1. Comparison of transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in wild-type and PPARα knockout mouse hepatocytes.
- Author
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Heintz MM, Klaren WD, East AW, Haws LC, McGreal SR, Campbell RR, and Thompson CM
- Subjects
- Animals, Mice, Fluorocarbons toxicity, Propionates pharmacology, Propionates toxicity, Mice, Inbred C57BL, Male, Cells, Cultured, Gene Expression Profiling, Acetaminophen toxicity, Cytotoxins toxicity, Butyrates, Phenylurea Compounds, Hepatocytes drug effects, Hepatocytes metabolism, PPAR alpha agonists, PPAR alpha genetics, PPAR alpha metabolism, Mice, Knockout, PPAR gamma agonists, PPAR gamma genetics, PPAR gamma metabolism, Transcriptome drug effects
- Abstract
Recent in vitro transcriptomic analyses for the short-chain polyfluoroalkyl substance, 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 (PPARα) activator-induced rodent hepatocarcinogenesis mode of action (MOA). Transcriptomic responses in HFPO-DA-treated rodent hepatocytes have high concordance with those treated with a PPARα agonist and lack concordance with those treated with PPARγ agonists or cytotoxic agents. To elucidate whether HFPO-DA-mediated transcriptomic responses in mouse liver are PPARα-dependent, additional transcriptomic analyses were conducted on samples from primary PPARα knockout (KO) and wild-type (WT) mouse hepatocytes exposed for 12, 24, or 72 h with various concentrations of HFPO-DA, or well-established agonists of PPARα (GW7647) and PPARγ (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 PPARα KO hepatocytes, albeit with a distinct temporal and concentration-dependent delay potentially mediated by compensatory responses. This delay was not observed in PPARα 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 PPARα in vitro indicates these compounds share a common MOA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology.)
- Published
- 2024
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