Abstract
Perfluorooctanesulfonic acid (PFOS) is a widely recognized environment pollutant known for its high bio- accumulation potential and a long elimination half-life. Several studies have shown that PFOS can alter multiple biological pathways and negatively affect human health. Considering the direct exposure to the gastrointestinal (GI) tract to environmental pollutants, PFOS can potentially disrupt intestinal homeostasis. However, there is limited knowledge about the effect of PFOS exposure on normal intestinal tissues, and its contribution to GI- associated diseases remains to be determined. In this study, we examined the effect of PFOS exposure on the gene expression profile of intestinal tissues of C57BL/6 mice using RNAseq analysis. We found that PFOS exposure in drinking water significantly downregulates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting ketogenic enzyme, in intestinal tissues of mice. We found that diets containing the soluble fibers inulin and pectin, which are known to be protective against PFOS exposure, were ineffective in reversing the downregulation of HMGCS2 expression in vivo. Analysis of intestinal tissues also demonstrated that PFOS exposure leads to upregulation of proteins implicated in colorectal carcinogenesis, including β-catenin, c- MYC, mTOR and FASN. Consistent with the in vivo results, PFOS exposure leads to downregulation of HMGCS2 in mouse and human normal intestinal organoids in vitro. Furthermore, we show that shRNA-mediated knockdown of HMGCS2 in a human normal intestinal cell line resulted in increased cell proliferation and upregulation of key proliferation-associated proteins such as cyclin D, survivin, ERK1/2 and AKT, along with an increase in lipid accumulation. In summary, our results suggest that PFOS exposure may contribute to pathological changes in normal intestinal cells via downregulation of HMGCS2 expression and upregulation of pro-carcinogenic signaling pathways that may increase the risk of colorectal cancer development.
Document Type
Article
Publication Date
2024
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.chemosphere.2024.142332
Funding Information
This work is supported by National Institute of Environmental Health Sciences grant P42 ES007380 (University of Kentucky Superfund Research Center, Project 1-YZ), National Cancer Institute grant R01 CA249734 (YZ), and National Natural Science Foundation of China 82373942 (PD). The publishing fee will be paid by the National Institute of Environmental Health Sciences grant P42 ES007380.
Repository Citation
Tessmann, Josiane Weber; Deng, Pan; Durham, Jerika; Li, Chang; Banerjee, Moumita; Wang, Qingding; Goettl, Ryan A.; He, Daheng; Wang, Chi; Lee, Eun Y.; Evers, B. Mark; Hennig, Bernhard; and Zaytseva, Yekaterina Y., "Perfluorooctanesulfonic acid exposure leads to downregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 2 expression and upregulation of markers associated with intestinal carcinogenesis in mouse intestinal tissues" (2024). Markey Cancer Center Faculty Publications. 211.
https://uknowledge.uky.edu/markey_facpub/211
Included in
Environmental Chemistry Commons, Environmental Engineering Commons, Environmental Health Commons, Occupational Health and Industrial Hygiene Commons, Oncology Commons, Other Chemistry Commons, Other Public Health Commons, Toxicology Commons
Notes/Citation Information
0045-6535/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/).