Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, Edmonton, Alberta, T6G 2E1, Canada.
Biol Trace Elem Res. 2024 Nov;202(11):5071-5080. doi: 10.1007/s12011-023-04050-y. Epub 2024 Jan 10.
Methylmercury (MeHg) and 2,3,7,8-tetrachlorodibenzodioxin (TCDD) are potent environmental pollutants implicated in the modulation of xenobiotic-metabolizing enzymes, particularly the cytochrome P450 1 family (CYP1) which is regulated by the aryl hydrocarbon receptor (AHR). However, the co-exposure to MeHg and TCDD raises concerns about their potential combined effects, necessitating thorough investigation. The primary objective of this study was to investigate the individual and combined effects of MeHg and TCDD on AHR-regulated CYP1 enzymes in mouse extrahepatic tissues. Therefore, C57BL/6 mice were administrated with MeHg (2.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) for 6 and 24 h. The AHR-regulated CYP1 mRNA and protein expression levels were measured in the heart, lung, and kidney, using RT real-time PCR and western blot, respectively. Interestingly, treatment with MeHg exhibited mainly inhibitory effect, particularly, it decreased the basal level of Cyp1a1 and Cyp1a2 mRNA and protein, and that was more evident at the 24 h time point in kidney followed by heart. Similarly, when mice were co-exposed, MeHg was able to reduce the TCDD-induced Cyp1a1 and Cyp1a2 expression, however, MeHg potentiated kidney Cyp1b1 mRNA expression, opposing the observed change on its protein level. Also, MeHg induced antioxidant NAD(P)H:quinone oxidoreductase (NQO1) mRNA and protein in kidney, while heme-oxygenase (HO-1) mRNA was up-regulated in heart and kidney. In conclusion, this study reveals intricate interplay between MeHg and TCDD on AHR-regulated CYP1 enzymes, with interesting inhibitory effects observed that might be significant for procarcinogen metabolism. Varied responses across tissues highlight the potential implications for environmental health.
甲基汞（MeHg）和 2,3,7,8-四氯二苯并二恶英（TCDD）是两种强效的环境污染物，它们可能会调节外来物质代谢酶，特别是细胞色素 P450 1 家族（CYP1），而该家族受芳香烃受体（AHR）调控。然而，MeHg 和 TCDD 的共同暴露引起了人们对它们潜在联合效应的关注，需要进行深入研究。本研究的主要目的是研究 MeHg 和 TCDD 对小鼠肝外组织中 AHR 调节的 CYP1 酶的单独和联合作用。因此，将 C57BL/6 小鼠用 MeHg（2.5mg/kg）处理，同时存在或不存在 TCDD（15μg/kg），分别处理 6 小时和 24 小时。使用 RT 实时 PCR 和 Western blot 分别在心脏、肺和肾脏中测量 AHR 调节的 CYP1 mRNA 和蛋白表达水平。有趣的是，MeHg 处理主要表现出抑制作用，特别是在肾脏中，它降低了 Cyp1a1 和 Cyp1a2 mRNA 和蛋白的基础水平，并且在 24 小时时间点更为明显，其次是心脏。同样，当小鼠共同暴露时，MeHg 能够降低 TCDD 诱导的 Cyp1a1 和 Cyp1a2 表达，但它增强了肾脏 Cyp1b1 mRNA 表达，与观察到的蛋白水平变化相反。此外，MeHg 在肾脏中诱导抗氧化 NAD(P)H：醌氧化还原酶（NQO1）mRNA 和蛋白，而血红素加氧酶（HO-1）mRNA 在心脏和肾脏中上调。总之，本研究揭示了 MeHg 和 TCDD 对 AHR 调节的 CYP1 酶之间的复杂相互作用，观察到有趣的抑制作用，这可能对前致癌物代谢具有重要意义。不同组织的不同反应突出了对环境健康的潜在影响。
