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PFOS exposure/diet effects on intestinal tissue

ABSTRACT: 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/β-catenin and TGF-β. 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 β-hydroxybutyrate (βHB), 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE248402 | GEO | 2024/06/12

REPOSITORIES: GEO

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Project description:The potential effects of poly- and perfluoroalkyl substances (PFAS) are a recent human and environmental health concern. There is a persistent link between PFAS exposure and cancer, but the mechanisms are poorly understood. Although epidemiological evidence supporting PFAS exposure and cancer in general is conflicting, there is a relatively strong evidence linking PFAS and testicular germ cell tumors (TGCTs). However, there have been no mechanistic studies to date cancerning PFAS and TGCTs. In this report, the effects of the legacy PFAS, perfluorooctanesulfonic acid (PFOS) and the newer "clean energy" PFAS, lithium bis(trifluoromethylsulfonyl)imide (LiTFSi and called HQ-115) on TGCT tumorigenicity, survival, metabolism, and gene regulation were investigated. In vitro, proliferation and survival of both chemo-sensitive and -resistant TGCT cells were minimally affected by a wide concentration range of PFOS and HQ-115. However, both chemicals promoted the growth of TGCT cells in mouse xenografts at doses consistenet with human exposure but had minimal acute toxicity, as assessed by total body, kidney, and testis weight. PFOS, but not HQ-115, increased liver weight. Transcriptiomic alterations of PFOS-exposed normal mouse testes were dominated by cancer-related pathways and gene expression altersations associated with the H3K27me3 polycomb pathway and DNA methylation, epigenetic pathways were previously shown to be critical for the survival of TGCT cells after cisplatin-based chemotherapy. Similar pattersn of PFOS-mediated gene expression occured in PFOS-exposed cells in vitro. Metabolomic studies revealed that PFOS also altered metabolites associiated with steroid biosynthesis and fatty acid metabolism in TGCT cells, consistent with the proposed ability of PFAS to mimic fatty acied based ligands controlling lipid metabolism and the proposed role of PFAS as endocrine disrupters. Our data, this first cell and animal based study on PFAS in TGCTs, support a pro-tumorigenic effect of PFAS on TGCT biology and suggests epigenetic, metabolic, and endocrine disruption as potential mechanisms of action that are consistent with the non-mutagenic nature of the PFAS class.

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PFOS exposure/diet effects on intestinal tissue

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