Mechanisms of DNA repair and mutagenesis induced by acetaldehyde, acrolein, aristolochic acids, and vinyl chloride.

Humans are continually exposed to a diverse array of environmental chemicals that can damage DNA and compromise genomic integrity. Among these genotoxic agents, acetaldehyde, acrolein, aristolochic acids, and vinyl chloride are particularly concerning due to their widespread presence in industrial emissions, dietary sources, and lifestyle-related exposures such as smoking and alcohol consumption. These compounds can induce structurally distinct forms of DNA damage including bulky DNA adducts, interstrand crosslinks, and other replication-blocking lesions. While canonical DNA repair pathways serve as the primary defense against such DNA damage, some lesions persist, challenging the capacity of DNA repair systems. If not efficiently repaired, DNA lesions may disrupt replication and transcription. In many cases, translesion synthesis polymerases are recruited to bypass unrepaired lesions, introducing mutations that contribute to agent-specific mutational signatures found in cancer genomes. This review systematically examines how each of these four exogenous chemicals induces DNA damage, the DNA repair pathways responsible for removing their lesions, and the role of translesion synthesis in shaping their mutational signatures. We also highlight how three-dimensional genome organization regulates lesion susceptibility and repair, contributing to variability of mutational landscapes.