Abstract
GenX is an alternative to environmentally persistent long-chain perfluoroalkyl and polyfluoroalkyl substances. Mice exposed to GenX exhibit liver hypertrophy, elevated peroxisomal enzyme activity, and other apical endpoints consistent with peroxisome proliferators. To investigate the potential role of peroxisome proliferator-activated receptor alpha (PPARα) activation in mice, and other molecular signals potentially related to observed liver changes, RNA sequencing was conducted on paraffin-embedded liver sections from a 90-day subchronic toxicity study of GenX conducted in mice. Differentially expressed genes were identified for each treatment group, and gene set enrichment analysis was conducted using gene sets that represent biological processes and known canonical pathways. Peroxisome signaling and fatty acid metabolism were among the most significantly enriched gene sets in both sexes at 0.5 and 5 mg/kg GenX; no pathways were enriched at 0.1 mg/kg. Gene sets specific to the PPARα subtype were significantly enriched. These findings were phenotypically anchored to histopathological changes in the same tissue blocks: hypertrophy, mitoses, and apoptosis. In vitro PPARα transactivation assays indicated that GenX activates mouse PPARα. These results indicate that the liver changes observed in GenX-treated mice occur via a mode of action (MOA) involving PPARα, an important finding for human health risk assessment as this MOA has limited relevance to humans.
Highlights
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are anthropogenic compounds used in a variety of industrial and consumer products, including industrial surfactants and emulsifiers, firefighting foams, stain-resistant coatings for textiles, oilresistant coatings for food packaging, personal care products, and nonstick coatings on cookware.[1,2,3] The same physical properties that make PFAS useful in the aforementioned applications make them resistant to biodegradation, hydrolysis, and photooxidation, resulting in their persistence in the environment.[1]
An important strength of this study is the fact that the same liver tissues were used for both histopathological examination and transcriptomic analysis
The results of the analyses presented provide additional evidence that liver lesions observed in mice exposed to GenX are related to peroxisome proliferator-activated receptor alpha (PPARa) and are similar to those induced by peroxisome proliferators
Summary
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are anthropogenic compounds used in a variety of industrial and consumer products, including industrial surfactants and emulsifiers, firefighting foams, stain-resistant coatings for textiles, oilresistant coatings for food packaging, personal care products, and nonstick coatings on cookware.[1,2,3] The same physical properties that make PFAS useful in the aforementioned applications make them resistant to biodegradation, hydrolysis, and photooxidation, resulting in their persistence in the environment.[1]. Various groups have concluded that shortand long-term toxicity studies on GenX indicate that the liver is the primary target of toxicity following oral exposure.[6,7] Several studies of GenX in the mouse have reported hepatocyte “single-cell necrosis” in the liver[8,9] and some recent risk assessments for GenX have been based on concerns of liver necrosis due to the presence of the so-called “single-cell
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