Minor structural modifications of bisphenol A strongly affect physiological responses of HepG2 cells

Bisphenols represent a large group of structurally similar compounds. In contrast to bisphenol A (BPA) and bisphenol S (BPS), however, toxicological data are usually scarce, thus making bisphenols an ideal candidate for read-across assessments. BPA, bisphenol C (BPC) and a newly synthesized bisphenol A/C (BPA/C) differ only by one methyl group attached to the phenolic ring. Their EC₅₀ values for cytotoxicity and logP_OW values are comparable. However, the estrogenic activities of these bisphenols are not comparable and among this group only BPC leads to a decrease of the mitochondrial membrane potential and ATP concentration in HepG2 cells. Conversely, the cell division rate was decreased by BPS, BPA, BPC and BPA/C at 10% toxicity (EC₁₀). At lower concentrations, only BPC significantly affected proliferation. The pro-inflammatory cytokines TGFB1 and TNF were significantly upregulated by BPC only, while SPP1 was upregulated by BPA, BPA/C and BPS. BPC led to the release of cytochrome c from mitochondria, indicating that this compound is capable of inducing apoptosis. In conclusion, the read-across approach revealed non-applicable in the case of the various structurally and physicochemically comparable bisphenols tested in this study, as the presence of one or two additional methyl group(s) attached at the phenol ring profoundly affected cellular physiology.