Hexavalent chromium [Cr (VI)] compounds are used in metallurgical, chemical and refractory industries. Their carcinogenicity has been supported by a number of epidemiological and animal studies; however, their carcinogenic mode of action is still incompletely understood. To identify mechanisms involved in cancer development from toxicologically relevant exposures to Cr(VI), we analyzed gene expression data from duodena of mice exposed for 7 or 90 days to Cr(VI) in drinking water at concentrations 0.3-520 mg/L. This analysis included identification of upstream regulatory molecules that are likely responsible for the observed gene expression changes, and identification of annotated gene expression data from public repositories that correlate with gene expression changes in duodena of Cr(VI)-exposed mice. We identified the CFTR gene among top scoring upstream regulators, including at low exposure levels that, for the given timepoints, did not induce observable tissue damage. Furthermore, the expression data from duodena of Cr(VI)-exposed mice displayed a positive correlation with other datasets in public repositories associated with the inactive CFTR gene, of which the top scoring were datasets for ilea and duodena of Cftr-knockout mice. Our results support the tumor-suppressor role of the CFTR gene, which was previously suggested for intestinal carcinogenesis in humans and mice. Furthermore, our findings indicate, for the first time, the role of CFTR inactivation in chemical carcinogenesis and expand the range of plausible mechanisms that may be operative in Cr(VI)-mediated carcinogenesis of intestinal and possibly other tissues. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.
Citation Format: Roman Mezencev, Scott S. Auerbach. Inactivation of the CFTR gene in duodena of mice exposed to hexavalent chromium (Cr(VI)) in drinking water supports its tumor-suppressor status and implies its role in Cr(VI)-induced carcinogenesis of the small intestines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB230.