Bisphenol S and Epidermal Growth Factor Receptor Signaling in Human Placental Cytotrophoblasts

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.

We tested whether BPS interferes EGFR signaling and disrupts human cytotrophoblast syncytialization.

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.

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 ($200\text{\hspace{0.17em}ng}/\mathrm{mL}$), a dose within urinary BPS concentrations detected in humans.

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.