The differentiation of cardiomyocytes from mouse embryonic stem cells is altered by dioxin

Tui Neri, Valeria Merico, Fabio Fiordaliso, Monica Salio, Paola Rebuzzini, Lucia Sacchi, Riccardo Bellazzi, Carlo Alberto Redi, Maurizio Zuccotti, Silvia Garagna

Research output: Contribution to journalArticle

Abstract

2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD) causes abnormalities during heart development. Cardiomyocytes derived from embryonic stem (ES) cells are a robust model for the study of early cardiomyogenesis. Here, we evaluated the effects of TCDD at key stages during the differentiation of mouse ES cells into cardiomyocytes analysing: (i) the transcription of lineage differentiation (Brachyury, Nkx-2.5, Actc-1), cardiac-specific (Alpk3, cTnT, cTnI, cTnC) and detoxification phase I (Cyp1A1, Cyp1A2 and Cyp1B1) and phase II (Nqo1, Gsta1 and Ugt1a6) genes; (ii) the global gene expression; (iii) the ultrastructure of ES-derived cardiomyocytes; (iv) level of ATP production and (v) the immunolocalisation of sarcomeric α-actinin, β-myosin heavy chain and cTnT proteins. We show that TCDD affects the differentiation of ES cells into cardiomyocytes at several levels: (1) induces the expression of phase I genes; (2) down-regulates a group of heart-specific genes, some involved in the oxidative phosphorylation pathway; (3) reduces the efficiency of differentiation; (4) alters the arrangement of mitochondria, that show twisted and disrupted cristae, and of some sarcomeres, with misalignement or disarrangement of the myofibrillar organisation and (5) reduces ATP production. This study provides novel evidences that TCDD impairs cardiomyocyte differentiation. Sarcomeres and mitochondria could be a target for dioxin toxicity, their disruption representing a possible mechanism developing cardiac injury.

Original languageEnglish
Pages (from-to)226-236
Number of pages11
JournalToxicology Letters
Volume202
Issue number3
DOIs
Publication statusPublished - May 10 2011

Keywords

  • Cardiomyocytes differentiation
  • Dioxin
  • Embryonic stem cells
  • Mouse
  • Myofibrils

ASJC Scopus subject areas

  • Toxicology

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    Neri, T., Merico, V., Fiordaliso, F., Salio, M., Rebuzzini, P., Sacchi, L., Bellazzi, R., Redi, C. A., Zuccotti, M., & Garagna, S. (2011). The differentiation of cardiomyocytes from mouse embryonic stem cells is altered by dioxin. Toxicology Letters, 202(3), 226-236. https://doi.org/10.1016/j.toxlet.2011.02.008