Diethylhexyl phthalate magnifies deposition of 14 C-bisphenol A in reproductive tissues of mice.

Endocrine disrupting chemicals are found in diverse common products, including cosmetics, food packaging, thermal receipt paper and plastic containers. This exposes most people in developed countries through ingestion, skin absorption and inhalation. Two ubiquitous endocrine disrupting chemicals, bisphenol A (BPA) and diethylhexyl phthalate (DEHP) can interact in disrupting blastocyst implantation in inseminated females. We hypothesized that DEHP might increase the bioavailability of BPA in tissues by competing for metabolic enzymes. We injected 0, 3, 9 or 18 mg DEHP into female and male mice and allowed 30 min for the chemical to circulate before giving them a food supplement containing 50 µg kg-1 14 C-BPA. Animals were dissected 1 h following 14 C-BPA administration and various tissue samples were acquired. Samples were solubilized and radioactivity was measured via liquid scintillation counting. In cycling females, DEHP increased BPA deposition in the muscle, uterus, ovaries and blood serum relative to controls. In peri-implantation females, DEHP increased deposition of BPA in the uterus, ovaries and serum relative to controls. In males, DEHP doses increased BPA deposition in serum and epididymis relative to controls. These results are consistent with the hypothesis that DEHP competes with BPA for conjugating enzymes such as UDP-glucuronosyltransferase, thereby magnifying the presence of BPA in estrogen-binding reproductive tissues. Copyright © 2017 John Wiley & Sons, Ltd.

Concurrent administration of diethylhexyl phthalate reduces the threshold dose at which bisphenol A disrupts blastocyst implantation and cadherins in mice.

Many people are repeatedly exposed to both bisphenol A (BPA) and diethylhexyl phthalate (DEHP), but there has been little research concerning their effects in combination. Both can disrupt blastocyst implantation in inseminated females, albeit at high doses. We exposed mice on gestation days (GD) 1-4 to combinations of BPA and DEHP in doses below the threshold necessary to disrupt implantation on their own. On GD 6, there were fewer normally-developed implantation sites and more underdeveloped implantation sites in females given the combined subthreshold doses. Uterine epithelial cadherin (e-cadherin), a protein that assists in blastocyst adhesion to the uterine epithelium, was significantly reduced by these combined doses, but not by the individual doses. A similar trend was seen in integrin αvß3, another uterine adhesion molecule. Cadherin-11 was disrupted by BPA but not DEHP. These data are consistent with competition of BPA and DEHP for conjugating enzymes.

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.