Developmental exposure to bisphenol A impairs the uterine response to ovarian steroids in the adulthood

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

ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2008 vol. 149 p. 5848 - 5860

0013-7227

Morphoregulator genes like members of the Hox gene family regulate uterine development and are associated to endocrine-related processes such as endometrial proliferation and differentiation in the adult uterus.  Neonatal endocrine disruptors exposure could affect signalling events governed by Hox genes, altering the developmental trajectory of the uterus with lasting consequences.  We investigated whether neonatal exposure to bisphenol A (BPA) alters Hoxa10 and Hoxa11 mRNA uterine expression shortly after treatment and in the adulthood.  Moreover, we studied whether xenoestrogen exposure may affect the adult uterine response to hormonal stimuli.  Newborn females received on postnatal days (PND) 1, 3, 5, 7: vehicle, BPA.05 (0.05 mg/kg/day), BPA20 (20 mg/kg/day), or diethylstilbestrol (DES, 0.2 mg/kg/day).  At PND8, real time RT-PCR assays showed a decrease in Hoxa10 and Hoxa11 expression in all xenoestrogen-treated groups.  To evaluate the long-term effects, we used adult ovariectomized rats with hormonal replacement.  The subepithelial stroma in BPA- and DES-animals showed an impaired proliferative response to steroid treatment, associated with a silencing of Hoxa10, but not associated with changes in the methylation pattern of the Hoxa10 promoter.  BPA animals showed that the Hoxa10 reduction was accompanied by an increased stromal expression of the silencing mediator for retinoic acid and thyroid hormone receptor (SMRT).  The spatial coexpression of steroid receptors, Hoxa10 and SMRT was established using immunofluorescence.  Our data indicate that postnatal BPA exposure affects the steroid hormone-responsiveness of uterine stroma in the adulthood.  Whether this impaired hormonal response is associated with negative effects on uterine receptivity and decidualization is under investigation.