Abstract 1480: Perfluorooctanesulfonic acid exposure promotes pathological changes in normal intestinal tissues which may lead to an increased risk of colorectal cancer development

Abstract Introduction: Long-term exposures to per- and polyfluoroalkyl substances (PFAS) have been increasingly linked to negative health outcomes including metabolic disorders, reduced immune responses, and increased risk of cancer. PFOS, one the most frequently detected PFAS in drinking water, is readily absorbed in the GI tract and distributes predominantly to the plasma and liver. Even though recent studies demonstrate that PFOS can cause an imbalance of cecal gut microbiota, alter microbiota diversity, and promote inflammation and gut barrier dysfunction, there is still not much known about the effects of PFOS exposure on normal and pre-malignant intestinal tissues and its contribution to carcinogenesis. Therefore, the goal of this study is to investigate the effects of PFOS on normal (I) and malignant intestinal cells (II). Methods: The effect of PFOS on gene expression profile was assessed by RNAseq analysis in intestinal tissue of C57BL/6 mice. Tumor organoids were established from Apc/VillinCre mice (adenoma models). Organoid cultures, colorectal cancer (CRC) and primary normal intestinal cell lines have been treated with 1μg/ml of PFOS. To access the mechanisms involved in PFOS-induced intestinal alterations, qRT-PCR, western blot, immunofluorescence, cytokine array and metabolomics analysis have been performed. Results: The RNAseq analysis showed that PFOS exposure is associated with transcriptome alterations with exacerbated changes in pathways involved in lipid metabolism, immune system regulation and pro-carcinogenesis signaling. PFOS exposure leads to a significant decrease in expression of 3-hydroxy-3-methylglutaryl-Coa synthase 2 (HMGCS2), a rate limiting ketogenic enzyme, in intestinal tissues. We also showed that PFOS exposure upregulates fatty acid synthase, a key enzyme of de novo lipogenesis, programmed death-ligand, an immune checkpoint inhibitor, and altered the levels of pro-inflammatory cytokines and metabolites. Using HMGCS2 knockout cells, we identified the possible contribution of HMGCS2 in cytokine regulation and activation of oncogenic pathways. Conclusion: In summary, our data suggests that PFOS may induce gastrointestinal pathological changes that can increase the risk of CRC development. Further studies are warranted to determine the functional significance of PFOS-mediated downregulation of HMGCS2 and upregulation of lipid metabolism in intestinal cells. Delineating the effects of PFOS on intestinal epithelium may contribute to development of interventional strategies to eliminate harmful effects of these environmental pollutants. Citation Format: Josiane Weber Tessmann, Jerika Durham, Ryan Goettl, Dang he, Chi Wang, Pan Deng, Bernhard Hennig, Yekaterina Zaytseva. Perfluorooctanesulfonic acid exposure promotes pathological changes in normal intestinal tissues which may lead to an increased risk of colorectal cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1480.