This is an in vitro developmental toxicity method that could be used to evaluate whether a test compound may have the potential for teratogenicity in humans. The test method measures changes in a ration between two metabolic biomarkers (cystine and ornithine) present in cell culture media of human induced undifferentiated pluripotent stem (hiPS) cells exposed to a compound. Changes in two metabolites, ornithine and cystine, are measured in response to treatment and then used in a ratio (o/c ratio) across an 8-point dose response curve. The teratogenicity potential is the interpolated exposure level (concentration) of a test compound where the dose response curve crosses a defined teratogenicity threshold. Exposure levels greater than this concentration are associated with teratogenicity. Its performance suggests that the assay is amenable to predicting teratogens regardless of their classification as weak or strong.
Cytotoxicity is provided as a...
This is an in vitro developmental toxicity method that could be used to evaluate whether a test compound may have the potential for teratogenicity in humans. The test method measures changes in a ration between two metabolic biomarkers (cystine and ornithine) present in cell culture media of human induced undifferentiated pluripotent stem (hiPS) cells exposed to a compound. Changes in two metabolites, ornithine and cystine, are measured in response to treatment and then used in a ratio (o/c ratio) across an 8-point dose response curve. The teratogenicity potential is the interpolated exposure level (concentration) of a test compound where the dose response curve crosses a defined teratogenicity threshold. Exposure levels greater than this concentration are associated with teratogenicity. Its performance suggests that the assay is amenable to predicting teratogens regardless of their classification as weak or strong.
Cytotoxicity is provided as a secondary endpoint at the same eight concentrations as those tested for the o/c ratio. The design and sensitivity of the assay allows for identification of teratogenic potential at non-cytotoxic levels of the test compound, by negating the confounding effects of changes in metabolite abundance due solely to cytotoxicity. The assay is performed with undifferentiated human iPS cells, providing an opportunity to evaluate disruptions in human development.
