Neonatal Genistein Exposure and Glucocorticoid Signaling in the Adult Mouse Uterus.

ABSTRACT: BACKGROUND:Female reproductive tract development is sensitive to the endocrine-disrupting potential of environmental estrogens. Early-life exposure to the dietary phytoestrogen genistein impairs fertility and persistently alters the transcriptome in the oviduct and uterus of rodents. Glucocorticoid signaling, which has recently been shown to be essential for normal fertility in the female mouse uterus, is antagonized by genistein. OBJECTIVE:Our goal was to determine whether early-life exposure to genistein disrupts glucocorticoid signaling in the mouse uterus, which may contribute to infertility. METHODS:Female C57Bl/6 mice were exposed to either 50 mg/kg?per?day genistein, 10 ?g/kg?per?day estradiol, or vehicle (corn oil) on postnatal days 1-5 (PND1-5), and then treated with the synthetic glucocorticoid dexamethasone (Dex: 1 mg/kg) or vehicle (saline) on PND5, at weaning on PND21, or as adults on PND56 following adrenalectomy and ovariectomy to evaluate glucocorticoid responsiveness. Uteri were isolated following treatment for gene expression or chromatin immunoprecipitation. RESULTS:Neonatal exposure to genistein altered the uterine transcriptome of adult mice and caused substantial changes to the transcriptional response to glucocorticoids. Although expression of the glucocorticoid receptor was not affected, genistein exposure disrupted glucocorticoid receptor recruitment to specific regulatory sites in target genes. Many genes involved in chromatin remodeling were dysregulated in genistein-exposed mice, suggesting that epigenetic reprograming may contribute to the altered glucocorticoid response of the uterus following early-life exposure to genistein. These changes affected the biological activity of glucocorticoids within the uterus, as glucocorticoids antagonized the proliferative effects of estradiol in the uterus of control mice but not genistein-exposed mice. CONCLUSIONS:Our findings suggest that disruption of glucocorticoid signaling due to early-life exposure to environmental estrogens may in part render the uterus unable to support implantation. https://doi.org/10.1289/EHP1575.

SUBMITTER: Whirledge SD 

PROVIDER: S-EPMC6071733 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature