Comparison of phenotypic and transcriptomic profiles between HFPO-DA and prototypical PPARa, PPAR?, and cytotoxic agents in wild-type and PPARa knockout mouse livers

Recent transcriptomic analyses in vitro comparing the transcriptomic profile of the short-chain per- and polyfluoroalkyl substances (PFAS) HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate) to that of other chemicals with known MOAs add to the current weight of evidence supporting the peroxisome proliferator-activated receptor alpha (PPARa) activator-induced rodent hepatocarcinogenesis mode of action (MOA) for HFPO-DA-mediated liver effects in rodents. To further inform the MOA of HFPO-DA and evaluate the PPARa-dependence of HFPO-DA-mediated liver effects in vivo, phenotypic and transcriptomic responses in wild-type (WT) and PPARa knockout (KO) mice were investigated following short-term exposure to HFPO-DA or well-established agonists of PPAR? (GW7647) and PPARg (rosiglitazone), or cytotoxic agent (acetaminophen [APAP]). Phenotypic and transcriptomic assessment of mouse livers demonstrated a general lack of response to HFPO-DA or GW7647 exposure in PPARa KO but not WT mice, whereas exposure to rosiglitazone or APAP elicited similar, if not greater phenotypic and transcriptomic responses in PPARa KO mice compared to WT mice. Dose-dependent increases in liver weight and increased karyomegaly and mitosis scores via histopathology, as well as increased transcriptomic signaling related to PPARa activation and cell proliferation were observed in HFPO-DA or GW7647-exposed WT mice. The consistent phenotypic and transcriptomic signaling patterns between HFPO-DA and GW7647 in WT mice, and the lack of changes in PPARa KO mice, provide further support that HFPO-DA-mediated liver effects in mice are PPARa-dependent and occur via the PPARa MOA. Thus, these adverse effects in mice are not appropriate for use as the basis of toxicity values for human health risk assessment. Overall design: Comparative gene expression profiling analysis of TempO-Seq data from FFPE liver tissue of male WT (J:ARC(S) and B6129SF2/J) and PPARa KO mouse strains exposed to various dose levels of HFPO-DA (0, 3, 15, 30 mg/kg-d), or well-established agonists of PPARa (GW7647; 0, 5, 10, 20 mg/kg-d) and PPARg (rosiglitazone; 0, 5, 10, 20 mg/kg-d), or hepatotoxicant (acetaminophen [APAP]; 0, 150, 300, 600 mg/kg) for 5 days via oral gavage or for 6 h via intraperitoneal injection (APAP only).