Dataset Information

A New Approach Methods Strategy for Risk-based Prioritization of PFAS [hepatocytes]

ABSTRACT: Per- and polyfluoroalkyl substances (PFAS) are a very large (thousands of chemicals) category; these substances have important industrial and consumer product applications. PFAS are highly persistent in the environment, and some are known to pose human health hazard. Regulatory agencies worldwide are considering restrictions and outright bans of PFAS; however, little data exists to make informed decisions. Therefore, a prioritization strategy is urgently needed for evaluation of potential hazards of PFAS. Structure-based grouping could expedite selection of PFAS for testing; still, the hypothesis that structure-effect relationships exist requires confirmation. We tested 26 structurally diverse PFAS from 8 groups in two human cell types from organs that are thought to be targets for PFAS. We used human induced pluripotent stem cell-derived hepatocytes and cardiomyocytes and tested concentration-response effects on both cell function and gene expression. Few phenotypic effects were observed in hepatocytes, but negative chronotropy was observed for 8 of 26 PFAS. Substance- and cell-dependent transcriptomic changes were more pronounced; however, little evidence of group-specific effects was observed. In hepatocytes, we found up-regulation of stress-related and extracellular matrix organization pathways, and down-regulation of fat metabolism. In cardiomyocytes, contractility-related pathways were most affected. Using these data, we derived phenotypic and transcriptomic point of departure estimates and compared them to predicted PFAS exposures. The conservative estimates for bioactivity and exposure were used to derive margin-of-exposure (MOE) for each PFAS. We found that most (23 of 26) PFAS had MOE>1. Overall, our data suggests that chemical structure-based grouping of PFAS may not be an appropriate strategy to predict their biological effects. This means that testing of the individual PFAS would be needed for confident decision-making. Our proposed strategy of using two human cell types and considering both phenotypic and transcriptomic effects, combined with dose-response analysis, may be used for prioritization of PFAS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244107 | GEO | 2024/02/27

REPOSITORIES: GEO

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Project description:Per- and polyfluoroalkyl substances (PFAS) are a very large (thousands of chemicals) category; these substances have important industrial and consumer product applications. PFAS are highly persistent in the environment, and some are known to pose human health hazard. Regulatory agencies worldwide are considering restrictions and outright bans of PFAS; however, little data exists to make informed decisions. Therefore, a prioritization strategy is urgently needed for evaluation of potential hazards of PFAS. Structure-based grouping could expedite selection of PFAS for testing; still, the hypothesis that structure-effect relationships exist requires confirmation. We tested 26 structurally diverse PFAS from 8 groups in two human cell types from organs that are thought to be targets for PFAS. We used human induced pluripotent stem cell-derived hepatocytes and cardiomyocytes and tested concentration-response effects on both cell function and gene expression. Few phenotypic effects were observed in hepatocytes, but negative chronotropy was observed for 8 of 26 PFAS. Substance- and cell-dependent transcriptomic changes were more pronounced; however, little evidence of group-specific effects was observed. In hepatocytes, we found up-regulation of stress-related and extracellular matrix organization pathways, and down-regulation of fat metabolism. In cardiomyocytes, contractility-related pathways were most affected. Using these data, we derived phenotypic and transcriptomic point of departure estimates and compared them to predicted PFAS exposures. The conservative estimates for bioactivity and exposure were used to derive margin-of-exposure (MOE) for each PFAS. We found that most (23 of 26) PFAS had MOE>1. Overall, our data suggests that chemical structure-based grouping of PFAS may not be an appropriate strategy to predict their biological effects. This means that testing of the individual PFAS would be needed for confident decision-making. Our proposed strategy of using two human cell types and considering both phenotypic and transcriptomic effects, combined with dose-response analysis, may be used for prioritization of PFAS.

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:The potential effects of poly- and perfluoroalkyl substances (PFAS) are a recent human and environmental health concern. There is a persistent link between PFAS exposure and cancer, but the mechanisms are poorly understood. Although epidemiological evidence supporting PFAS exposure and cancer in general is conflicting, there is a relatively strong evidence linking PFAS and testicular germ cell tumors (TGCTs). However, there have been no mechanistic studies to date cancerning PFAS and TGCTs. In this report, the effects of the legacy PFAS, perfluorooctanesulfonic acid (PFOS) and the newer "clean energy" PFAS, lithium bis(trifluoromethylsulfonyl)imide (LiTFSi and called HQ-115) on TGCT tumorigenicity, survival, metabolism, and gene regulation were investigated. In vitro, proliferation and survival of both chemo-sensitive and -resistant TGCT cells were minimally affected by a wide concentration range of PFOS and HQ-115. However, both chemicals promoted the growth of TGCT cells in mouse xenografts at doses consistenet with human exposure but had minimal acute toxicity, as assessed by total body, kidney, and testis weight. PFOS, but not HQ-115, increased liver weight. Transcriptiomic alterations of PFOS-exposed normal mouse testes were dominated by cancer-related pathways and gene expression altersations associated with the H3K27me3 polycomb pathway and DNA methylation, epigenetic pathways were previously shown to be critical for the survival of TGCT cells after cisplatin-based chemotherapy. Similar pattersn of PFOS-mediated gene expression occured in PFOS-exposed cells in vitro. Metabolomic studies revealed that PFOS also altered metabolites associiated with steroid biosynthesis and fatty acid metabolism in TGCT cells, consistent with the proposed ability of PFAS to mimic fatty acied based ligands controlling lipid metabolism and the proposed role of PFAS as endocrine disrupters. Our data, this first cell and animal based study on PFAS in TGCTs, support a pro-tumorigenic effect of PFAS on TGCT biology and suggests epigenetic, metabolic, and endocrine disruption as potential mechanisms of action that are consistent with the non-mutagenic nature of the PFAS class.

Project description:Per- and polyfluoroalkyl substances (PFAS) represent a large group of contaminants of concern based on their widespread use, distribution and persistence in the environment, and potential toxicity. Many of the traditional models for estimating toxicity, bioaccumulation, and other relevant toxicological properties are not well suited for PFAS. Consequently, there is a need to generate hazard information for a large number of PFAS in an efficient and cost-effective manner. In the present study, Daphnia magna were exposed to multiple concentrations of 22 different PFAS for 24 h, in a 96-well plate format. Following exposure, whole body RNA was extracted and pooled extracts, each representing five exposed individuals, were subjected to RNA sequencing. Following analytical measurements to verify PFAS exposure concentrations in-well, and quality control on processed cDNA libraries for sequencing, concentration-response modeling was applied to the data sets for 18 of the tested compounds, and the concentration at which a concerted molecular response occurred (transcriptomic point of departure; tPOD) was calculated. The tPODs, based on average measured concentration of PFAS in the exposure wells, generally ranged from 0.03-0.58 µM (9.9-350 µg/L; interquartile range). In most cases, these concentrations were two orders of magnitude lower than similarly calculated tPODs for human cell lines exposed to PFAS. They were also lower than apical effect concentrations reported for seven PFAS for which some crustacean or invertebrate toxicity data were available, although there were a few exceptions. However, despite being lower than most other available hazard benchmarks, the Daphnia magna tPODs were, on average, four orders of magnitude greater than the maximum aqueous concentrations of PFAS measured in Great Lakes tributaries. Overall, this high throughput transcriptomics assay with Daphnia magna holds promise as a component of a tiered hazard evaluation strategy employing new approach methodologies.

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A New Approach Methods Strategy for Risk-based Prioritization of PFAS [hepatocytes]

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