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A novel in silico model for systematic prediction of developmental toxicity.
Citation:
Hunter, S., K. Grode, Mitch Rosen, D. Kapraun, N. Baker, AND R. Judson. A novel in silico model for systematic prediction of developmental toxicity. Tenth World Congress alternatives and animal use in the life sciences, Seattle, Washington, August 20 - 24, 2017.
Impact/Purpose:
Animal-based methods are the standard approach to assess developmental toxicity. Mechanism-based in vitro assays and in silico predictive tools are desired alternatives. We used 4 elements to develop a novel in silico predictive model: 1. Mouse Genome Informatics database to compile all gene signals linked to morphological development; 2. Panther Gene Ontology to organize genes into pathway-based classification models; 3. ToxCast in vitro bioactivity database to identify chemical-gene target pairs for >1000 chemicals and concentration response profiles; 4. Fetal high-throughput toxicokinetic model to estimate human fetal serum concentrations following a 1 mg/kg/day oral exposure during gestational week 12. The classification model for cardiovascular development identified 88 (of 416 chemicals) potential cardiac disrupters at realistic maternal exposures. This in silico approach can be used to rank or prioritize untested environmental chemicals for further action. This abstract does not present US EPA policy
Description:
Animal-based methods are the standard approach to assess developmental toxicity. Mechanism-based in vitro assays and in silico predictive tools are desired alternatives. We used 4 elements to develop a novel in silico predictive model: 1. Mouse Genome Informatics database to compile all gene signals linked to morphological development; 2. Panther Gene Ontology to organize genes into pathway-based classification models; 3. ToxCast in vitro bioactivity database to identify chemical-gene target pairs for >1000 chemicals and concentration response profiles; 4. Fetal high-throughput toxicokinetic model to estimate human fetal serum concentrations following a 1 mg/kg/day oral exposure during gestational week 12. The classification model for cardiovascular development identified 88 (of 416 chemicals) potential cardiac disrupters at realistic maternal exposures. This in silico approach can be used to rank or prioritize untested environmental chemicals for further action. This abstract does not present US EPA policy