PFOA/PFOS Facilitated Intestinal Fatty Acid Absorption by Activating the PPARα Pathway: Insights from Organoids Model

Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) continue to be extensively present in the natural environment and seriously threaten human health. The intestinal tract is the primary organ of PFOA/PFOS exposure due to the consumption of contaminated food and drinking water. However, it remains unclear how PFOA/PFOS affects intestinal function and overall health. The aim of this study was to investigate the influence of PFOA/PFOS on the absorption of fatty acids in the intestine and the underlying mechanisms using three-dimensional (3D) intestinal organoids. Our results showed that PFOS, but not PFOA, could significantly enhance the fatty acid uptake capacity without obvious damage to the organoids. Furthermore, PFOS markedly reduced the protein levels of ChgA in enteroendocrine cells, but with no observed impact on aldolase B⁺ enterocytes. Mechanistically, exposure to PFOS induced the activation of the peroxisome proliferator-activated receptor (PPAR) α pathway in intestinal organoids, with enhanced expression of PPARα target genes associated with fatty acid metabolism, such as <i>Fabp1</i> and <i>Cd36</i> (fatty acid transporter genes), <i>Acox1</i> and <i>Pdk4</i> (fatty acid oxidation genes), and <i>Plin2</i> and <i>Plin3</i> (lipid droplet synthesis genes). These data suggest that PFOS have the potential to affect the absorption function of the intestinal epithelium through the PPARα pathway, and its effect is much stronger than that of PFOA. Our findings also highlight that organoids can be used as a valuable model for conducting toxicological research on environmental chemicals.