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Gathering evidence of endocrine pathway conservation for cross-species extrapolation using new approach methods.
Citation:
Vliet, S., C. LaLone, AND D. Blatz. Gathering evidence of endocrine pathway conservation for cross-species extrapolation using new approach methods. Computational Toxicology Specialty Section for the Society of Toxicology Virtual Meeting, Duluth, MN, December 02, 2020. https://doi.org/10.23645/epacomptox.13058225
Impact/Purpose:
The U.S. Environmental Protection Agency’s (U.S. EPA) mission to protect both human health and wildlife requires an understanding of how different species respond to chemical exposures in the environment. Although it’s clear that some chemicals cause negative effects across species, very few chemicals have been tested because of the many resources and animals needed to test each chemical. Using computer-based experiments, carrying out large reviews of available toxicity data, and conducting laboratory experiments, the Great Lakes Toxicology and Ecology Division (GLTED) is working to understand if current mammalian-based testing methods can predict toxicity in other organisms. Results of this research will provide evidence for conservation of chemical targets across species and inform the use of mammalian tests to predict toxicity in non-mammalian species.
Description:
The US Environmental Protection Agency’s endocrine disruptor screening program (EDSP) is tasked with assessing thousands of chemicals for their potential to adversely impact human health and the environment through perturbation of endocrine pathways. Traditionally, chemical screening is performed using a tiered toxicity testing strategy that includes whole-animal studies. This approach, however, has proven challenging due to the extensive time, resources, and animals needed to evaluate a single chemical for endocrine activity. Therefore, the EDSP has been transitioning towards the use of in-vitro high-throughput screening (HTS) techniques to rapidly and efficiently prioritize chemicals for further testing. Despite their utility, the ability of these mammalian-based HTS assays to accurately reflect chemical interactions with non-mammalian targets remains uncertain. One goal of the EDSP is to evaluate biological pathway conservation across taxa to understand how broadly these HTS results can be extrapolated to non-mammalian species. Identification of chemicals that modulate the androgen receptor (AR) is of interest to the EDSP because many chemicals have androgenic activity that can disrupt the endocrine system by mimicking or antagonizing natural hormones. Therefore, the objective of this study is to gather weight of evidence for AR pathway conservation across species using a combination of computational in-silico structural comparisons and systematic review of available toxicity literature, both in vitro and in vivo, to determine whether current AR HTS assays are predictive of activity in other vertebrates. Results of this work provide lines of evidence toward structural conservation of AR across vertebrate species and suggest that chemicals shown to interact with AR ligand binding domain in mammalian HTS assays should behave similarly in non-mammalian vertebrates.
URLs/Downloads:
DOI: Gathering evidence of endocrine pathway conservation for cross-species extrapolation using new approach methods.