A High Throughput Metabolite-Based Biomarker Approach to Predict Developmental Toxicity Using Human Embryonic Stem Cells
Presented at the American College of Toxicology 33rd Annual Meeting, November 2012, in Orlando, Florida.
Birth defects are the largest cause of infant morbidity and mortality in the United States. Teratogens, defined as substances that cause one or more fetal abnormalities during development, are responsible for 5-10% of all birth defects. Availability of more predictive developmental toxicity screens would increase pharmaceutical and chemical safety and could reduce the prevalence of birth defects associated with exposure to these compounds. Current rodent models for developmental toxicity testing do not adequately correlate to human response, resulting in only 62% concordance to humans. Human embryonic stem (hES) cell technology is an innovative alternative model to predict developmental toxicity of chemicals utilized in Stemina’s devTOX assays. We have developed a targeted, rapid, and highly predictive assay of developmental toxicity based on specific biomarker metabolites identified in the hES based LC-MS metabolomics computational devTOX model trained using 23 known human teratogens and non-teratogens. These biomarkers represent different metabolic pathways and show high individual predictivity (70-88%), while combinations result in better predictions (88-93%). The targeted biomarker approach produces a metabolic index that is predictive of the potential for human developmental toxicity. When combined with a 9 point dose curve and cell viability analysis, the metabolic index can be used to model developmental toxicity.View PDF