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Dryad

Supplementary data for: Comparison of transcriptomic profiles between HFPO-DA and prototypical PPARa, PPARg, and cytotoxic agents in wild-type and PPARa knockout mouse hepatocytes

Abstract

Recent in vitro transcriptomic analyses for the short-chain polyfluoroalkyl substance (PFAS), HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), support conclusions from in vivo data that HFPO-DA-mediated liver effects in mice are part of the early key events of the peroxisome proliferator-activated receptor alpha (PPARa)activator-induced rodent hepatocarcinogenesis mode of action (MOA). Transcriptomic responses in HFPO-DA-treated rodent hepatocytes have high concordance with those treated with a PPARa agonist and lack concordance with those treated with PPARg agonists or cytotoxic agents. To elucidate whether HFPO-DA-mediated transcriptomic responses in mouse liver are PPARa-dependent, additional transcriptomic analyses were conducted on samples from primary PPARaknockout (KO) and wild-type (WT) mouse hepatocytes exposed for 12, 24 or 72 hours with various concentrations of HFPO-DA, or well-established agonists of PPARa (GW7647) and PPARg (rosiglitazone), or cytotoxic agents (acetaminophen or d-galactosamine). Pathway and predicted upstream regulator-level responses were highly concordant between HFPO-DA and GW7647 in WT hepatocytes. A similar pattern was observed in PPARa KO hepatocytes, albeit with a distinct temporal and concentration-dependent delay potentially mediated by compensatory responses. This delay was not observed in PPARa KO hepatocytes exposed to rosiglitazone, acetaminophen, d-galactosamine. The similarity in transcriptomic signaling between HFPO-DA and GW7647 in both the presence and absence of PPARa in vitro indicates these compounds share a common mechanism of action and supports the PPARa-dependence of HFPO-DA-mediated effects in mouse liver.