title: The differentiation of cardiomyocytes from mouse embryonic stem cells is altered by dioxin.
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.
authors.affiliation: Laboratorio di Biologia dello Sviluppo, Dipartimento di Biologia Animale, Universita' degli Studi di Pavia, Via Ferrata 9, 27100 Pavia, Italy.
authors.forename: Tui
authors.initials: T
authors.lastname: Neri
authors.forename: Valeria
authors.initials: V
authors.lastname: Merico
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.forename: Monica
authors.initials: M
authors.lastname: Salio
authors.forename: Paola
authors.initials: P
authors.lastname: Rebuzzini
authors.forename: Lucia
authors.initials: L
authors.lastname: Sacchi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bellazzi
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Redi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zuccotti
authors.forename: Silvia
authors.initials: S
authors.lastname: Garagna
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D058732:Embryoid Bodies / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000502:physiology; D004785:Environmental Pollutants / Q000633:toxicity*; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D050216:Metabolic Detoxication, Phase I / Q000235:genetics; D050217:Metabolic Detoxication, Phase II / Q000235:genetics; D051379:Mice; D046529:Microscopy, Electron, Transmission; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D013723:Teratogens / Q000633:toxicity*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004785:Environmental Pollutants; D004798:Enzymes; D000072317:Polychlorinated Dibenzodioxins; D013723:Teratogens; D000255:Adenosine Triphosphate