Histopathological and toxicogenomic evaluation of 1,4-dioxane toxicity after a 14-day repeated oral administration

Abstract

1,4-dioxane (DON) has been widely used as a pharmaceutical ingredient, a solvent in organic synthesis reactions, and a stabilizer in chlorinated organic solvents. Although DON shows hepatocarcinogenicity in mice and rats, the mode of action has not fully been elucidated. Therefore, to understand the toxicological potential of DON in high doses after repeated oral administration and the adverse effects on the liver in terms of molecular mechanisms, we analyzed a results of repeated dose 14-day oral toxicity test integrating a gene expression analysis using DNA microarray. Rats were orally administered a dose of DON (0, 150, 500 and 1500 mg/kg/day) and examinations on hematology, blood biochemistry, organ weights and histopathology were conducted. Surplus liver was harvested to gene expression analysis to identify genes and molecular pathways related to the adverse effect of DON. As a result, centrilobular hypertrophy of hepatocytes (liver), tubular vacuolation/basophilic change (kidney), and vacuolation (pituitary posterior lobe) were observed as pathological findings. Gene expression analysis revealed genes related to oxidative stress, xenobiotic receptor response, immune response, and hepatocellular carcinoma were significantly enriched. Under middle dose group, DNA damage response related genes were not significantly enriched and histopathological change in liver was not observed suggesting a threshold. Continuous alteration of these gene expression profiles related to hepato-carcinogenesis may have an important role in the non-genotoxic mode of action of DON. Our results would be useful in further understanding the general toxicity of DON and in considering early changes in the liver which lead to carcinogenesis.