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.

Project description:Perfluoroalkyl substances (PFAS) are a class of synthetic chemicals that are persistent in the environment. Due to concerns linked with longer chain PFAS, shorter chain chemicals were used as replacements, but developmental toxicity assessments of the shorter chain chemicals are limited. The aim of this study was to compare the developmental toxicity of three perfluoroalkyl acids (PFAAs): perfluorooctanoic acid (PFOA), composed of 8 carbon (C8), perfluorohexanoic acid (PFHxA, C6), and perfluorobutanoic acid (PFBA, C4) using the zebrafish (Danio rerio). LC50s at 120 hour post fertilization (hpf) were determined to assess the potency of each PFAA by exposing developing zebrafish (1-120 hpf) to a range of concentrations. In sublethal assessments, zebrafish were exposed to 0, 4, 40, or 400 parts per billion (ppb; µg/L) of the PFAAs throughout embryonic development (1-72 hpf). Effects of the embryonic exposure on locomotor activities was completed with the visual motor response test at 120 hpf. At 72 hpf, morphological changes including total body length, head length, and head width were assessed. Additionally, transcriptomic profiles of PFOA, PFHxA, and PFBA were determined at 72 hpf to compare altered molecular and disease pathways. The LC50 ranking was PFOA > PFHxA > PFBA, which followed trend as expected based on chain length. PFOA caused hyperactivity and PFBA hypoactivity, while PFHxA did not change behavior. PFOA, PFHxA, and PFBA caused morphological and transcriptomic alterations that were unique for each chemical and were concentration dependent. Cancer was a top enriched disease for PFOA, while FXR/RXR activation was a top canonical pathway in all PFBA exposures. Overall, an embryonic exposure to PFOA, PFHxA, or PFBA resulted in morphological alterations in zebrafish eleuthero-embryos; however, only PFOA and PFBA induced neurobehavioral alterations. The transcriptomic profile of each chemical was unique indicating different toxicity mechanisms and were aligned with human adverse health outcomes supporting predictive value.

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Deciphering PFAS Potency: Cracking the Code with Gene Expression Profiles of Liver Toxic and Non-Liver-Toxic Reference Compounds

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