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Verification of In Vivo Estrogenic Activity for Four Polyfluoroalkyl Substances (PFAS) Identified as Estrogen Receptor Agonists in High-Throughput Screening
Citation:
Cavallin, J., G. Ankley, B. Blackwell, J. Hoang, R. Hofer, K. Houck, K. Jensen, M. Kahl, R. Kutsi, A. Opseth, K. Santana Rodriguez, E. Stacy, AND Dan Villeneuve. Verification of In Vivo Estrogenic Activity for Four Polyfluoroalkyl Substances (PFAS) Identified as Estrogen Receptor Agonists in High-Throughput Screening. SETAC North America 42nd Annual meeting, Portland, OR, November 14 - 18, 2021. https://doi.org/10.23645/epacomptox.17064230
Impact/Purpose:
Poster presented to the Society of Environmental Toxicology and Chemistry (SETAC) Meeting November 2021. 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 polyfluoroalkyl substances (PFAS) are a large class of fluorinated organic chemicals of concern due to their broad occurrence and persistence in humans and the environment and potential health effects. In response to these concerns, over 140 PFAS were screened for 81 different transcription factor activities in two multi-factorial transactivation assays. Over 40 distinct PFAS structures including perfluorooctanoic acid (PFOA) and many less studied PFAS showed activity against the estrogen receptor (ER). Most were partial agonists with maximum efficacy less than that of 17β-estradiol (E2), with 1H,1H,8H,8H-perfluoro-3,6-dioxaoctane-1,8-diol (PFDOD) identified as a notable exception that displayed full agonist activity. The aim of the present study was to evaluate whether the ER agonist activity detected through in vitro high-throughput screening would translate into estrogen-dependent effects in fish in vivo. Adult male fathead minnows (Pimephales promelas) were exposed to four ER-active PFAS including PFOA, PFDOD, 1H,1H,8H,8H-Perfluorooctane-1,8-diol (FC8-diol) and 1H,1H,10H,10H-Perfluorodecane-1,10-diol (FC10-diol) for 4 days. Five concentrations, with the maximum concentration set at either 50x (FC8-diol, FC10-diol) or 5x (PFDOD and PFOA) the 50% activity concentration (AC50) of the in vitro assays were tested. Following exposure, liver tissues were collected and expression of four genes known to be modulated by estrogen exposure - vtg and esr1, upregulated; apoeb and igf1, downregulated – was evaluated by quantitative real time polymerase chain reaction. Data collected to date show that while PFOA did not elicit impacts on gene expression consistent with those observed for the positive control (E2), 0.15-1.5 mg FC8-diol/L caused induction of vtg and esr1 expression and suppression of igf1 and apoeb at magnitudes similar to that elicited by the E2 positive control. These data suggest that at least some novel PFAS are able to elicit effects in vivo consistent with exposure to a steroidal estrogen. These results suggest ER-active PFAS likely warrant further monitoring in the environment to evaluate whether environmental exposures to these compounds may reach concentrations sufficient to elicit adverse effects previously associated with estrogenic endocrine disruption. The contents of this abstract neither constitute, nor necessarily reflect, US EPA policy.
URLs/Downloads:
DOI: Verification of In Vivo Estrogenic Activity for Four Polyfluoroalkyl Substances (PFAS) Identified as Estrogen Receptor Agonists in High-Throughput Screening
CAVALLIN ET AL 2021 SETAC ER PFAS POSTER.PDF (PDF, NA pp, 407.462 KB, about PDF)