Evaluation of PFHpA impact on liver metabolism using human liver spheroids
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE253186 | GEO | 2025/09/18
REPOSITORIES: GEO
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Project description:Perfluoroalkyl substances (PFASs) are a family of toxicants universally detected in human serum and known to cause dyslipidemia in animals and humans. Non-alcoholic fatty liver disease (NAFLD) is most prevalent form of liver disease in the United States and has been rising in global prevalence over recent years. This study explored diet-PFAS interactions and their potential role in the increasing global incidence of NAFLD. Male C57BL/6 mice were fed with either a low-fat diet (10% kcal from fat) or a moderately high fat diet (45% kcal from fat) with or without perfluorooctanesulfonic acid (PFOS) or perfluorononanoic acid (PFNA) at a low dose of 0.0003% w/w in feed for 12 weeks. Livers were excised for histology and quantification of PFASs and lipids. Proteomics and transcriptomics were utilized to conduct mechanistic pathway exploration. In a high fat diet, PFOS and PFNA protected against the onset of hepatic lipid accumulation and inflammatory progression. Genes and proteins related to lipid metabolism, synthesis, transport, and storage were modulated by PFAS exposure and further impacted by the presence of dietary fat. When combined with a high fat diet, low dose PFOS and PFNA are protective against the onset of NAFLD suggesting that dietary fat impacts the behavior of PFASs in vivo. Furthermore, both dietary fat content and the chemical functional head group exerted significant influence on tissue partitioning and the resulting hepatic biochemical signature.
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Project description:Per- and polyfluoroalkyl substances (PFAS) are some of the most prominent organic contaminants in human blood that have the potential to disrupt biological processes and pathways in the liver. Although the toxicological implications from human exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are well established, data on other, lesser-understood PFAS are limited. A challenge for regulatory authorities is to determine acceptable levels of human exposure to large, diverse classes of environmental contaminants. New approach methodologies (NAMs) that apply bioinformatics tools to interpret biological data are being increasingly considered to inform risk assessment when traditional toxicology methodologies are not amenable. The aim of the current investigation was to identify the biological responses relevant to PFAS mode of action as the concentration (benchmark dose) that these effects take place in order to utililze this information to inform/facilitate read-across for risk assessment of data-poor PFAS. A TempO-Seq platform (BioSpyder) measured gene expression changes in human liver microtissues (i.e., spheroids) after 1-day and 10-day exposures to increasing concentrations of PFAS. A bioinformatics framework was applied to 23 PFAS sub-classed into carboxylates (PFCAs), sulfonates (PFSAs), or PFAS precursors that were analyzed for the total altered transcripts, the concentration where effects take place, and identifying target genes of interest. Both PFCAs and PFSAs exhibited a trend toward increased transcriptional changes with carbon chain-length. Specifically, longer-chain compounds (7 to 10 carbons) were more likely to surpass liver-toxic transcriptomic thresholds established from previous studies than shorter chain PFAS. Longer-chain PFAS were also more potent, inducing transcriptional effects at lower concentrations. However, PFOS was the most potent PFAS and of all precursors, only PFOSA (a PFOS precursor) induced a response. The combined high-throughput transcriptomic and bioinformatics analyses revealed the capability of NAMs to assess the effects of PFAS in liver microtissues; such data improves our understanding of PFAS-related effects in humans and facilitates the use of read-across in human health risk assessment for other data-poor chemicals.
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