Estrogen receptor 1 expression and methylation of Esr1 promoter in mouse fetal prostate mesenchymal cells induced by gestational exposure to bisphenol A or ethinylestradiol

Fetal/neonatal environmental estrogen exposures alter developmental programing of the prostate gland causing onset of diseases later in life. We have previously shown in vitro that exposures to 17 beta-estradiol (E2) and the endocrine disrupting chemical bisphenol A, at concentrations relevant to human exposure, cause an elevation of estrogen receptor alpha (Esr1) mRNA in primary cultures of fetalmouse prostatemesenchymal cells; a similar result was observed in the fetal rat urogenital sinus. Effects of these chemicals on prostatemesenchyme in vivo are not well understood. Here we show effects inmice of fetal exposure to the estrogenic drug inmixed oral contraceptives, 17 alpha-ethinylestradiol (EE2), at a concentration of EE2 encountered by human embryos/fetuses whosemothers become pregnant while on EE2-containing oral contraceptives, or bisphenol A at a concentration relevant to exposures observed in human fetuses in vivo. Expression of Esr1 was elevated by bisphenol A or EE2 exposures, which decreased the global expression of DNA methyltransferase 3A (Dnmt3a), whilemethylation of Esr1 promoter was significantly increased. These results show that exposures to the environmental estrogen bisphenol A and drug EE2 cause transcriptional and epigenetic alterations to expression of estrogen receptors in developing prostate mesenchyme in vivo.