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Defining the taxonomic domain of applicability for mammalian-based high-throughput screening assays
Citation:
LaLone, C., Dan Villeneuve, J. Doering, B. Blackwell, S. Degitz, A. Williams, AND G. Ankley. Defining the taxonomic domain of applicability for mammalian-based high-throughput screening assays. SETAC Focused Topic, Durham, NC, April 16 - 18, 2018.
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:
Cell-based high throughput screening (HTS) technologies are becoming mainstream in chemical safety evaluations. The US Environmental Protection Agency (EPA) Toxicity Forecaster (ToxCastTM) and the multi-agency Tox21 Programs have been at the forefront in advancing this science, making screening results publically accessible for both research and regulatory decision-making. Initially these programs were developed with the intent of screening chemicals for hazard potential as a means to prioritize further in vivo toxicity testing for the protection of human health. Therefore, primarily mammalian-based HTS assays were developed. Subsequently, it was recognized that ToxCast screening data may be more broadly applicable for the protection of wildlife. Therefore, a challenge emerged for understanding whether these predominantly mammalian-based prioritization approaches reasonably reflect potential impacts on other species. To address this species-extrapolation challenge, the US EPA Sequence Alignment to Predict Across Species Susceptibility tool (SeqAPASS; https://seqapass.epa.gov/seqapass/) was employed. SeqAPASS evaluations comparing primary amino acid sequences and functional domains were performed for all 450 molecular targets associated with the ToxCast assays and data are being made publically available through both the SeqAPASS tool and the Comptox Chemistry Dashboard (https://comptox.epa.gov/dashboard). To demonstrate the practical application of the SeqAPASS approach to a current regulatory challenge, case studies relevant to the US endocrine disruptor screening program were developed evaluating androgen receptor, enzymes involved in the sex steroid synthesis, and proteins found in the thyroid axis. Overall, conservation of these mammalian protein targets suggest that screening results identifying chemical disruption via HTS assays could be reasonably extrapolated across vertebrate species. The contents of this abstract neither constitute nor reflect official US EPA policy