Endocrine disrupting chemicals (EDCs) are compounds that can interfere with normal endocrine functions. Human exposure to EDCs is particularly concerning during vulnerable times in life, such as early development and pregnancy due to the plasticity of the fetus' developing organs during the prenatal period. EDCs are pervasive, with studies demonstrating that most EDCs can cross the placental barrier, reaching fetal circulation. Chemical transfer into fetal circulation could have negative implications for the developing progeny. However, often overlooked is the effect that these chemicals may pose to the placenta. Being a transient yet complex steroidogenic endocrine organ, with abundant expression of hormone receptors, the placenta is highly sensitive to EDC exposures. Such exposures during pregnancy can alter the development and function of the placenta, resulting in adverse birth outcomes like intrauterine growth restriction, or complex obstetric disorders like preeclampsia. This dissertation will present research which advances our understanding of EDC exposures on the development and function of the placenta.Bisphenols are a class of chemical used in the production of industrial and consumer plastics, epoxy resins, thermal receipt paper, and canned food lining. The most widely studied of these is bisphenol A (BPA), but little is known about commonly used emerging bisphenols, like bisphenol S (BPS) and bisphenol F (BPF). BPA, BPS, and BPF are the three most common bisphenols in human circulation worldwide and are detected concomitantly in biomonitoring studies. Despite broad human environmental exposures, the toxicokinetics of emerging bisphenols, particularly in mixture, and during pregnancy, remain unknown. Therefore, the first aim of this dissertation was to determine the comparative toxicokinetics of BPA, BPS, and BPF, in mixture versus a single compound, in a pregnancy model. As a sub-aim, this toxicokinetic dataset was used to develop predictive pregnancy physiologically-based toxicokinetic models for BPA and BPS. These mathematical models were developed to be employed as risk assessment tools to better understand maternal and fetal exposures to emerging EDCs across gestation.As previous studies have shown BPA exposure negative effects placental development in mice, we aimed to study this effect following exposure to BPS and hypothesized that chronic gestational exposure to both BPA and BPS would disrupt placental development and endocrine function. Here, we observed a novel placental defect in endocrine function and altered fused placental trophoblast populations resultant from chronic BPS, but not BPA, exposure. As a sub-aim, and for the purpose of interspecies translatability, we use in vitro techniques to evaluate the effect of BPS on primary isolated human placental trophoblast cell fusion; a necessary process for the development and function of the placenta.Data from aim two are suggestive of BPS-induced repression of gap junction intercellular communication (GJIC). Because primary isolated placental trophoblast cells are unsuitable to conduct functional assays to assess this outcome, ovarian theca cells, which have a similar expression of proteins forming gap junctions were used. Therefore, the third aim of this dissertation was to evaluate the effects of in vitro exposure to BPA, BPS, and BPF on GJIC, and hypothesized that BPS would inhibit GJIC in ovarian theca cells. Importantly, BPS was observed to enhance GJIC through the mitogen-activated protein kinase signaling pathway in sheep and human theca cells. A sub-aim of this study was to develop a parachute assay capable of measuring GJIC in immortalized placental trophoblast cells.Together, the data presented in this dissertation evaluates the pregnancy toxicokinetics of three prominent bisphenols, identifies a novel placental defect following chronic gestational exposure to BPS, a potential mechanisms through which this defect may be occurring, and provides an overall cohesive insight into the risk emerging EDCs, like BPS, pose to the development and function of the placenta.
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