A Biomarker-Based Human Stem Cell Assay Applied for Ranking a Retinoid Series Based on Relative Developmental Toxicity Potential [SOT 2015]

Presented at the Society of Toxicology’s 55th Annual Meeting and ToxExpo, March 2015, in San Diego, California.

We previously developed an in vitro, biomarker-based, human induced pluripotent stem (iPS) cell-based assay to screen compounds for developmental toxicity. The assay measures changes in two amino acids (ornithine and cystine) involved in cell proliferation and differentiation. This assay (devTOXqP) is currently being applied as an alternative model to aid in ongoing worldwide efforts to reduce animal testing.In this work we demonstrate the use of the assay to rank order the relative developmental toxicity potential of compounds within a chemical series using a well-characterized set of retinoids. Results were compared to published data for both in vivo and other in vitro models. In vivo response to retinoids is variable for both human and animal models due to the developmental toxicity potency of these compounds in early development. Because retinoic acid signaling plays a key role in embryogenesis we also tested the mechanistic relevance of our in vitro model using the retinoic acid receptor (RAR) antagonist Ro 41-5253. Overall, rankings in the absence of the antagonist were concordant with published values for other in vitro studies, but do not completely correspond with in vivo potency rankings. The lack of in vivo kinetic and metabolic processes and species-specific differences in metabolism could explain these differences. Observations in the presence of Ro 41-5253 were consistent with the developmental toxicity response being mediated through RAR and suggest iPS cells do not have the ability to metabolize etretinate to its active form. These data illustrate the importance of the RAR pathway in mediating developmental toxicity responses and show how this assay can be applied for compound decision making and bridging chemical series.

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