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The current obesity epidemic is calling for action in the determination of contributing factors. Although social and life-style factors have been traditionally associated with metabolic disruption, a subset of endocrine-disrupting chemicals (EDCs), called obesogens are garnering increasing attention for their ability to promote adipose tissue differentiation and accumulation. For some chemicals, such as tributyltin, there is conclusive evidence regarding their ability to promote adipogenesis and their mechanism of action. In recent years, the list of chemicals that exert obesogenic potential is increasing. In this chapter, we review current knowledge of the most recent developments in the field of emerging obesogens with a specific focus on food additives, surfactants, and sunscreens, for which the mechanism of action remains unclear. We also review new evidence relative to the obesogenic potential of environmentally relevant chemical mixtures and point to potential therapeutic approaches to minimize the detrimental effects of obesogens. We conclude by discussing the available tools to investigate new obesogenic chemicals, strategies to maximize reproducibility in adipogenic studies, and future directions that will help propel the field forward.

Shearing during the latter half of pregnancy is a common practice to improve flock health and productivity. Previous studies have demonstrated that shearing pregnant ewes at mid or late pregnancy is associated with an increase in lamb birth weight. In the present study, we used singleton Polypay × Dorset pregnant sheep, to investigate the potential roles of placental function and changes in maternal metabolism in underlying this increased birth weight response. Two groups were randomly established and blocked at enrollment by animal BW, body condition score and subcutaneous adipose tissue depth. The groups were shorn (SH; n = 18) or not (C; n = 20) at gestational day (GD) 107 ± 1 (mean ± SEM). Weekly maternal plasma samples were collected between shearing and birth, but only six samples were assayed for progesterone, pregnancy-associated glycoproteins (PAG1), glucose and non-esterified fatty acids (NEFAs). At birth, sex, birth weight, and newborn body mass index (BMI) were recorded. Maternal BW during mid- to late-pregnancy was similar between groups. Shearing resulted in increased lamb birth weight and BMI (P < 0.05) regardless of fetal sex but did not affect the maternal concentration of PAG1 or progesterone from GDs 100 to 142. After shearing (GD100) and up to lambing, shorn females had higher circulating glucose concentrations (P < 0.05), but not NEFA, compared to the control group. Maternal circulating PAG1, progesterone, glucose or NEFA concentration across pregnancy did not differ according to lamb sex. Across pregnancy, birth weight was positively associated with PAG1 (P < 0.001), but not with progesterone concentrations. In conclusion, weight and BMI at birth were higher in both sexes upon shearing in singleton pregnancies. Despite PAG1 being associated with birth weight, late-pregnancy shearing did not alter the placental endocrine response. Whether other placental factors are altered upon shearing and may influence the increase in birth weight and BMI remain to be investigated.

Predictions from physiologically based toxicokinetic (PBTK) models can help inform human health risk assessment for potentially toxic chemicals in the environment. Bisphenol S (BPS) is the second most abundant bisphenol detected in humans in the United States, after bisphenol A (BPA). We have recently demonstrated that BPS, much like BPA, can cross the placental barrier and disrupt placental function. Differences in physicochemical properties, toxicokinetics, and exposure outcomes between BPA and other bisphenols prevent direct extrapolation of existing BPA PBTK models to BPS. The current study aimed to develop pregnancy-specific PBTK (p-PBTK) models for BPA and BPS, using a common p-PBTK model structure. Novel paired maternal and fetal pregnancy data sets for total, unconjugated, and conjugated BPA and BPS plasma concentrations from three independent studies in pregnant sheep were used for model calibration. The nine-compartment (maternal blood, liver, kidney, fat, placenta and rest of body, and fetal liver, blood and rest of body) models simulated maternal and fetal experimental data for both BPA and BPS within one standard deviation for the majority of the experimental data points, highlighting the robustness of both models. Simulations were run to examine fetal exposure following daily maternal exposure to BPA or BPS at their tolerable daily intake dose over a two-week period. These predictive simulations show fetal accumulation of both bisphenols over time. Interestingly, the steady-state approximation following this dosing strategy achieved a fetal concentration of unconjugated BPA to levels observed in cord blood from human biomonitoring studies. These models advance our understanding of bisphenolic compound toxicokinetics during pregnancy and may be used as a quantitative comparison tool in future p-PBTK models for related chemicals.

Epidemiological studies indicate that elevated alkaline phosphatase activity is associated with increased cardiovascular disease risk. Other epidemiological data demonstrate that mothers giving multiple childbirths (multipara) are also at increased risk of developing late-onset cardiovascular disease. We hypothesized that these two associations stem from a common cause, the insufficient plasma level of the ectopic mineralization inhibitor inorganic pyrophosphate, which is a substrate of alkaline phosphatase. As alkaline phosphatase activity is elevated in pregnancy, we hypothesized that pyrophosphate concentrations decrease gestationally, potentially leading to increased maternal vascular calcification and cardiovascular disease risk in multipara. We investigated plasma pyrophosphate kinetics pre- and postpartum in sheep and at term in humans and demonstrated its shortage in pregnancy, mirroring alkaline phosphatase activity. Next, we tested whether multiparity is associated with increased vascular calcification in pseudoxanthoma elasticum patients, characterized by low intrinsic plasma pyrophosphate levels. We demonstrated that these patients had increased vascular calcification when they give birth multiple times. We propose that transient shortages of pyrophosphate during repeated pregnancies might contribute to vascular calcification and multiparity-associated cardiovascular disease risk threatening hundreds of millions of healthy women worldwide. Future trials are needed to assess if gestational pyrophosphate supplementation might be a suitable prophylactic treatment to mitigate maternal cardiovascular disease risk in multiparous women.

The placenta supports fetal growth and is vulnerable to exogenous chemical exposures. We have previously demonstrated that exposure to the emerging chemical bisphenol S (BPS) can alter placental endocrine function. Mechanistically, we have demonstrated that BPS interferes with epidermal growth factor receptor (EGFR) signaling, reducing placenta cell fusion. Extravillous trophoblasts (EVTs), a placenta cell type that aids with vascular remodeling, require EGF to invade into the maternal endometrium. We hypothesized that BPS would impair EGF-mediated invasion and proliferation in EVTs. Using human EVTs (HTR-8/SVneo cells), we tested whether BPS could inhibit the EGF response by blocking EGFR activation. We also evaluated functional endpoints of EGFR signaling, including EGF endocytosis, cell invasion and proliferation, and endovascular differentiation. We demonstrated that BPS blocked EGF-induced phosphorylation of EGFR by acting as a competitive antagonist to EGFR. Transwell assay and a three-dimensional microfluidic chip invasion assay revealed that BPS exposure can block EGF-mediated cell invasion. BPS also blocked EGF-mediated proliferation and endovascular differentiation. In conclusion, BPS can prevent EGF-mediated EVT proliferation and invasion through EGFR antagonism. Given the role of EGFR in trophoblast proliferation and differentiation during placental development, our findings suggest that maternal exposure to BPS may contribute to placental dysfunction via EGFR-mediated mechanisms.

Background: Bisphenol S (BPS) is an endocrine-disrupting chemical and the second most abundant bisphenol detected in humans. In vivo BPS exposure leads to reduced binucleate cell number in the ovine placenta. Binucleate cells form by cellular fusion, similar to the human placental syncytiotrophoblast layer. Given that human placental syncytialization can be stimulated through epidermal growth factor (EGF), we hypothesized that BPS would reduce human cytotrophoblast syncytialization through disruption of EGF receptor (EGFR) signaling. OBJECTIVE: We tested whether BPS interferes EGFR signaling and disrupts human cytotrophoblast syncytialization. Methods: We first tested BPS competition for EGFR using an EGF/EGFR AlphaLISA assay. Using human primary term cytotrophoblast cells (hCTBs) and MDA-MD-231 cells, a breast cancer cell line with high EGFR expression, we evaluated EGFR downstream signaling and tested whether BPS could inhibit the EGF response by blocking EGFR activation. We also evaluated functional end points of EGFR signaling, including EGF endocytosis, cell proliferation, and syncytialization. RESULTS: BPS blocked EGF binding in a dose-dependent manner and reduced EGF-mediated phosphorylated EGFR in both cell types. We further confirmed that BPS acted as an EGFR antagonist as shown by a reduction in EGF internalization in both hCTBs and MDA-MD- 231 cells. Finally, we demonstrated that BPS interfered with EGF-mediated cell processes, such as cell proliferation in MDA-MD-231 cells and syncytialization in hCTBs. EGF-mediated, but not spontaneous, hCTB syncytialization was fully blocked by BPS (200ng/mL), a dose within urinary BPS concentrations detected in humans. Conclusions: Given the role of EGFR in trophoblast proliferation and differentiation during placental development, this study suggests that exposures to BPS at environmentally relevant concentrations may result in placenta dysfunction, affecting fetal growth and development. https://doi.org/10.1289/EHP7297, Introduction A variety of structurally diverse compounds classified as endocrine-disrupting chemicals (EDCs) have been reported to affect the endocrine system through direct receptor binding or through alternative pathways that can [...]