Xenoestrogen exposure imprints expression of genes (Hoxa10) required for normal uterine development

The developing reproductive tract is sensitive to endocrine perturbation. Bisphenol A (BPA), a xenoestrogen, is a common component of food storage plastics and dental composites. We tested the ability of BPA to alter expression of HOXA10, a gene necessary for uterine development. A dose-response increase in HOXA10 mRNA expression was demonstrated in Ishikawa cells treated with 0.1 nM to 25 microM BPA. To determine whether in utero BPA exposure resulted in a lasting alteration of uterine HOXA10 expression, mice were treated with 0.5-5.0 mg/kg BPA on gestational days 9-16. A dose-responsive increase was seen in stromal cell HOXA10 expression in 2- and 6-week-old mice exposed in utero. To discern the mechanism of BPA action, the HOXA10 estrogen response element (ERE) and autoregulatory element (ARE) were tested for BPA responsiveness. BPA drove luciferase expression from HOXA10-ERE and ARE reporter constructs. HOXA10 ERE mediated induction was blocked by ER antagonist ICI, while HOXA10 ARE induction was blocked by either ICI or HOXA10 antisense. BPA affects HOXA10 expression through the HOXA10 ERE and indirectly through the ARE. BPA initially alters HOXA10 expression through the ERE, however, the response is imprinted and uncoupled from estrogen stimulation in the adult. Several xenoestrogens alter HOX gene expression, indicating that HOX genes are a common target of endocrine disruption. In utero exposure to a xenoestrogen produces reproductive tract alterations by imprinting essential developmental regulatory genes.