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Advanced Systematic Review for Understanding Cross-Species Conservation of Androgen Receptor-Based Chemical Toxicity
Citation:
Vliet, S., K. Markey, S. Lynn, K. Vitense, AND C. LaLone. Advanced Systematic Review for Understanding Cross-Species Conservation of Androgen Receptor-Based Chemical Toxicity. Society of Toxicology, San Diego, CA, March 27 - 31, 2022. https://doi.org/10.23645/epacomptox.19699522
Impact/Purpose:
Poster presented to the Society of Toxicology (SOT) annual meeting March 2022. 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 chemicals for their potential to perturb endocrine pathways such as the androgen receptor (AR). EDSP employs a tiered toxicity testing strategy that includes whole-animal studies; however, this has proven challenging due to the extensive time, resources, and animals needed to evaluate a single chemical. To address this challenge, EDSP is transitioning towards the use of in vitro high-throughput (HT) assays to screen chemicals efficiently. The ability of these mammalian-based assays to accurately reflect chemical interactions in non-mammalian targets, however, remains uncertain. Therefore, a goal of the EDSP is to evaluate biological conservation across taxa to understand how broadly HT results can be extrapolated. To assess cross-species conservation of the AR pathway, we used a combination of computational analyses and systematic literature review (SLR) methodology to conduct a comprehensive analysis of existing data at in silico, in vitro, and in vivo levels. First, molecular target conservation was assessed across 585 diverse species based on the structural similarity of androgen receptors. These results indicate vertebrate AR shares a high degree of similarity relative to invertebrates and are predicted to be similarly susceptible. Novel, semi-automated SLR efforts targeted published toxicity data relevant to in vitro and in vivo AR assays across non-mammalian species. Database searches resulted in 3,216 in vitro articles and 1,775 in vivo articles. Following human- and machine learning-driven article screening, 33 in vitro and 245 in vivo articles were judged relevant for data extraction. Across relevant in vitro articles, most data (25 articles) were for fish species with less data obtained for other non-mammalian taxa (5 avian, 2 amphibians, and 1 reptile). Similarly, relevant in vivo articles also contained primarily fish data (196 articles) with less representation across other taxa (20 avian, 29 amphibians, and 1 reptile). Although data analysis is ongoing, preliminary analyses of extracted data suggests AR-chemical responses are conserved across vertebrate species and that chemicals with androgenic activity in mammalian systems should also be considered priority chemicals in nonmammalian vertebrates. The views expressed in this abstract do not necessarily reflect the policies of the US EPA.
URLs/Downloads:
DOI: Advanced Systematic Review for Understanding Cross-Species Conservation of Androgen Receptor-Based Chemical Toxicity
SVLIET_SOT2022_POSTER.PDF (PDF, NA pp, 1472.204 KB, about PDF)