Nonessential Metals and Toxic Epitranscriptomic Remodeling

Abstract RNA N6-methyladenosine (m6A) is a major epitranscriptomic regulator linking environmental metal exposure to disease. Metals such as lead, aluminum, hexavalent chromium, and cadmium can disrupt redox homeostasis and induce dynamic m6A remodeling by altering the activity of writers (METTL3, METTL14, METTL16), erasers (FTO, ALKBH5), and readers (YTH domain-containing proteins). These changes reshape post-transcriptional networks involved in antioxidant defense, mitochondrial function, iron metabolism, endoplasmic reticulum stress, and regulated cell death. Mechanistically, oxidative stress may influence m6A regulation through Fe2+/α-ketoglutarate-dependent dioxygenases, methyl donor availability, and stress-responsive signaling pathways, while m6A-dependent regulation of redox-related transcripts may establish bidirectional interactions between epitranscriptomic and cellular oxidative states. Emerging evidence links m6A dysregulation to neuroinflammation, ferroptosis, metabolic dysfunction, and tissue-specific toxicity. However, challenges in accurate detection, quantitative characterization, and causal inference limit mechanistic interpretation. This review summarizes advances in m6A-mediated environmental metal toxicity, emphasizing methodological standardization, exposure-relevant biomarker discovery, and causal validation, and discusses its implications for risk assessment and precision toxicology.