Comparison of transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in wild-type and PPARα knockout mouse hepatocytes.
Toxicol Sci
; 200(1): 183-198, 2024 Jun 26.
Article
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| ID: mdl-38574385
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.
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Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Ratones Noqueados
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Hepatocitos
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PPAR alfa
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PPAR gamma
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Transcriptoma
Límite:
Animals
Idioma:
En
Revista:
Toxicol Sci
Asunto de la revista:
TOXICOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos