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

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 -actinin, -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.