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.

The consequence of NAC on sodium arsenite-induced uterine oxidative stress

“…In newborn and pregnant mice, structural changes in the thymus gland were investigated [ 14 ]. Several in vitro studies on female reproduction revealed that long term exposure of arsenic is associated with reduced lactation, abortion, low birth weight [ 15 ] and toxicity of embryonic cells [ 16 ]. Undeniably arsenic in drinking water that exceeds the admissible limit leads to disturbances in reproduction [ 17 ], undesirable pregnancy outcomes [ 18 ], and spontaneous abortion [ 19 ].…”

Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation

“…In the human prostate, PrSPCs give rise to basal cells, luminal PrECs, and rare neuroendocrine cells (Strand and Goldstein 2015). Because iAs alters differentiation in a variety of stemprogenitor cells (Bain et al 2016;McCoy et al 2015;Rebuzzini et al 2015;Yen et al 2010), we tested whether iAs influences this process in PrSPCs. Primary PrSPCs cultured for 7 d from diseasefree PrECs were isolated and mixed with embryonic rat urogenital sinus mesenchyme (UGM) and grafted under renal capsules of nude mice.…”

Mechanism of arsenite toxicity in embryonic stem cells

“…Together, these results confirm the teratogenicity of iAs as reported previously based on animal studies (Hood et al ., ; Leonard & Lauwerys, ; Chaineau et al ., ; Machado et al ., ). In contrast, recent reports claimed ESC differentiation into cardiomyocytes, skeletal muscles and neurons was impaired or inhibited by iAs exposure (Liu & Bain, ; Rebuzzini et al ., ; Wang et al ., ). However, we did not investigate the directed differentiation of ESCs into specific cell lineages in the presence of iAs.…”