Human Bisphenol a Biomonitoring and Biotransformation Programming in the Developing Fetus.

Abstract

The ubiquitous monomer, bisphenol A (BPA), is an endocrine active compound used in the production of polycarbonate plastics and epoxy resin. Environmental biomonitoring and epidemiology studies report continuous exposure in humans that are associated with different adverse health outcomes. The overall goal of this work was to characterize BPA concentrations, toxicokinetic and toxicodynamic profiles that influence tissue-specific BPA biotransformation via xenobiotic metabolizing enzymes (XME), and BPA dependent changes in biotransformation using healthy 1st-2nd trimester clinical specimens obtained from a fetal biobank.

First, we reported a wide range of BPA concentrations in N=50 fetal liver specimens (total BPA range: below limit of quantification - 96.8 ng/g). Both concentrations and metabolic profiles varied across age with significant reduction in BPA-specific XME gene expression of UGT2B15, SULT1A1, and STS in fetal versus adult livers. Next, we examined matched fetal liver, kidney, and placenta in N=12 subjects and observed significant tissue-dependent differences in BPA concentrations, XME expression profiles, and global DNA methylation. Fetal livers exhibited higher BPA concentrations compared to matched tissues; however, XME expression profiles suggest an increased likelihood of BPA-glucuronide deconjugation and BPA-sulfate conjugation across the fetal compartments. With organ-specific differences in the epigenome, only placental global methylation measurements were associated with BPA. Finally, we investigated BPA’s role in pathway specific biological outcomes and regulation in fetal liver. In particular, we identified 14 different XME candidate genes that were down regulated with higher BPA concentrations.

In summary, results suggest that the 1st-2nd trimester human fetus is exposed to a considerable amount of BPA in utero, especially of the active free BPA form. XME expression profiles reveal an altered capacity for BPA biotransformation in the fetus compared to adults, with distinct metabolic profiles across different tissues. Interestingly, higher BPA concentrations in fetal liver were associated with reduced expression of novel XME candidate genes mediated by epigenetic mechanisms. These findings indicate that environmentally relevant concentrations of BPA, even across a short window of development, result in detectable changes in the host’s toxicological defense system.