Bromacil attenuates benzo[a]pyrene cytotoxicity and mutagenesis through the AhR and Nrf2 pathways

The aryl hydrocarbon receptor (AhR) is known to respond to various chemicals as a sensor for environmental chemicals that induce drug-metabolizing enzymes; however, reports on its activation by pesticides and herbicides remain limited. We evaluated compounds from commonly used pesticides and herbicides that modulate AhR using a yeast reporter gene assay. Notably, bromacil (Brm), which is a uracil herbicide, exhibited ligand-like activity with mouse AhR in a yeast-based assay used for first screening., functioning as an antagonist and inducing AhR nuclear translocation in human cells, while exhibiting no cytotoxicity or mutagenicity. Although AhR modulators may be nontoxic, they could alter the mutagenicity of procarcinogens, which are metabolically activated by inducing the expressions of drug-metabolizing enzymes. Co-exposure to Brm and benzo[a]pyrene (BaP) reduced BaP-induced cytotoxicity and mutagenicity. Moreover, Brm induced Nrf2 activation and upregulated its target gene mRNA levels in an AhR-dependent manner, which may contribute to the observed attenuation of BaP-induced cytotoxicity and mutagenicity. These findings indicated that Brm is a novel AhR antagonist that modifies AhR-mediated chemical toxicity through AhR inhibition and Nrf2 activation.