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In vivo effects of four per- and polyfluoroalkyl substances identified as estrogenic via in vitro screening.
Citation:
Villeneuve, D., B. Blackwell, J. Cavallin, J. Collins, J. Hoang, R. Hofer, K. Houck, K. Jensen, M. Kahl, R. Kutsi, A. Opseth, K. Santana Rodriguez, C. Schaupp, E. Stacy, AND G. Ankley. In vivo effects of four per- and polyfluoroalkyl substances identified as estrogenic via in vitro screening. Society of Toxicology 62nd Annual Meeting, Nashville, TN, March 19 - 23, 2023. https://doi.org/10.23645/epacomptox.24749445
Impact/Purpose:
Per- and polyfluorinated alkyl substances (PFAS) are a large class of organic contaminants that are of significant concern to EPA and its stakeholders due to persistence in the environment, widespread detection in humans and the environment, and potential toxicity. Recent high throughput screening identified over 25% of PFAS structures evaluated to have biological activities associated with endocrine disruption. However, animal studies with prominent PFAS like PFOS and PFOA have been somewhat inconsistent as to whether these compounds may cause endocrine disruption in intact animals. The present study evaluates the possible endocrine disrupting properties of PFOA and three additional compounds for which no intact animal data are presently available to assess whether they elicit effects in fish consistent with in vivo activity as endocrine active substances. In combination with appropriate source and exposure data, these results will help to inform ecological risk assessment associated with this broader spectrum of PFAS which is of interest to multiple EPA program offices.
Description:
Per- and polyfluroalkyl substances (PFAS) are a large group of chemicals of concern based on their potential persistence, bioaccumulation, and toxicity. A tiered approach to screening and testing using new approach methodologies has been proposed as one of the few tractable approaches for evaluating thousands of PFAS for human health and environmental hazards. Based on previous conducted in vitro screening assays with human cell lines, four PFAS identified as estrogenic and one PFAS identified as non-estrogenic were subsequently tested for estrogenic actions in vivo. Male fathead minnows were exposed to the selected PFAS for 96 h and hepatic expression of four estrogen regulated genes was examined. Of the four estrogenic PFAS, the three perfluorinated alcohols, which ranked among the most potent estrogenic PFAS out of over 140 screened, elicited concentration-dependent up-regulation of vitellogenin and estrogen receptor alpha transcripts and down-regulation of insulin-like growth factor 1 and apolipoprotein eb transcripts in exposed male fathead minnows. In contrast, perfluorooctanoic acid, which was a substantially less potent estrogen receptor agonist in vitro, and perfluoro-2-methyl-3oxahexanoic acid (GenX), which was non-estrogenic in vitro, elicited no concentration-dependent effects on the estrogen regulated transcripts. After accounting for differences in measured bioconcentration in plasma, the in vitro and in vivo rank orders of potency aligned. The results provide increased confidence in the use of human cell-based assays to identify estrogenic environmental hazards of PFAS. Results also contribute a predicted no effect concentration for use in screening level assessments of potential PFAS-related estrogenic activity at contaminated sites and provide a basis to identify structurally related PFAS that should be evaluated for estrogenic activity. The contents of this abstract neither constitute nor necessarily reflect US EPA policy.
URLs/Downloads:
DOI: In vivo effects of four per- and polyfluoroalkyl substances identified as estrogenic via in vitro screening.
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