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Gathering Evidence of Endocrine Pathway Conservation for Cross-Species Extrapolation Using New Approach Methods
Citation:
Vliet, S., S. Lynn, K. Markey, AND C. LaLone. Gathering Evidence of Endocrine Pathway Conservation for Cross-Species Extrapolation Using New Approach Methods. SETAC North America, Fort Worth, TX, November 15 - 19, 2020. https://doi.org/10.23645/epacomptox.13125434
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. Identifying chemicals that act of endocrine targets 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 similar and different endocrine targets, such as the androgen and estrogen receptor, are across groups of organisms and how these differences many change the toxicity of chemicals. Using computer-based experiments, carrying out large reviews of available toxicity data, and conducting laboratory experiments will help determine whether current mammalian-based screening methods can predict endocrine activity in other organisms. Results of this research demonstrate that new screening methods can predict the conservation of endocrine pathways across 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 targets. 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. In response to these challenges, the EDSP has been transitioning towards the use of new approach methodologies (NAMs) such as in-vitro high-throughput screening techniques to rapidly and efficiently prioritize chemicals for further testing. Despite their utility, the ability of these mammalian-based assays to accurately reflect chemical interactions for non-mammalian targets remains uncertain. Therefore, one goal of the EDSP is to evaluate biological pathway conservation across taxa to understand how broadly these results can be extrapolated to non-mammalian species. A new approach method that can be used to computationally examine biological pathway conservation across taxa is the US EPA Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool. The SeqAPASS tool, using publicly available data, allows users to rapidly evaluate protein target sequence and structural similarity to understand conservation of biological targets. In this presentation, we demonstrate the ability of the SeqAPASS tool to assess the conservation of endocrine targets across species and generate predictions of chemical susceptibility across diverse species. Using literature review techniques and technological advances in data curation science, we then demonstrate a framework for the evaluation of existing in vitro and in vivo data to anchor SeqAPASS-derived in-silico predictions of species susceptibility and provide weight of evidence for the extrapolation of androgen and estrogen responses across species. Finally, using the steroidogenesis enzyme CYP19A1 (aromatase), we highlight current efforts to expand and validate in silico predictions through laboratory techniques (e.g. site-directed mutagenesis). Overall, this presentation provides a framework for addressing the conservation of endocrine targets across species and understanding the degree to which mammalian-based NAMs can accurately reflect chemical interactions with non-mammalian targets.
URLs/Downloads:
DOI: Gathering Evidence of Endocrine Pathway Conservation for Cross-Species Extrapolation Using New Approach Methods