Bisphenol (BP) compounds are endocrine-disrupting organic pollutants. BPs may increase the messenger RNA (mRNA) transcripts of nuclear receptors (NRs) regulating the expression of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes. Their impact on the genotoxicity of metabolically activated carcinogens, however, remains unknown. In this study, effects of the bisphenols A, F, S, and AF on the expression of the aryl hydrocarbon receptor (AhR), the pregnane X receptor (PXR), the constitutive androstane receptor, and individual xenobiotic-metabolizing CYP enzymes in a human hepatoma (HepG2) cell line were investigated, along with in silico binding studies of BPs to each receptor. The results indicated that each BP at 1 to 100 nM concentrations increased the mRNA transcripts and protein levels of AhR, PXR, CYP1A1, 1A2, 1B1, 2E1, and 3A4. The predicted affinities of the BPs for binding AhR were comparable to those of potent agonists. Pretreatment of HepG2 cells with each BP potentiated the induction of micronuclei by benzo[a]pyrene, aflatoxin B1, benzene, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; this effect was abolished/reduced by inhibitors of NRs and/or CYPs. Our study suggests that BPs at human exposure levels may aggravate chromosome damage by several impactful carcinogens in human cells by inducing relevant CYP enzymes, mostly via NR modulation.
Keywords: bisphenols; cytochrome P450 (CYP); micronuclei; nuclear receptors; procarcinogens.