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

Reprod Toxicol. 2017 Oct:73:350-361. doi: 10.1016/j.reprotox.2017.07.011. Epub 2017 Jul 23.

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.

Keywords: Cystine; Developmental toxicity; Human pluripotent stem cells; In vitro; Ornithine; Retinoic acid receptor; Retinoids; Series ranking.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biological Assay
  • Cells, Cultured
  • Cystine / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / drug effects*
  • Induced Pluripotent Stem Cells / metabolism
  • Ornithine / metabolism
  • Retinoic Acid Receptor alpha / metabolism*
  • Retinoids / pharmacology*

Substances

  • Retinoic Acid Receptor alpha
  • Retinoids
  • Cystine
  • Ornithine