Carcinogenicity of Dimethylarsinic Acid: Evidence From Experimental Models and Mechanistic Insights.

Arsenic is a well-established human carcinogen and a major global environmental health concern. However, the mechanisms underlying arsenic-induced carcinogenesis remain incompletely understood. This review focuses on dimethylarsinic acid (DMAV), a principal urinary metabolite of inorganic arsenic in humans. Using various animal models, we demonstrated that DMAV promotes carcinogenesis in multiple organs, including the urinary bladder, liver, kidney, and thyroid gland. Two-year bioassays confirmed that DMAV functions as a complete carcinogen in the rat bladder. Furthermore, transplacental exposure to DMAV induced lung and liver tumors in male offspring, highlighting increased fetal susceptibility. Mechanistic investigations revealed a central role for oxidative DNA damage and gene dysregulation in DMAV-induced tumorigenesis. We also identified epigenetic alterations, including aberrant DNA methylation and histone modifications, as key contributors to tumor development, with distinct patterns observed between fetal and adult exposures. Collectively, these findings provide robust experimental evidence for the carcinogenic potential of DMAV and clarify its underlying mechanisms. Our work contributed significantly to the classification of DMAV as "probably carcinogenic to humans" (Group 2 A) by the International Agency for Research on Cancer, underscoring its relevance to human health risk assessment.