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 (DMA^V), a principal urinary metabolite of inorganic arsenic in humans. Using various animal models, we demonstrated that DMA^V promotes carcinogenesis in multiple organs, including the urinary bladder, liver, kidney, and thyroid gland. Two-year bioassays confirmed that DMA^V functions as a complete carcinogen in the rat bladder. Furthermore, transplacental exposure to DMA^V 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 DMA^V-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 DMA^V and clarify its underlying mechanisms. Our work contributed significantly to the classification of DMA^V as "probably carcinogenic to humans" (Group 2 A) by the International Agency for Research on Cancer, underscoring its relevance to human health risk assessment.