Modulation of Aryl Hydrocarbon Receptor-Regulated Genes by Methylmercury

Abstract

Environmental pollution poses a significant threat to public health, with various contaminants contributing to a wide range of adverse health effects. Among these contaminants, ؤ (MeHg) and the aryl hydrocarbon receptor (AHR) ligand 2,3,7,8-tetrachlorodibenzodioxin (TCDD) are particularly concerning due to their persistence in the environment and potent biological activities. Both compounds have been extensively studied for their individual effects, but the potential health risks associated with their combined exposure are less understood. The primary objective of this work was to investigate the individual and combined effects of MeHg and TCDD on AHR-regulated enzymes. This investigation was conducted using the murine hepatoma Hepa-1c1c7 cell line and extended to mouse hepatic and extrahepatic tissues. The effects of MeHg on Ahr-regulated gene expression were examined in the absence and presence of TCDD, along with evaluations of protein expression and enzymatic catalytic activity. In hepatic tissue, both MeHg and Hg2+ inhibited the TCDD-mediated induction of Cyp1a1/1a2 mRNA levels. However, only Hg2+ inhibited the TCDD-mediated induction of CYP1A1/1A2 protein and catalytic activity at posttranscriptional levels, indicating differential modulation by Hg2+ and MeHg. Additionally, the inhibitory role of HO-1 (heme oxygenase-1) on CYP1A activity induced by TCDD was investigated in vitro using the HO-1 competitive inhibitor tin-mesoporphyrin, which partially restored the MeHg-mediated decrease in CYP1A1 activity. In extrahepatic tissues, MeHg exhibited mainly inhibitory effects, particularly decreasing the basal level of Cyp1a1 and Cyp1a2 mRNA and protein, which was more evident at the 24-hour time point in kidneys, followed by hearts. Similarly, when mice were co-exposed, MeHg reduced the TCDD-induced Cyp1a1 and Cyp1a2 expression. However, MeHg potentiated kidney Cyp1b1 mRNA expression, opposing the observed change in its protein level. Exposure to MeHg induces several antioxidant enzymes, including NAD(P)H:quinone oxidoreductase (NQO1), whose expression is regulated by both AHR and nuclear factor erythroid 2-related factor-2 (NRF2). This co-regulation prompted an investigation into which transcription factor primarily orchestrates NQO1 expression upon MeHg exposure. Our findings demonstrate that NQO1 induction by MeHg is, at least in part, mediated by NRF2. In conclusion, the findings of this work reveal an intricate interplay between MeHg and TCDD on AHR-regulated CYP1 enzymes, with notable inhibitory effects that might be significant for procarcinogen metabolism. Varied responses across tissues highlight the potential implications for environmental health.