Poly- and perfluoroalkylated substances (PFAS) are chemicals that persist and bioaccumulate in the environment and are found in nearly all human populations through several routes of exposure. Human occupational and community exposure to PFAS has been associated with several cancers, including cancers of the kidney, testis, prostate, and liver. While evidence suggests that PFAS are not directly mutagenic, many diverse mechanisms of carcinogenicity have been proposed. In this mini-review, we organize these mechanisms into three major proposed pathways of PFAS action—metabolism, endocrine disruption, and epigenetic perturbation—and discuss how these distinct but interdependent pathways may explain many of the proposed pro-carcinogenic effects of the PFAS class of environmental contaminants. Notably, each of the pathways is predicted to be highly sensitive to the dose and window of exposure which may, in part, explain the variable epidemiologic and experimental evidence linking PFAS and cancer. We highlight testicular and prostate cancer as models to validate this concept.

Perfluorooctanoic acid (PFOA) has been implicated in various toxicities including neurotoxicity, genotoxicity, nephrotoxicity, epigenetic toxicity, immunotoxicity, reproductive toxicity, and hepatotoxicity. However, information on the accumulation of PFOA in the intestine and its toxic effects on intestinal epigenetics and tight junction (TJ) genes is sparse. CD1 mice were dosed with PFOA (1, 5, 10, or 20 mg/kg/day) for 10 days, and its accumulation and induced alterations in the expression of epigenetic and tight junction genes in the small intestine and colon were evaluated using LC–MS and qPCR techniques. PFOA reduced the expression levels of DNA methyltransferases (Dnmt1, Dnmt3a, Dnmt3b) primarily in the small intestine whereas, in the colon, a decrease was observed only at high concentrations. Moreover, ten-eleven translocation genes (Tet2 and Tet3) expression was dysregulated in the small intestine, whereas in the colon Tets remained unaffected. The tight junction genes Claudins (Cldn), Occludin (Ocln), and Tight Junction Protein (Tjp) were also heavily altered in the small intestine. TJs responded differently across the gut, in proportion to PFOA dosing. Our study reveals that PFOA triggers DNA methylation changes and alters the expression of genes essential for maintaining the physical barrier of intestine, with more profound effects in the small intestine compared to the colon.

Alterations of the normal gut microbiota can cause various human health concerns. Environmental chemicals are one of the drivers of such disturbances. The aim of our study was to examine the effects of exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS)—specifically, perfluorooctane sulfonate (PFOS) and 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy) propanoic acid (GenX)—on the microbiome of the small intestine and colon, as well as on liver metabolism. Male CD-1 mice were exposed to PFOS and GenX in different concentrations and compared to controls. GenX and PFOS were found to have different effects on the bacterial community in both the small intestine and colon based on 16S rRNA profiles. High GenX doses predominantly led to increases in the abundance of Clostridium sensu stricto, Alistipes, and Ruminococcus, while PFOS generally altered Lactobacillus, Limosilactobacillus, Parabacteroides, Staphylococcus, and Ligilactobacillus. These treatments were associated with alterations in several important microbial metabolic pathways in both the small intestine and colon. Untargeted LC-MS/MS metabolomic analysis of the liver, small intestine, and colon yielded a set of compounds significantly altered by PFOS and GenX. In the liver, these metabolites were associated with the important host metabolic pathways implicated in the synthesis of lipids, steroidogenesis, and in the metabolism of amino acids, nitrogen, and bile acids. Collectively, our results suggest that PFOS and GenX exposure can cause major perturbations in the gastrointestinal tract, aggravating microbiome toxicity, hepatotoxicity, and metabolic disorders.

• Mouse lung accumulates high concentration of dosed PFOA. • PFOA downregulates lungs epigenetic regulators, DNA methylation genes. • PFOA upregulates SARS-CoV-2 target genes in lung, Ace2 and Tmprss2. • Promotor region of Tmprss2 is hypomethylated in PFOA treated mice.