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A Key Event Relationship by Key Event Relationship Approach to Adverse Outcome Pathway Development: Peroxisome Proliferator-Activated Receptor Alpha Agonism Impairs Fish Fertility
Citation:
Hoang, J., R. Kutsi, J. Olker, K. Jensen, G. Ankley, AND Dan Villeneuve. A Key Event Relationship by Key Event Relationship Approach to Adverse Outcome Pathway Development: Peroxisome Proliferator-Activated Receptor Alpha Agonism Impairs Fish Fertility. SETAC North America 42nd Annual meeting, Portland, OR, November 14 - 18, 2021. https://doi.org/10.23645/epacomptox.16980628
Impact/Purpose:
Per- and polyfluorinated alkyl substances (PFAS) are a large class of organic contaminants that are of significant concern to EPA. High throughput screening data has indicated that multiple PFAS can interact with and activate the peroxisome proliferator activated receptor alpha (PPARa). However, ecological hazards associated with PPARa activity are not well understood. The present study reviewed available literature to develop a weight of evidence evaluation of the potential links between PPARa activation and reduced fertility in fish. In particular, an key event relationship-focused approach that aids assembly of evidence using the adverse outcome pathway framework was employed. Results of this research both help to establish ecological hazards of potential concern in relation to PFAS exposures and demonstrate effective approaches to AOP development that can be used by others. The products of this research will aid EPA’s program offices and regions in more effectively evaluating ecological hazards associated with PFAS in the environment.
Description:
As per- and polyfluoroalkyl substances (PFAS) have been increasingly found in surface waters and sediment, there has been growing demand to better understand the potential ecological effects of these chemicals. Recent high throughput screening of over 140 PFAS has shown peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor that regulates transcription of various genes involved in fatty acid beta oxidation and lipid homeostasis, is one of the prominent biological targets affected by multiple PFAS. To better understand the ecological significance of PPARα activation, we reviewed the scientific literature with the aim of developing one or more adverse outcome pathways (AOPs) relevant to PPARα agonism. In this presentation, we will focus on PPARα agonism and its potential effect on reproduction. Review of multiple studies involving exposure to fibrates, synthetic ligands of PPARα prescribed to reduce cholesterol in humans, provided weight of evidence (WOE) for connecting PPARα agonism to decreased cholesterol (Key event relationship[KER] 2073) and decreased cholesterol to decreased 11-ketotestosterone (11-KT; KER 2072). The current presentation details the development of the WOE for the last two additional KERs (2076 and 2274), which connect decreased 11-KT to impaired spermatogenesis and impaired spermatogenesis to impaired fertility utilizing a KER by KER approach. This approach began with a literature search utilizing AbstractSifter which pulls literature from Pubmed based on key search terms. Afterwards, literature was filtered based on relevance and compiled maintaining both supporting and conflicting evidence to ensure objectivity. The WOE was then quality checked, organized into concordance tables, and uploaded to the AOP wiki. Overall, this approach was effective in establishing plausibility and empirical support involving dose-response and temporal concordance while maintaining objectivity. While AbstractSifter was effective in pulling empirical support in support for the KERs, KER 2274 was primarily supported by studies that did not involve use of chemical stressors. This presentation summarizes the evidence assembled and some of the advantages and challenges encountered when implementing the approach. Overall, the KER by KER approach taken here was effective for collaborative AOP development. The contents of this abstract neither constitute, nor necessarily reflect, official US EPA policy.
URLs/Downloads:
DOI: A Key Event Relationship by Key Event Relationship Approach to Adverse Outcome Pathway Development: Peroxisome Proliferator-Activated Receptor Alpha Agonism Impairs Fish Fertility
HOANG ET AL., 2021 SETAC MODULAR AOP-M.PDF (PDF, NA pp, 892.25 KB, about PDF)