Bisphenol S Impairs Invasion and Proliferation of Extravillous Trophoblasts Cells by Interfering with Epidermal Growth Factor Receptor Signaling

Abstract

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.

Antibody dependent cellular cytotoxicity-inducing anti-EGFR antibodies as effective therapeutic option for cutaneous melanoma resistant to BRAF inhibitors

“…Notably, exogenous EGF slightly upregulated EGFR phosphorylation also in Mel 599 P cells, suggesting that the EGFR constitutively expressed by these cells is functional. EGF stimulation triggered downregulation of EGFR, in line with literature data reporting degradation of activated EGFR (54)(55)(56)(57)(58)(59)(60)(61). Independent of the degree of constitutive EGFR phosphorylation, activation of the AKT pathway emerged as a common feature of VR cells, as demonstrated by the increased phosphorylation of AKT1 found in 3 out of 4 VR cell cultures as compared to their P isogenic cells.…”

Bisphenol S moderately decreases the expression of syncytiotrophoblast marker genes and induces apoptosis in human trophoblast lineages

“…Conversely, when proliferation is excessively stimulated, CT differentiation becomes inhibited, resulting in the impairment of ST and EVT formation. A previous study demonstrated that BPS does not affect the proliferation of HTR8/SVneo cells (Ticiani et al, 2022). This cell line is immortalized and has characteristics of the non-proliferative extravillous trophoblast cells which are completely different from the progenitor CTs or TSCs.…”

“…Therefore, it is imperative to conduct a comprehensive examination of the potential toxic effects of this chemical to ascertain whether it is safe to the human body and pregnancy. It has been demonstrated that BPS affects EGF signaling in human trophoblast cells (Ticiani et al, 2022), impairs endocrine functions in the sheep placenta (Gingrich et al, 2018), and induces morphological defects in the junctional zone of the mouse placenta (Mao et al, 2020). However, the impacts of BPS on human placenta development remains to be clarified.…”

Modulation of fetoplacental growth, development and reproductive function by endocrine disrupters

“…Data show that exposure to endocrine-disrupting chemicals like bisphenols A and their substitutions (BPS, BPF, TBBPA, BADGE) affect early development stages. Early developmental involves implantation, trophoblast invasion, and remodelling are modulated by BPA ( 16 , 17 , 26 – 32 ), BPS ( 33 , 34 ), BPF ( 32 , 34 ), and TBBPA ( 35 ) exposure. The trophoblast Syncytialization and nutrient exchange across the placenta are affected by BPA ( 22 , 23 ), and BPS ( 36 ) exposure.…”

“…Single-headed arrow indicates an independent study reported so far available from the PubMed database. BPA, Bisphenol A ( 23 , 24 , 26 – 28 , 38 ); BPS, Bisphenol S ( 25 , 33 , 36 , 42 , 150 , 151 ); BPF, Bisphenol F ( 34 , 39 ); TBBPA, Tetrabromo Bisphenol A ( 35 , 40 , 43 , 152 , ( 44 ); BADGE, Bisphenol A diglycidyl ether ( 45 ).…”