Bisphenol S enhances gap junction intercellular communication in ovarian theca cells

Gap junction intercellular communication (GJIC) is necessary for ovarian function, and it is temporospatially regulated during follicular development and ovulation. At outermost layer of the antral follicle, theca cells provide structural, steroidogenic, and vascular support. Inter- and extra-thecal GJIC is required for intrafollicular trafficking of signaling molecules. Because GJIC can be altered by hormones and endocrine disrupting chemicals (EDCs), we tested if any of five common EDCs (bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), perfluorooctanesulfonic acid (PFOS), and triphenyltin chloride (TPT)) can interfere with theca cell GJIC. Since most chemicals are reported to repress GJIC, we hypothesized that all chemicals tested, within environmentally relevant human exposure concentrations, will inhibit theca cell GJICs. To evaluate this hypothesis, we used a scrape loading/dye transfer assay. BPS, but no other chemical tested, enhanced GJIC in a dose- and time-dependent manner in ovine primary theca cells. A signal-protein inhibitor approach was used to explore the GJIC-modulatory pathways involved. Phospholipase C and mitogen-activated protein kinase (MAPK) inhibitors significantly attenuated BPS-induced enhanced GJIC. Human theca cells were used to evaluate translational relevance of these findings. Human primary theca cells had a ∼40% increase in GJIC in response to BPS, which was attenuated with a MAPK inhibitor, suggestive of a conserved mechanism. Upregulation of GJIC could result in hyperplasia of the theca cell layer or prevent ovulation by holding the oocyte in meiotic arrest. Further studies are necessary to understand in vitro to in vivo translatability of these findings on follicle development and fertility outcomes.