Environmental Heavy Metals, Oxidative Stress and Disease Potential: NRF2 Centered Genetic and Epigenetic Mechanisms

Humans are exposed to environmental heavy metals such as methylmercury, manganese, cobalt, cadmium and arsenic throughout their lifespan. A growing body of evidence has demonstrated strong associations between environmental pollutants and human health. Redox toxicity is considered to be one of the main mechanisms of chemical-induced pathology. The nuclear factor erythroid 2-related factor 2 (NRF2) has attracted much attention as a sensor of oxidative stress and a positive regulator of antioxidants in recent years. However, the role of NRF2 in the environmental heavy metal toxicity has not been systematically investigated. Here, we summarize the function of NRF2 in response to environmental heavy metals and its regulation through KEAP1-dependent and KEAP1-independent pathways. Finally, we shed light on the epigenetic regulation of NRF2, including DNA methylation, histone acetylation, noncoding RNAs and N6-methyladenosine modification. In brief, alterations in NRF2 upon exposure to environmental heavy metals are regulated by both genetic and epigenetic aspects, and, in turn, may participate in the etiology of various diseases.