Abstract

Dimethylated monothioarsenate (DMMTA), an emerging thiolated organic arsenical frequently detected in rice, exhibits in vitro cytotoxicity comparable to trivalent inorganic arsenic. However, its in vivo hepatotoxicity and underlying mechanisms remain largely unknown. Here, a 28-day subacute DMMTA exposure study was conducted in C57BL/6 mice, integrating hepatic transcriptomics, targeted bile acid metabolomics and 16S rRNA microbiome profiling to elucidate DMMTA-induced perturbations along the gut-liver axis. Phenotypically, DMMTA induced an atypical hepatotoxicity characterized by paradoxical liver atrophy coexisting with severe steatosis, alongside inflammatory infiltration and a non-monotonic elevation of liver ALT activity. Mechanistically, DMMTA critically impaired hepatic detoxification and redox homeostasis, evidenced by the inhibited nuclear translocation of Nrf2 and the concerted suppression of downstream xenobiotic-metabolizing genes (e.g., Gsts , Ugts ). Targeted metabolomics revealed a profound disruption of enterohepatic circulation, marked by a 29% reduction in the primary to secondary bile acid ratio and 6.0-fold increase in toxic accumulation of 6,7-diketo LCA. Concurrently, microbiome profiling identified a highly selective dysbiosis driven by the massive expansion of Negativibacillus (71.1-fold) and the depletion of Blautia (20.3-fold). Multi-omics integration (Procrustes, M² < 0.46, P < 0.05) robustly linked these microbiota shifts to the accumulation of hepatotoxic secondary bile acids. Collectively, this study challenges the traditional “low toxicity” paradigm of organic arsenicals and highlights the gut-liver axis as a central mediator of DMMTA hepatotoxicity, providing vital mechanistic evidence to refine environmental risk assessment for rice-based diets.