic compounds affect female reproductive tract development and function, and how these compounds influence embryo development within the female reproductive tract through the time of implantation. These studies are relevant to human fertility because genistein levels similar to those reached in our mouse model are measured in babies on soy-based infant formula, and many other estrogenic compounds are found in the environment and could affect reproductive tract development and function. Female mice treated neonatally with DES are infertile at reproductive age and develop uterine cancer as older adults. During the past year we performed a series of experiments to determine how the neonatal exposure changes gene expression profiles in the adult uterus that may explain these phenotypes. We found that neonatal DES exposure changes protein levels of several chormatin-modifying proteins and causes permanent alterations in epigenetic marks at specific gene loci. We are continuing studies to determine the epigenetic mechanisms underlying the effects of both genistein and DES on female reproductive tract function. There is evidence in rodents that prenatal exposure to environmentally relevant doses of bisphenol A (BPA) causes abnormal ovarian and female reproductive tract development. Although the rodent studies have raised concerns regarding human exposure to BPA, there is minimal information regarding the effects of BPA on development in humans or non-human primate models. Dr. Patricia Hunt (Washington State Univ.) and Dr. Cathy VandeVoort (UC Davis Primate Center) initiated a study to examine the effects of maternal BPA exposure during either the 2nd or 3rd trimesters of pregnancy on development of female Rhesus monkey fetuses. The monkeys were treated using 2 different BPA dosing strategies, and all tissues have been collected. We have finished our evaluation of the morphology and gene expression in the female reproductive tract. This project generated a gene expression profile of developing normal Rhesus monkey oviduct and uterus, and also provided evidence for differences in the gene expression profiles and histology when comparing control and BPA-treated groups. This work has been submitted for publication.

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Suen, Alisa A; Jefferson, Wendy N; Wood, Charles E et al. (2016) SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer. Mol Cancer Res 14:849-58
Ho, Shuk-Mei; Cheong, Ana; Adgent, Margaret A et al. (2016) Environmental factors, epigenetics, and developmental origin of reproductive disorders. Reprod Toxicol :
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Winuthayanon, Wipawee; Bernhardt, Miranda L; Padilla-Banks, Elizabeth et al. (2015) Oviductal estrogen receptor α signaling prevents protease-mediated embryo death. Elife 4:e10453
Calhoun, Kathryn C; Padilla-Banks, Elizabeth; Jefferson, Wendy N et al. (2014) Bisphenol A exposure alters developmental gene expression in the fetal rhesus macaque uterus. PLoS One 9:e85894
Jensen, E T; Daniels, J L; Stürmer, T et al. (2014) Maternal hormonal contraceptive use and offspring overweight or obesity. Int J Obes (Lond) 38:1275-81
Jefferson, Wendy N; Chevalier, Dominique M; Phelps, Jazma Y et al. (2013) Persistently Altered Epigenetic Marks in the Mouse Uterus After Neonatal Estrogen Exposure. Mol Endocrinol :
Padilla-Banks, Elizabeth; Jefferson, Wendy N; Myers, Page H et al. (2012) Neonatal phytoestrogen exposure causes hypospadias in female mice. Mol Reprod Dev 79:3
Jefferson, Wendy N; Patisaul, Heather B; Williams, Carmen J (2012) Reproductive consequences of developmental phytoestrogen exposure. Reproduction 143:247-60

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