Neonatal exposure to bisphenol A alters uterine implantation-associated gene expression and induces female subfertility.

VARAYOUD J; RAMOS JG; BOSQUIAZZO VL; LOWER M; MUÑOZ-DE-TORO M; LUQUE EH

ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2011 vol. 152 p. 1101 - 1111

0013-7227

Endocrine disrupters have been associated with reproductive pathologies such as infertility and gynecological tumors. Using a model of early postnatal exposure to bisphenol A (BPA) we evaluated the long-term effects on: 1) female reproductive performance, 2) uterine Hoxa10 and Hoxa10-target gene expression, and 3) ovarian steroid levels and uterine estrogen receptor α (ERα) and progesterone receptor (PR) expression. Newborn females received vehicle, BPA.05 (0.05 mg/kg/day), BPA20 (20 mg/kg/day), diethylstilbestrol DES.2 (0.2 mg/kg/day) or DES20 (20 mg/kg/day) on postnatal days (PNDs) 1, 3, 5 and 7. A significant decrease in the number of implantation sites was assessed in the xenoestrogen-exposed females. To address alterations at a molecular level we evaluated the expression of implantation-associated genes on day 5 of pregnancy (pre-implantation uterus). All xenoestrogen-treated rats showed a lower expression of Hoxa10 mRNA. In the same animals, two Hoxa10-downstream genes were misregulated in the uterus. b3 integrin (ITGB3), which is upregulated by Hoxa10 in controls, was decreased, whereas empty spiracles homolog 2 (EMX-2), which is downregulated by Hoxa10, was increased. Furthermore a clear downregulation of ERα and PR expression was detected without changes in estradiol and progesterone serum levels. The early exposure to BPA produced a lower number of implantation sites in association with a defective uterine environment during the pre-implantation period. Alterations in the endocrine-regulated Hoxa10 gene pathways (steroid receptors—Hoxa10—ITGB3/EMX-2) could explain, at least in part, the BPA effects on the implantation process.