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  • A human induced pluripotent stem cell-based in vitro assay predicts developmental toxicity through a retinoic acid receptor-mediated pathway for a series of related retinoid analogues.

A human induced pluripotent stem cell-based in vitro assay predicts developmental toxicity through a retinoic acid receptor-mediated pathway for a series of related retinoid analogues.

Reproductive toxicology (Elmsford, N.Y.) (2017-07-27)
Jessica A Palmer, Alan M Smith, Laura A Egnash, Michael R Colwell, Elizabeth L R Donley, Fred R Kirchner, Robert E Burrier
ABSTRACT

The relative developmental toxicity potency of a series of retinoid analogues was evaluated using a human induced pluripotent stem (iPS) cell assay that measures changes in the biomarkers ornithine and cystine. Analogue potency was predicted, based on the assay endpoint of the ornithine/cystine (o/c) ratio, to be all-trans-retinoic acid>TTNPB>13-cis-retinoic acid≈9-cis-retinoic acid>acitretin>etretinate>retinol. These rankings correlate with in vivo data and demonstrate successful application of the assay to rank a series of related toxic and non-toxic compounds. The retinoic acid receptor α (RARα)-selective antagonist Ro 41-5253 inhibited the cystine perturbation caused by all-trans-retinoic acid, TTNPB, 13-cis-retinoic acid, 9-cis-retinoic acid, and acitretin. Ornithine was altered independent of RARα in all retinoids except acitretin. These results suggest a role for an RARα-mediated mechanism in retinoid-induced developmental toxicity through altered cystine metabolism.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
L-Ornithine-13C5 hydrochloride, 99 atom % 13C, 98% (CP)
Pricing and availability is not currently available.
Sigma-Aldrich
Ro 41-5253, ≥98% (HPLC)
Pricing and availability is not currently available.
Sigma-Aldrich
Acitretin, ≥98.0% (HPLC)
Pricing and availability is not currently available.
Sigma-Aldrich
TTNPB
Pricing and availability is not currently available.