PFOS exposure/diet effects on intestinal tissue
PFOS, a member of the chemical group known as per- and polyfluoroalkyl substances (PFAS), is a well-documented environmental contaminant. Its high bioaccumulation potential and long elimination half-life can disrupt multiple biological pathways negatively affecting human health. The gastrointestinal tract (GI) is directly exposed to environmental pollutants via contaminated drinking water and food, potentially influencing intestinal homeostasis under both physiological and pathological conditions. Although some studies have highlighted the potential role of PFOS in tumor development, scientific literature on PFOS exposure in the GI is limited and the association between this environmental pollutant and GI-associated diseases remains to be determined. Therefore, this study aims to delineate the effects of PFOS on normal intestinal cells. The effect of PFOS on gene expression profiles was assessed through RNAseq analysis conducted on the intestinal tissue of C57BL/6 mice. Through RNAseq analysis, we identified the top pathways upregulated by PFOS as cancer, lipid metabolism and immune system. The KEGG analysis further highlighted significant gene enrichment in pro-oncogenic signaling pathways, including NOTCH, WNT/ß-catenin and TGF-ß. The RNAseq, q-RT-PCR and western blot analyses of normal intestinal tissues revealed that PFOS exposure leads to downregulation of 3-hydroxy-3-methylglutaryl-Coa synthase 2 (HMGCS2), a key enzyme in the synthesis of ß-hydroxybutyrate (ßHB), a critical ketogenic molecule.  In summary, our data suggests that PFOS may induce GI pathological changes that can increase the risk of CRC development. We identified that downregulation of ketogenesis and upregulation of lipid metabolism are the major effects of PFOS exposure in intestinal epithelium. Overall design: To investigate the effect of PFOS in gene expression profile in normal intestinal tissues, we used 7-week-old C57BL/6 male mice. The mice were placed on an irradiated diet supplemented with one of three fibers: cellulose (control), inulin, or pectin.  The mice were exposed to PFOS at 3µg/Kg BW?per?day by drinking water and maintained on the diet for 7 weeks. The composition of the diets was the following: Fiber: 8% wt/wt, Fat: 35% kcal, protein: 20% kcal and carbohydrate: 45% kcal.