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Evaluation of Cross-Species Conservation of the Androgen Receptor and the basis for Identifying Androgenic Chemicals in Nonmammalian Taxa Using Mammalian Test Systems.
Citation:
Vliet, S., S. Lynn, K. Markey, AND C. LaLone. Evaluation of Cross-Species Conservation of the Androgen Receptor and the basis for Identifying Androgenic Chemicals in Nonmammalian Taxa Using Mammalian Test Systems. U.S. Environmental Protection Agency – Japan Ministry of the Environment, 14th Bilateral Meeting on Endocrine Disruption Test Methods Development, Duluth, MN, June 09 - 10, 2021. https://doi.org/10.23645/epacomptox.14721117
Impact/Purpose:
Scientific research suggests that environmental contaminants can disrupt the endocrine system by mimicking naturally produced hormones and binding to receptors in the body. This can lead to negative health outcomes in both humans and wildlife. The androgen receptor (AR) is a particularly important endocrine target because many environmental chemicals can bind to the AR and disrupt biological processes. Identifying chemicals that bind to the AR is essential to determine the risk of these chemicals to human health and the environment. Although it’s clear that some chemicals cause endocrine-disrupting effects, very few chemicals have been tested because of the many resources and animals needed to test each chemical. New screening methods with mammalian cells can quickly test chemicals and prioritize them for further testing. Although these screening methods are useful, it’s unclear if the results of these mammalian tests will predict toxicity in non-mammalian species. To address this question, the goal of this research is to understand how AR is similar and different across groups of organisms and how these differences many change the toxicity of AR-targeting chemicals. Using computer-based experiments and reviewing available toxicity data, this research will help determine whether current mammalian-based screening methods can predict AR activity in other organisms. Results of this research help provide evidence that AR is similar across all vertebrate species and suggests that chemicals that interact with mammalian AR should behave similarly in non-mammalian vertebrates.
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 prioritize chemicals rapidly and efficiently 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 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. The contents of this abstract neither constitute nor necessarily reflect US EPA policy.
URLs/Downloads:
DOI: Evaluation of Cross-Species Conservation of the Androgen Receptor and the basis for Identifying Androgenic Chemicals in Nonmammalian Taxa Using Mammalian Test Systems.
SVLIET_US-JAPAN ENDOCRINE DISRUPTION BILATERAL 2021.PDF (PDF, NA pp, 3858.443 KB, about PDF)