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Extrapolation of mammalian-based ToxCast assay results to non-mammalian species to evaluate endocrine disruption
Citation:
LaLone, C. Extrapolation of mammalian-based ToxCast assay results to non-mammalian species to evaluate endocrine disruption. Fresenius Conference ‘Endocrine Disruptors’, Cologne, GERMANY, November 29 - 30, 2017.
Impact/Purpose:
Increasingly cell-based screening methods are being used to identify chemicals that may disrupt the endocrine system. Typically, these methods use mammalian cells. Therefore, it is of interest to understand how broadly the results from such assays may be extrapolated across other species, including non-mammalian species. Here we applied a web-based computational approach to species extrapolation, the US EPA’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS; https://seqapass.epa.gov/seqapass/), to begin to understand whether chemicals identified as potential endocrine disruptors in such cell-based assays may be extrapolated to other species. Case studies were developed that focus on the endocrine system to demonstrate the utility of the SeqAPASS tool for addressing such challenges in species extrapolation.
Description:
In vitro high-throughput screening (HTS) and in silico technologies have emerged as 21st century tools for chemical hazard identification. In 2007 the U.S. Environmental Protection Agency (EPA) launched the ToxCast Program, which has screened thousands of chemicals in hundreds of (primarily) mammalian-based HTS assays for biological activity suggestive of potential toxic effects. Data generated through this effort are being used to prioritize toxicity testing on chemicals most likely to lead to adverse health effects. To realize the full potential of the ToxCast data for predicting adverse effects to both humans and wildlife, it is necessary to understand how broadly these data may plausibly be extrapolated across species. Therefore, the U.S. EPA Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool was used to assess conservation of the 460 protein targets represented in the ToxCast assay suite. The SeqAPASS query sequence was selected based on the model organism used in the ToxCast assay (e.g., human, cattle, chimpanzee, guinea pig, rabbit, rat, mouse, pig, or sheep). Similarity of primary amino acid sequences and sequences from appropriate functional domains were compared across species to understand conservation of each assay target across taxa and probe questions of species extrapolation. To demonstrate the applicability of the SeqAPASS data for extrapolation of ToxCast targets, we developed case studies focused on the extrapolation of targets being evaluated as a component of the Endocrine Disruptor Screening Program, including the androgen receptor, enzymes involved in steroidogenesis, and proteins in thyroid axis function. These case studies demonstrate the utility of SeqAPASS for informing the extrapolation of HTS data and identification of model organisms likely to be suitable for follow-up or complementary in vivo toxicity tests.