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Derivation of transcriptomics-based points of departure for twenty per- or polyfluoroalkyl substances (PFAS) using a larval fathead minnow (Pimephales promelas) reduced transcriptome assay.

ABSTRACT: 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.

ORGANISM(S): Pimephales promelas

PROVIDER: GSE246120 | GEO | 2024/10/23

REPOSITORIES: GEO

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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.

Project description:Nanoparticles are compounds of emerging concern with largely unknown risks for human and ecological health. It is crucial to evaluate their potential biological impact to prevent unintended adverse effects on human health and the environment. We analyzed the transcriptional effects of polyvinylpyrrolidone-coated silver nanoparticles (PVP-AgNPs) and silver nitrate (AgNO3) on the fathead minnow (Pimephales promelas) to understand their potential toxicity and adverse outcomes. We also tested the feasibility of the fathead minnow as an alternative species to elucidate potential adverse effects on humans. Fathead minnow females were exposed to either 4 Âµg/L of AgNO3 or 70 Âµg/L of PVP-AgNPs for 96h. Microarray analyses were performed on liver and brain. Functional analysis identified potential toxicity pathways and molecular initiating events (MIEs) that were confirmed with functional assays. Data suggested that AgNO3 and PVP-AgNPs had both common and distinct transcriptional effects. The nanoparticles were linked to neurotoxicity and oxidative stress, and identified as a dopamine receptor antagonist. Silver nitrate was also identified as a potential neurotoxicant and was confirmed as adrenergic and cannabinoid receptors antagonist. While silver nitrate and PVP-AgNPs were both potential neurotoxicants, they appeared to act through different MIEs. Fathead minnow is a promising alternative species to elucidate potential adverse effects of relevance to human health. We analyzed the transcriptional effects of polyvinylpyrrolidone-coated silver nanoparticles (PVP-AgNPs) and silver nitrate (AgNO3) on the fathead minnow (Pimephales promelas) to understand their potential toxicity and adverse outcomes. FHM were obtained from Aquatic Biosystems (Fort Collins, CO), held in aerated dechlorinated tap water and fed three times daily with ZeiglerÂ® AquaTox Feed Gardners, PA, USA). Fathead minnow females were exposed to either 4 Âµg/L of AgNO3 or 70 Âµg/L of PVP-AgNPs (Luna Innovations, Blackburn, VA) for 96h at 24Â°C Â± 1 with a 90% water change at 48 hours. Microarray analyses were performed on liver and brain.

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Derivation of transcriptomics-based points of departure for twenty per- or polyfluoroalkyl substances (PFAS) using a larval fathead minnow (Pimephales promelas) reduced transcriptome assay.

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