Stress lowers the threshold dose at which bisphenol A disrupts blastocyst implantation, in conjunction with decreased uterine closure and e-cadherin

Exposure to stress can disrupt blastocyst implantation in inseminated female mice, and evidence implicates elevation of the female's estrogen:progesterone ratio. Exposure to the xenoestrogen, bisphenol A (BPA) can also disrupt implantation. Undisturbed control female CF-1 mice were compared to other females that were exposed to predators (rats) across a wire-mesh grid during gestation days (GD) 1-4, a procedure that elevates corticosterone but does not on its own disrupt implantation in this genetic strain. They were concurrently exposed to varied doses of BPA that on their own were below the threshold dose sufficient to disrupt implantation. On GD 6, we measured the number of intrauterine implantation sites and extracted their uteri, which subsequently were stained and analyzed for uterine luminal area and epithelial cadherin (e-cadherin), a molecule that causes uterine closure and adhesion of blastocysts to the uterine epithelium. The combination of rat-exposure stress and BPA significantly disrupted implantation and increased uterine luminal area, whereas either manipulation on its own did not. E-cadherin was significantly reduced by exposure to BPA, positively correlated with the number of implantation sites, and inversely correlated with luminal area. BPA exposure was also associated with nonmonotonic perturbation of urinary corticosterone concentrations and increased urinary estradiol concentrations on GD 6. These data are consistent with a potential summation of stress-induced estrogen and xenoestrogen activity.