title: Arsenic trioxide alters the differentiation of mouse embryonic stem cell into cardiomyocytes.
abstract: Chronic arsenic exposure is associated with increased morbidity and mortality for cardiovascular diseases. Arsenic increases myocardial infarction mortality in young adulthood, suggesting that exposure during foetal life correlates with cardiac alterations emerging later. Here, we investigated the mechanisms of arsenic trioxide (ATO) cardiomyocytes disruption during their differentiation from mouse embryonic stem cells. Throughout 15 days of differentiation in the presence of ATO (0.1, 0.5, 1.0 μM) we analysed: the expression of i) marker genes of mesoderm (day 4), myofibrillogenic commitment (day 7) and post-natal-like cardiomyocytes (day 15); ii) sarcomeric proteins and their organisation; iii) Connexin 43 and iv) the kinematics contractile properties of syncytia. The higher the dose used, the earlier the stage of differentiation affected (mesoderm commitment, 1.0 μM). At 0.5 or 1.0 μM the expression of cardiomyocyte marker genes is altered. Even at 0.1 μM, ATO leads to reduction and skewed ratio of sarcomeric proteins and to a rarefied distribution of Connexin 43 cardiac junctions. These alterations contribute to the dysruption of the sarcomere and syncytium organisation and to the impairment of kinematic parameters of cardiomyocyte function. This study contributes insights into the mechanistic comprehension of cardiac diseases caused by in utero arsenic exposure.
authors.affiliation: Laboratorio di Biologia dello Sviluppo, Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani', Università degli Studi di Pavia, Pavia, Italy.|Center for Health Technologies (CHT), Via Ferrata 1, Università of Pavia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rebuzzini
authors.affiliation: Laboratorio de Reproducción y Fisiopatología Materno-Embrionaria, Instituto de Fisiología, Biología Molecular y Neurociencias, Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cebral
authors.affiliation: Dipartimento di Ingegneria Industriale e dell'Informazione, Università degli Studi di Pavia, Pavia, Italy.|Center for Health Technologies (CHT), Via Ferrata 1, Università of Pavia, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Fassina
authors.affiliation: Laboratorio di Biologia dello Sviluppo, Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani', Università degli Studi di Pavia, Pavia, Italy.|Center for Health Technologies (CHT), Via Ferrata 1, Università of Pavia, Italy.|Centro Ricerche di Medicina Rigenerativa, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Alberto Redi
authors.affiliation: Unita' di Anatomia, Istologia ed Embriologia, Dipartimento di Scienze Biomediche, Biotecnologiche e Traslazionali, Università degli Studi di Parma, Parma, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zuccotti
authors.affiliation: Laboratorio di Biologia dello Sviluppo, Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani', Università degli Studi di Pavia, Pavia, Italy.|Center for Health Technologies (CHT), Via Ferrata 1, Università of Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Garagna
mesh_terms: D000185:Actinin / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001696:Biomechanical Phenomena; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism; D005326:Fetal Proteins / Q000235:genetics; D005455:Fluorescent Antibody Technique; D050991:GATA4 Transcription Factor / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D019209:Troponin C / Q000235:genetics; D020107:Troponin T / Q000378:metabolism; D000098908:Brachyury Protein
chemical_list: D000185:Actinin; D000970:Antineoplastic Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals; D018031:Connexin 43; D005326:Fetal Proteins; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D010087:Oxides; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D019209:Troponin C; D020107:Troponin T; D000098908:Brachyury Protein; C484469:Nkx2-5 protein, mouse