Environmental Chemical Exposures During Mid-gestation and Biomarkers of Placental Development

Abstract

While the mechanisms and periods of sensitivity remain undefined, in utero exposures to environmental chemicals (ECs) are associated with placenta-mediated fetal and maternal health complications. To investigate the relationship between EC exposures and human placental development during mid-gestation, we performed a two-part analysis: 1) an evaluation of polybrominated diphenyl ethers (PBDEs), per- and poly-fluorinated alkyl substances (PFAS), and organophosphate flame retardants (OPFRs) exposures in matched samples of maternal serum, urine, placenta, and/or fetal liver collected from healthy women undergoing elective termination procedures during the 2nd trimester (2014-16); and 2) a semi-quantitative characterization of biomarkers of human placental development in relation to EC levels (n=62). We examined chemical levels and their associations with biomarkers of placental development using censored Kendall’s tau correlation and maximum likelihood regression. We profiled placental cytotrophoblast (CTB) expression of key molecules involved in CTB differentiation and uterine invasion─ ITGA1, CDH5, MMP1─and morphological features: leukocyte recruitment, fibrinoid deposition, and endovascular CTB invasion. Specific ECs were widely detected and differentially distributed across the tested biomatrices. For example, PBDEs were identified in all maternal serum, fetal liver and placental biomatrices, and prior to lipid adjustment, wet-weight levels of PBDE congeners were highest in the fetal liver as compared to the other compartments (p<0.001). Furthermore, we observed significant associations between PBDE (placenta), PFAS (serum), and OPFR (urine) levels and immunoreactivity of ITGA1 (endovascular CTBs; inverse) or CDH5 (interstitial CTBs; positive), suggesting that the localized expression of these molecules in the placenta may be sensitive indicators of chemical exposure. Our results suggest that ECs are widely detected and differentially distributed in maternal-fetal compartments. Furthermore, we propose specific biomarkers of placental development as potential barometers of PBDE, PFAS, and OPFR exposure during mid-gestation. This paradigm could be extended to other environmental chemicals and placental-specific biomarkers.