Neonatal Exposure to Bisphenol A Alters Rat Uterine Implantation-Associated Gene Expression and Reduces the Number of Implantation Sites

Endocrine disrupters have been associated with reproductive pathologies such as infertility and gynecological tumors. Using a rat model of early postnatal exposure to bisphenol A (BPA), we evaluated the long-term effects on 1) female reproductive performance, 2) uterine homeobox A10 (Hoxa10) and Hoxa10-target gene expression, and 3) ovarian steroid levels and uterine estrogen receptor alpha and progesterone (P) receptor expression. Newborn female rats received vehicle, BPA.05 (0.05 mg/kg . d), BPA20(20 mg/kg . d), diethylstilbestrol. 2 (0.2 mu g/kg . d), or diethylstilbestrol 20 (20 mu g/kg . d) on postnatal d 1, 3, 5, and 7. A significant decrease in the number of implantation sites was assessed in the xenoestrogen-exposed females. To address the molecular effects of postnatal xenoestrogen exposure on the pregnant uterus, we evaluated the expression of implantation-associated genes on d 5 of pregnancy (preimplantation uterus). All xenoestrogen-treated rats showed a lower expression of Hoxa10. In the same animals, two Hoxa10-downstream genes were misregulated in the uterus. beta(3) Integrin, which is up-regulated by Hoxa10 in controls, was decreased, whereas empty spiracles homolog 2, which is down-regulated by Hoxa10, was increased. Furthermore a clear down-regulation of estrogen receptor alpha and P receptor expression was detected without changes in estradiol and P serum levels. The early exposure to BPA produced a lower number of implantation sites in association with a defective uterine environment during the preimplantation period. Alterations in the endocrine-regulated Hoxa10 gene pathways (steroid receptors-Hoxa10-beta(3) integrin/empty spiracles homolog 2) could explain, at least in part, the BPA effects on the implantation process. (Endocrinology 152: 1101-1111, 2011)