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

ABSTRACT: 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 PPARα 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE282998 | GEO | 2025/04/21

REPOSITORIES: GEO

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Project description:Per- and polyfluoroalkyl substances (PFAS) are chemicals that are relatively resistant to degradation. While such features are desirable in a variety of consumer and industry products, such as firefighting foams and non-stick cookware coating, some PFAS, including perfluorooctanoic acid (PFOA), are toxic and bioaccumulate. Hexafluoropropylene oxide dimer acid (HFPO-DA) is an emerging PFAS developed to replace PFOA and has not been extensively studied. To evaluate the potential toxicity of HFPO-DA with a cost- and time-efficient approach, we exposed C. elegans larvae to 4×10-9–4 g/L HFPO-DA in liquid media and performed assays measuring developmental, behavioral, locomotor, and transcriptional effects at various exposure levels. After 48 hours of 1.5–4 g/L HFPO-DA exposure, acute developmental toxicity was observed as developmental delay; statistically significantly delayed (p < 0.05) progeny production was observed in worms exposed to 2–4 g/L HFPO-DA. After 48 hours of 4×10-9–0.4 g/L exposure, no significant behavioral or locomotor effect was observed relative to the 0 g/L control group. Statistically significant differential gene expression was identified with over 99% confidence via the R-package NOISeq in all fourteen 48-hour 1.25×10¬-5–4 g/L HFPO-DA exposure groups, except for 6.25×10¬-5 g/L. Among 10298 genes analyzed, 2624 differentially expressed genes (DEGs) were identified in the developmentally delayed 4 g/L group only, and 78 genes were differentially expressed in at least one of the thirteen exposure groups testing 1.25×10¬-5–2 g/L HFPO-DA exposures. Genes encoding for detoxification proteins such as cytochrome P450 enzymes and UDP glucuronosyltransferases are upregulated in 0.25–4 g/L acute exposure groups. In the lower exposure concentration groups, statistically significant gene expression changes were also observed, though these DEGs did not share any biological functions, except for six ribosomal protein-coding genes. While our transcriptional data is insufficient for conclusive mechanistic explanation, the statistically significant gene expression differences detected at 1.25×10¬-5 g/L, the lowest concentration tested for transcriptional changes, is concerning and calls for further targeted analyses that focus on low-dose HFPO-DA exposure effects.

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

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