Oxidative stress, glutathione, and CYP2E1 in 1,4-dioxane liver cytotoxicity and genotoxicity: insights from animal models

Curr Opin Environ Sci Health. 2022 Oct:29:100389. doi: 10.1016/j.coesh.2022.100389. Epub 2022 Aug 15.


1,4-Dioxane (DX) is an emerging drinking water contaminant worldwide, which poses a threat to public health due to its demonstrated liver carcinogenicity and potential for human exposure. The lack of drinking water standards for DX is attributed to undetermined mechanisms of DX carcinogenicity. This mini-review provides a brief discussion of a series of mechanistic studies, wherein unique mouse models were exposed to DX in drinking water to elucidate redox changes associated with DX cytotoxicity and genotoxicity. The overall conclusions from these studies support a direct genotoxic effect by high dose DX and imply that oxidative stress involving CYP2E1 activation may play a causal role in DX liver genotoxicity and potentially carcinogenicity. The mechanistic data derived from these studies can serve as important references to refine the assessment of carcinogenic pathways that may be triggered at environmentally relevant low doses of DX in future animal and human studies.

Keywords: Water contaminants; liver carcinogenicity; mechanism of action; oxidative DNA damage.