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Evidence for cross species extrapolation of mammalian-based high-throughput screening assay results.
Citation:
LaLone, C., Dan Villeneuve, J. Doering, B. Blackwell, T. Transue, C. Simmons, J. Swintek, S. Degitz, A. Williams, AND G. Ankley. Evidence for cross species extrapolation of mammalian-based high-throughput screening assay results. ENVIRONMENTAL SCIENCE & TECHNOLOGY. American Chemical Society, Washington, DC, 52(23):13960-13971, (2018). https://doi.org/10.23719/1432209
Impact/Purpose:
Increasingly cell-based, robotic screening methods are being applied in chemical safety evaluations. Typically, these methods use human cells to identify chemicals that may cause and adverse effect in humans. It is of interest to understand how broadly the results from such assays may be extrapolated to other species, including non-mammalian species. Here we applied a web-based computer method to evaluate species similarity, the US EPA’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS; https://seqapass.epa.gov/seqapass/). Evaluating similarity of species at the molecular level will allow us to begin to understand whether chemicals that disrupt biology in human cells may also disrupt biology in other species. Case studies were developed that demonstrate the applicability of the SeqAPASS tool for the purpose of gaining a better understanding of how broadly human cell based methods can be predictive of chemical susceptibility in wildlife.
Description:
In vitro high-throughput screening (HTS) and in silico technologies have emerged as important tools for chemical hazard identification. In 2007 the US Environmental Protection Agency (EPA) launched the Toxicity ForeCaster (ToxCastTM) Program, which has screened thousands of chemicals in hundreds of (primarily) mammalian-based HTS assays for biological activity possibly indicative of toxic effects. Data generated through this effort are being used to prioritize toxicity testing on those chemicals most likely to lead to adverse health effects. To realize the full potential of the ToxCast data for predicting potential hazard to both humans and wildlife, it is necessary to understand how broadly these data may plausibly be extrapolated across species. Therefore, the US EPA Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS; https://seqapass.epa.gov/seqapass) tool was used to assess conservation of the 450 protein targets represented in the ToxCast assay suite. The query sequences were selected based on the species used in the ToxCast assay (typically human, cattle, chimpanzee, guinea pig, rabbit, rat, mouse, pig, or sheep). Similarity of primary amino acid sequences and sequences from appropriate functional domains was compared across species to better understand conservation of each assay target across taxa. To demonstrate the utility of the SeqAPASS data for guiding extrapolation of HTS results, we developed case studies focused on targets being evaluated as a component of the US endocrine disruptor screening program. These case studies demonstrate the utility of SeqAPASS for defining the taxonomic domain of applicability for HTS data and identifying model organisms suitable for follow-up or complementary in vivo toxicity tests.
URLs/Downloads:
DOI: Evidence for cross species extrapolation of mammalian-based high-throughput screening assay results.