Transcriptomic analyses of mouse livers from an 18-month oral carcinogenicity study of HFPO-DA with a 9-month chronic toxicity phase

Transcriptomic anlayses were conducted on liver tissue from male and female CD-1 mice orally exposed to 0, 0.05, 0.1, 0.5 or 5 mg/kg-bw/day HFPO-DA (ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate; CASRN 62037-80-3) in a 18-month carcinogencity study that included a 9-month chronic toxicity phase in support of an investigation of the mode of action for HFPO-DA-mediated liver toxicity. This combined chronic toxicity and carcinogenicity study complied with Good Laboratory Practice (GLP) and Organization for Economic Co-operation and Development (OECD) 453 test guidelines for combined chronic toxicity/carcinogenicity studies. Transcriptomic responses in exposed mice were compared to time-matched control mice. Pathway enrichment of differentially expressed genes, as well as benchmark dose modeling and functional classification of dose-responsive genes were conducted. A low hepatic transcriptomic response was observed in mice exposed to 0.05 or 0.1 mg/kg-bw/day HFPO-DA for 9 or 18 months. In mice exposed to 0.5 or 5 mg/kg-bw/day, the top most significantly enriched gene sets were similar in male and female mouse livers regardless of exposure duration. Upregulated gene sets were related to b-oxidation of fatty acids and fatty acid metabolism, PPAR signaling, and peroxisome signaling. Downregulated gene sets were related to innate immune responses and amino acid metabolism. Results from benchmark dose-response analysis indicate livers from male mice exposed to HFPO-DA for 9 months had the greatest transcriptomic response. Overall design: Comparative gene expression profiling analysis of RNA-seq data from FFPE liver tissue of male and female CD1 mice orally exposed to 0, 0.05, 0.1, 0.5 or 5 mg/kg-bw/day HFPO-DA (n= 3-5 per treatment group) once daily for a total of 9 or 18 months.