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Comparison of transcriptomic profiles between HFPO-DA and positive controls for PPARa, PPARg or cytotoxicity in mouse, rat, and pooled human hepatocytes

ABSTRACT: Like many per- or polyfluorinated alkyl substances (PFAS), toxicity studies with HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate; CASRN 62037-80-3), a short-chain PFAS used in the manufacture of some types of fluorinated polymers, indicate that the liver is the primary target of toxicity in rodents following oral exposure. Although the current weight of evidence supports the PPARa mode of action (MOA) for liver effects in HFPO-DA-exposed mice, alternate MOAs have also been hypothesized including PPARg or cytotoxicity. To further evaluate the MOA for HFPO-DA in rodent liver, transcriptomic analyses were conducted on samples from primary mouse, rat and pooled human hepatocytes treated for 12, 24 or 72 hours with various concentrations of HFPO-DA, or established agonists of PPARa (GW7647), PPARg (rosiglitazone), or cytotoxic agents (i.e., acetaminophen or d-galactosamine). Concordance analyses of enriched pathways across chemicals within each species demonstrated greatest concordance between HFPO-DA and PPARa agonist GW7647-treated hepatocytes compared to the other chemicals evaluated. These findings were supported by benchmark concentration modeling and predicted upstream regulator results. In addition, transcriptomic analyses across species demonstrated a greater transcriptomic response in rodent hepatocytes treated with HFPO-DA or agonists of PPARa or PPARg, indicating rodent hepatocytes are more sensitive to HFPO-DA or PPARa/g agonist treatment. These results are consistent with previously published transcriptomic analyses and further support that liver effects in HFPO-DA-exposed rodents are mediated through rodent-specific PPARa signaling mechanisms as part of the MOA for PPARa activator-induced rodent hepatocarcinogenesis.

ORGANISM(S): Mus musculus Rattus norvegicus Homo sapiens

PROVIDER: GSE248251 | GEO | 2024/04/30

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.

Project description:Per- and polyfluoroalkyl substances (PFAS) are persistent pollutants known for their bio-accumulative properties and prevalence in water supplies and household products. Although legacy PFAS, such as perfluorooctanoic acid, are phased out in the U.S. due to public health concerns, a PFAS variant hexafluoropropylene oxide-dimer acid (HFPO-DA) is an emerging replacement. HFPO-DA is a potential neurotoxicant that has been shown to cause dopaminergic neurodegeneration. We investigated the bioaccumulative potential of HFPO-DA and its effects on lifespan, locomotor activity, and brain gene expression in female and male Drosophila melanogaster (fruit flies). Flies were collected less than 4 hours post-eclosion and exposed to 0, 10, 10^2, 10^3, or 10^4 mg/kg/day HFPO-DA. To measure the effect of HFPO-DA on lifespan, surviving flies from each exposure were recorded every 24 hours. Flies were subjected to a negative geotaxis assay at 3, 7, and 14 days of exposure to measure the effects of acute, sub-chronic, and chronic exposures on locomotor ability. To capture HFPO-DA-induced sexually dimorphic gene expression responses in the brain, we sequenced brain-specific mRNA from flies exposed for 3, 7, or 14 days. The Bioconcentration Factor was 0.031 for females, and 0.026 for males. Dose and median lifespan were negatively correlated in both female (R^2 adj = 0.77, p<0.0001) and male flies (R^2 adj = 0.77, p<0.0001). Log-rank Mantel-Cox tests and one-way ANOVAs revealed that median lifespan was reduced in females starting at 10 mg/kg/day and in males starting at 10^2 mg/kg/day (p< 0.01). Acute exposure at 10 mg/kg/day significantly decreased locomotor ability in females (p<0.0001) while acute exposures at 1 mg/kg/day decreased locomotor activity in males (p <0.0001). Among 7500 genes analyzed, pairwise gene expression comparison between controls and treatments identified 2496 differentially expressed genes. While HFPO-DA does not readily bioaccumulate in fruit fly bodies, high-dose exposures have sex-specific effects on lifespan, locomotor ability, and brain gene expression. LOAEL for median lifespan is 10 mg/kg/day in females, and 10^2 mg/kg/day in males. Both locomotor ability and brain gene expression exhibited non-conventional dose-response as seen in other endocrine disrupting chemical exposures.

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Comparison of transcriptomic profiles between HFPO-DA and positive controls for PPARa, PPARg or cytotoxicity in mouse, rat, and pooled human hepatocytes

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