Neonatal exposure to bisphenol A alters rat uterine implantation-associated gene expression and reduces the number of implantation sites

Endocrinology. 2011 Mar;152(3):1101-11. doi: 10.1210/en.2009-1037. Epub 2011 Feb 1.


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 α 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 μg/kg · d), or diethylstilbestrol 20 (20 μg/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. β(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 α 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--β(3) integrin/empty spiracles homolog 2) could explain, at least in part, the BPA effects on the implantation process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Benzhydryl Compounds
  • Embryo Implantation / physiology*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Regulation, Developmental / drug effects*
  • Homeobox A10 Proteins
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Integrin beta3 / genetics
  • Integrin beta3 / metabolism
  • Male
  • Ovary / metabolism
  • Phenols / toxicity*
  • Pregnancy
  • Rats
  • Rats, Inbred Strains
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Uterus / physiology*


  • Benzhydryl Compounds
  • Estrogen Receptor alpha
  • HOXA10 protein, rat
  • Homeobox A10 Proteins
  • Homeodomain Proteins
  • Integrin beta3
  • Phenols
  • Receptors, Progesterone
  • Transcription Factors
  • empty spiracles homeobox proteins
  • bisphenol A