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.
Highlights
Stillbirth, reduction in birth weight, moderate risk of neonatal and infant mortality[19]
Mouse embryonic stem cells, continuously treated with 0.7–1.3 μ M Arsenic trioxide (ATO) for 10 days during their differentiation to cardiomyocytes, did not show beating capacity when analysed with the embryonic stem cell test (EST)[27]; and, when treated with 0.5–1.0 μ M monomethylarsonic acid for 1–3 days ceased proliferation and cardiomyocyte differentiation[28]
We analyzed the expression of the As3MT gene in undifferentiated R1 mouse embryonic stem cells (mESCs) and on day 4, 7 and 15 of cultured embryoid bodies (EBs)
Summary
Stillbirth, reduction in birth weight, moderate risk of neonatal and infant mortality[19]. The main aim of the present study is to investigate, at a molecular and functional level, the effects that a continuous exposure to ATO has on the process leading to the formation of fully differentiated post-natal cardiomyocytes To this end, we used mESCs as a well established in vitro model that recapitulates, through the formation of the three germ layers, from spheroid structures named embryoid bodies (EBs), the molecular events and the functional features of cardiomyocyte differentiation from primitive precursor cells up to highly specialised phenotypes[29,30]
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