THE IMPACT OF BISPHENOL A IN COMBINATION WITH STRESS AND DIETHYLHEXYL PHTHALATE ON IMPLANTATION, UTERINE MORPHOLOGY, AND ADHESION PROTEIN EXPRESSION IN INSEMINATED FEMALE MICE

Abstract

Bisphenol A (BPA), the monomer of polycarbonate plastics and epoxy resins, can disrupt intrauterine implantation of fertilized ova in mice. This effect is also induced by exposure to chronic stress or high doses of diethylhexyl phthalate (DEHP), a plasticizer found in polyvinyl chloride products. I assessed the potential combinatory effects of BPA and stress on blastocyst implantation, uterine morphology, adhesion protein expression, and urinary hormone levels. Subcutaneous injections of BPA administered from gestation days (GDs) 1–4 paired with a stressor (rat exposure across a grid) reduced the number of implantation sites on GD 6 at a dose where neither BPA nor stress had this effect on their own. Uterine luminal area was increased by BPA when paired with stress. BPA reduced epithelial cadherin (e-cadherin), a uterine adhesion protein, independently from the stressor. Urinary estradiol was significantly increased by BPA relative to controls, regardless of stress. In other experiments, effects of concurrent BPA and DEHP administered were assessed. Inseminated female mice were injected with BPA, DEHP, or BPA + DEHP from GDs 1–4. Implantation measured in uteri on GD 6 was disrupted by a combined dose but not by the individual doses. This dose also decreased the amount of e-cadherin and cadherin-11, another adhesion protein expressed by cells, while cadherin-11 was also affected by BPA alone. In further experiments designed to elucidate the interaction of BPA and DEHP, mice were fed 14C-BPA and injected with varied doses of DEHP, then tissues were excised and measured for radioactivity. When given DEHP, males and cycling and peri implantation females showed increased BPA deposition in reproductive tissues and serum. As people are commonly exposed to both DEHP and BPA through consumer products, it is important to determine their interactions and also to understand how dose-response is affected by other factors such as stress.