Risk-based prioritization of PFAS using phenotypic and transcriptomic data from human induced pluripotent stem cell-derived hepatocytes and cardiomyocytes
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ABSTRACT:
PROVIDER: PRJNA1021236 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26184200.fastq.gz | Fastqsanger.gz | |||
| SRR26184300.fastq.gz | Fastqsanger.gz | |||
| SRR26185600.fastq.gz | Fastqsanger.gz | |||
| SRR26185700.fastq.gz | Fastqsanger.gz | |||
| SRR26185800.fastq.gz | Fastqsanger.gz |
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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.
2024-02-27 | GSE244109 | GEO
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.
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Project description:A New Approach Methods Strategy for Risk-based Prioritization of PFAS [cardiomyocytes]
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Project description:A New Approach Methods Strategy for Risk-based Prioritization of PFAS [hepatocytes]
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Project description:Per- and polyfluoroalkyl substances (PFAS) are chemicals with important applications; they are persistent in the environment and may pose human health hazards. Regulatory agencies are considering restrictions and bans of PFAS; however, little data exists for informed decisions. Several prioritization strategies were proposed for evaluation of potential hazards of PFAS. Structure-based grouping could expedite the selection of PFAS for testing; still, the hypothesis that structure-effect relationships exist for PFAS requires confirmation. We tested 26 structurally diverse PFAS from 8 groups using human induced pluripotent stem cell-derived hepatocytes and cardiomyocytes, and tested concentration-response effects on cell function and gene expression. Few phenotypic effects were observed in hepatocytes, but negative chronotropy was observed in cardiomyocytes for 8 PFAS. Substance- and cell type-dependent transcriptomic changes were more prominent but lacked substantial group-specific effects. In hepatocytes, we found upregulation of stress-related and extracellular matrix organization pathways, and down-regulation of fat metabolism. In cardiomyocytes, contractility-related pathways were most affected. We derived phenotypic and transcriptomic points of departure and compared them to predicted PFAS exposures. Conservative estimates for bioactivity and exposure were used to derive a bioactivity-to-exposure ratio (BER) for each PFAS; 23 of 26 PFAS had BER > 1. Overall, these data suggest that structure-based PFAS grouping may not be sufficient to predict their biological effects. Testing of individual PFAS may be needed for scientifically-supported decision-making. Our proposed strategy of using two human cell types and considering phenotypic and transcriptomic effects, combined with dose-response analysis and calculation of BER, may be used for PFAS prioritization.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2024-02-26 | GSE244110 | GEO
Project description:Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants of concern due to their persistence and potential adverse health effects. Epidemiological studies have linked PFAS with an increased risk of uterine diseases including fibroids however, the mechanisms involved remain to be elucidated. This study investigated the effects of individual PFAS, including long-chain “legacy” PFAS [perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS)] and short-chain “alternative” PFAS compounds [undecafluoro-2-methyl-3-oxahexanoic acid (GENX/HFPO-DA), perfluorobutanesulfonic acid (PFBS)], as well as a mixture of these chemicals on the function and transcriptome of an immortalized human myometrial cell line (UT-TERT). UT-TERT cells exposed to individual PFAS displayed increased cell viability and proliferation. Flow cytometry analysis revealed that PFOS and the PFAS mixture altered cell cycle progression. Migration assays demonstrated that PFOS and the PFAS mixture significantly enhanced UT-TERT cell migration. Gap junction intercellular communication (GJIC) was impaired following PFOA, PFBS, and PFAS mixture exposure, indicating potential disruptions in cell-to-cell communication within the uterine environment. Transcriptomic analysis using RNA-seq identified substantial changes in gene expression after exposure to environmentally relevant levels of individual PFAS and PFAS mixture. Pathway analysis revealed common molecular pathways associated with PFAS exposure, including Cell-to-Cell Signaling, Lipid Metabolism, and Cell Death and Survival, while other pathways were unique to specific PFAS. These findings highlight the multifaceted effects of PFAS on myometrial cells, providing insights into the potential mechanisms underlying PFAS-associated health risks. Further research is necessary to elucidate the long-term implications of PFAS exposure on uterine function and overall reproductive health.
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Project description:Traditional toxicity testing has been unable to keep pace with the introduction of new chemicals into commerce. Consequently, there are limited or no toxicity data upon which to base a risk assessment for many chemicals to which fish and wildlife may be exposed. Per- and polyfluoroalkyl substances (PFAS) are emblematic of this issue in that most the ecological hazards of most PFAS remain uncharacterized. The present study employed a high throughput assay to identify the concentration at which 20 PFAS, with diverse properties, elicited a concerted gene expression response in larval fathead minnows (Pimephales promelas, 5-6 days post-fertilization) exposed for 24 h. Based on a reduced transcriptome approach that measured whole body expression of 1832 genes, the median transcriptomic point of departure (tPOD) for the 20 PFAS tested was 10 µM. Longer chain carboxylic acids (12-13 C-F) and an eight C-F di-alcohol, N-alkyl sulfonamide, and telomer sulfonic acid were among the most potent PFAS, eliciting gene expression responses at concentrations below 1 µM. With a few exceptions, larval fathead minnow tPODs were concordant with those based on whole transcriptome response in human cell lines. However, larval fathead minnow tPODs were often greater than those for Daphnia magna exposed to the same PFAS. The tPODs overlapped concentrations at which other sub-lethal effects have been reported in fish (available for 10 PFAS; including a range of species, life stages, and study designs). Nonetheless, fathead minnow tPODs were all orders of magnitude higher than aqueous PFAS concentrations detected in tributaries of the North American Great Lakes suggesting a substantial margin of safety in those systems, even for PFAS with significant potential for bioaccumulation. Overall, results broadly support the use of a fathead minnow larval transcriptomics assay to derive screening level potency estimates for use in ecological risk-based prioritization. Traditional toxicity testing has been unable to keep pace with the introduction of new chemicals into commerce. Consequently, there are limited or no toxicity data upon which to base a risk assessment for many chemicals to which fish and wildlife may be exposed. Per- and polyfluoroalkyl substances (PFAS) are emblematic of this issue in that most the ecological hazards of most PFAS remain uncharacterized. The present study employed a high throughput assay to identify the concentration at which 20 PFAS, with diverse properties, elicited a concerted gene expression response in larval fathead minnows (Pimephales promelas, 5-6 days post-fertilization) exposed for 24 h. Based on a reduced transcriptome approach that measured whole body expression of 1832 genes, the median transcriptomic point of departure (tPOD) for the 20 PFAS tested was 10 µM. Longer chain carboxylic acids (12-13 C-F) and an eight C-F di-alcohol, N-alkyl sulfonamide, and telomer sulfonic acid were among the most potent PFAS, eliciting gene expression responses at concentrations below 1 µM. With a few exceptions, larval fathead minnow tPODs were concordant with those based on whole transcriptome response in human cell lines. However, larval fathead minnow tPODs were often greater than those for Daphnia magna exposed to the same PFAS. The tPODs overlapped concentrations at which other sub-lethal effects have been reported in fish (available for 10 PFAS; including a range of species, life stages, and study designs). Nonetheless, fathead minnow tPODs were all orders of magnitude higher than aqueous PFAS concentrations detected in tributaries of the North American Great Lakes suggesting a substantial margin of safety in those systems, even for PFAS with significant potential for bioaccumulation. Overall, results broadly support the use of a fathead minnow larval transcriptomics assay to derive screening level potency estimates for use in ecological risk-based prioritization.
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2024-08-31 | GSE261668 | GEO