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In vitro embryotoxicity testing with human embryonic stem cells reveals markers for all-trans-retinoic acid

Smita Jagtap, Kesavan Meganathan, Vilas Wagh, John Antonydas Gaspar, J├╝rgen Hescheler and Agapios Sachinidis, Institute of Neurophysiology, University of Cologne, Germany

Many characteristics of human embryonic stem cells (hESCs) including pluripotency are useful tools for studying the harmful effects of reference compounds during early development. The early embryogenesis is recapitulated by pluripotent embryonic stem cells when differentiated in vitro, which makes hESC an effective tool for developmental toxicology and embryotoxicology. All-trans-retinoic acid is known to be embryotoxic in laboratory animals and for humans when applied during critical stages of embryonic development. Characteristic malformation patterning of craniofacial structures and defects in cardiac development were observed in human offsprings. In rat and mice, All-trans retinoic acid treatment resulted in craniofacial malformations and limb anomalies associated with embryo fetal alterations. In the following study, All-trans-retinoic acid (AtRA) was treated on undifferentiated hESC in the presence and absence of bFGF for a period of 7 days and a toxicogenomics profile was studied. The results revealed that mesoderm markers such as BMP2, COL1A1 and COL2A1, endoderm markers such as AFP, GATA4 and SERPINA1 were dysregulated. Ectodermal markers such as NEUROD1, PAX6 and TUBB3 were dysregulated in the presence or absence of bGFG. The results are further used to identify embryotoxic markers and also to test other compounds for embryotoxic potential.

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