Citation:

Vliet, S., K. Markey, S. Lynn, A. Adetona, D. Fallacara, P. Ceger, N. Choski, A. Karmaus, A. Watson, A. Ewans, A. Daniel, J. Hamm, K. Vitense, K. Wolf, A. Thomas, AND C. Lalone. Weight of evidence for cross-species conservation of androgen receptor-based biological activity. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 193(2):131-145, (2023). https://doi.org/10.1093/toxsci/kfad038

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, although chemical screening should be expanded to assess potential cross-species difference in sensitivity.

Description:

The U.S. Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP) is tasked with assessing chemicals for their potential to perturb endocrine pathways, including those controlled by androgen receptor (AR). To address challenges associated with traditional testing strategies, EDSP is considering in vitro high-throughput screening assays to screen and prioritize chemicals more efficiently. The ability of these assays to accurately reflect chemical interactions in nonmammalian species remains uncertain. Therefore, a goal of the EDSP is to evaluate how broadly results can be extrapolated across taxa. To assess the cross-species conservation of AR-modulated pathways, computational analyses and systematic literature review approaches were used to conduct a comprehensive analysis of existing in silico, in vitro, and in vivo data. First, molecular target conservation was assessed across 585 diverse species based on the structural similarity of ARs. These results indicate that ARs are conserved across vertebrates and are predicted to share similarly susceptibility to chemicals that interact with the human AR. Systematic analysis of over 5000 published manuscripts was used to compile in vitro and in vivo cross-species toxicity data. Assessment of in vitro data indicates conservation of responses occurs across vertebrate ARs, with potential differences in sensitivity. Similarly, in vivo data indicate strong conservation of the AR signaling pathways across vertebrate species, although sensitivity may vary. Overall, this study demonstrates a framework for utilizing bioinformatics and existing data to build weight of evidence for cross-species extrapolation and provides a technical basis for extrapolating hAR-based data to prioritize hazard in nonmammalian vertebrate species.

URLs/Downloads:

Record Details: