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Cross-species extrapolation of mammalian-based ToxCast Data using Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS)
Citation:
LaLone, C., G. Ankley, T. Tal, AND Dan Villeneuve. Cross-species extrapolation of mammalian-based ToxCast Data using Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS). SETAC North America, Salt Lake City, UT, November 01 - 05, 2015.
Impact/Purpose:
not applicable
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 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 species/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 specific functional domains were compared across species to understand conservation of each assay target across taxa and to probe the question of how broadly the ToxCast data may be extrapolated to other organisms. A case study involving 30 ToxCast assay targets representative of molecular initiating events in adverse outcome pathways leading to abnormal vascular development was developed. This case study demonstrates the utility of SeqAPASS for informing the extrapolation of ToxCast data and identification of model organisms likely to be suitable for follow-up or complementary in vivo toxicity tests.