Bisphenol S enhances gap junction intercellular communication in ovarian theca cells

Gingrich, Jeremy; Pu, Yuehua; Upham, Brad L.; Hulse, Madeline; Pearl, Sarah; Martin, Denny; Avery, Anita M.; Veiga-López, Almudena

doi:10.1016/j.chemosphere.2020.128304

Cited by 15 publications

(8 citation statements)

References 123 publications

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“…To note, BPS is being used as a replacement chemical in thermal paper (ECHA 2020), indicating that, like BPA (Hehn 2016) occupational exposure levels to BPS will continue to increase (Ndaw et al 2018) and likely surpass those currently observed for BPA (Hehn 2016). Our group has demonstrated that BPS exposures of as low as 100 ng=mL BPS can alter gap junction intercellular communication in steroidogenic ovarian theca cells (Gingrich 2020). Follow-up dose-response studies are necessary to determine the effect of low-dose BPS exposure on EGFR phosphorylation and downstream signaling.…”

Section: Discussionmentioning

confidence: 84%

“…2018 ) and likely surpass those currently observed for BPA ( Hehn 2016 ). Our group has demonstrated that BPS exposures of as low as

BPS can alter gap junction intercellular communication in steroidogenic ovarian theca cells ( Gingrich 2020 ). Follow-up dose–response studies are necessary to determine the effect of low-dose BPS exposure on EGFR phosphorylation and downstream signaling.…”

Section: Discussionmentioning

confidence: 99%

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

Ticiani

Gingrich

et al. 2021

Environ Health Perspect

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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 ( ), 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

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Section: Discussionmentioning

confidence: 84%

“…2018 ) and likely surpass those currently observed for BPA ( Hehn 2016 ). Our group has demonstrated that BPS exposures of as low as

Section: Discussionmentioning

confidence: 99%

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

Ticiani

Gingrich

et al. 2021

Environ Health Perspect

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“…In support of our previous findings on proliferation and invasion ( Figure 3 , Figure 4 and Figure 5 ), BPS in the presence of EGF, almost fully inhibited tube formation. Given the strength of this effect compared to other endpoints tested (i.e., proliferation, invasion, and endocytosis), it is possible that BPS elicited this effect via EGFR inhibition, or other pathways that control gap junction intercellular communication [ 59 ], or that intersect with angiogenic regulation [ 60 ]. For instance, cell-to-cell communication that involves Notch signaling is crucial for the formation of complex multicellular structures such as blood vessel networks [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

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

Ticiani

Gingrich

et al. 2022

IJMS

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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.

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“…Examples of primary cells used for functional assessment of GJIC include representatives of various organs, tissues and cell types isolated mostly from rodents (rat, mouse) and other animals (e.g., sheep, piglets) or humans. Most notably, GJIC has been assessed in cultured primary cells isolated from, e.g., the nervous system [46][47][48][49][50], liver [45,51], intestine [52], kidney [53][54][55][56], lung [57,58], smooth muscles, including myometrial cell cultures [59][60][61], cardiac myocytes [62,63], ovaries [64][65][66][67], prostate cells [68] or testicular cells [63,67,[69][70][71].…”

Section: Cell Lines and Methods For In Vitro Gjic Assessmentmentioning

confidence: 99%

Applicability of Scrape Loading-Dye Transfer Assay for Non-Genotoxic Carcinogen Testing

Sovadinová

Upham

Trosko

et al. 2021

IJMS

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Dysregulation of gap junction intercellular communication (GJIC) is recognized as one of the key hallmarks for identifying non-genotoxic carcinogens (NGTxC). Currently, there is a demand for in vitro assays addressing the gap junction hallmark, which would have the potential to eventually become an integral part of an integrated approach to the testing and assessment (IATA) of NGTxC. The scrape loading-dye transfer (SL-DT) technique is a simple assay for the functional evaluation of GJIC in various in vitro cultured mammalian cells and represents an interesting candidate assay. Out of the various techniques for evaluating GJIC, the SL-DT assay has been used frequently to assess the effects of various chemicals on GJIC in toxicological and tumor promotion research. In this review, we systematically searched the existing literature to gather papers assessing GJIC using the SL-DT assay in a rat liver epithelial cell line, WB-F344, after treating with chemicals, especially environmental and food toxicants, drugs, reproductive-, cardio- and neuro-toxicants and chemical tumor promoters. We discuss findings derived from the SL-DT assay with the known knowledge about the tumor-promoting activity and carcinogenicity of the assessed chemicals to evaluate the predictive capacity of the SL-DT assay in terms of its sensitivity, specificity and accuracy for identifying carcinogens. These data represent important information with respect to the applicability of the SL-DT assay for the testing of NGTxC within the IATA framework.

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Bisphenol S enhances gap junction intercellular communication in ovarian theca cells

Cited by 15 publications

References 123 publications

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

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

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

Applicability of Scrape Loading-Dye Transfer Assay for Non-Genotoxic Carcinogen Testing

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