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Importantly, PPAR\u03b1-mediated key events (KEs) including hepatocellular hypertrophy and proliferation that have been shown to occur prior to tumor development in this MOA are rodent-specific and likely not human-relevant. To further inform the MOA of HFPO-DA and evaluate other hypothesized MOAs, phenotypic and transcriptomic responses in wild-type (WT) and Ppara-null mice were investigated following short-term exposure to HFPO-DA or prototypical agonists of PPAR\u03b1 (GW7647), PPAR\u03b3 (rosiglitazone), or cytotoxicity (acetaminophen). Phenotypic and transcriptomic assessment of mouse livers demonstrated a general lack of response to HFPO-DA or GW7647 exposure in Ppara-null but not WT mice. Conversely, rosiglitazone or acetaminophen elicited similar phenotypic and transcriptomic responses between genotypes demonstrating a lack of PPAR\u03b1-dependence. In WT mice, HFPO-DA-mediated responses were similar to GW7647 but different from rosiglitazone or acetaminophen. Dose-dependent increases in liver weight, karyomegaly, and mitosis, as well as increased transcriptomic signaling related to PPAR\u03b1 activation and cell proliferation were observed in HFPO-DA and 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-null mice, provide further support that HFPO-DA-mediated early KEs in mouse liver are PPAR\u03b1-dependent, occur via the rodent-specific PPAR\u03b1 MOA, and therefore are not appropriate for use in human health risk assessment.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf049","type":"journal-article","created":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T02:13:36Z","timestamp":1744424016000},"page":"183-201","source":"Crossref","is-referenced-by-count":12,"title":["Comparison of phenotypic and transcriptomic profiles between HFPO-DA and prototypical PPAR\u03b1, PPAR\u03b3, and cytotoxic agents in wild-type and <i>Ppara<\/i>-null mouse livers"],"prefix":"10.1093","volume":"206","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8931-617X","authenticated-orcid":false,"given":"Melissa 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