Insights into cardiovascular development of zebrafish embryo after exposure to dolutegravir

The use of the up-to-date antiretroviral therapy (ART), including the integrase strand-transfer inhibitors (INSTIs), has significantly reduced mortality associated with human immunodeficiency virus (HIV) infection. Nonetheless, some INSTIs like dolutegravir (DTG) have been found to affect fetal development, particularly regarding neural tube defects. In vivo studies, mainly aimed to evaluate the DTG effects on neurodevelopment, also described cardiovascular defects, prompting further investigations into DTG cardiovascular embryotoxic potential. Here we used the zebrafish embryo model to elucidate the effect of DTG exposure on cardiovascular system function and development. Embryos were treated with DTG at several concentrations, resulting in cardiovascular toxicity, demonstrated by the presence of pericardial edema and hemorrhage. At dosage (1 µM), we found a profound impairment of cardiovascular function, characterized by decreased vessel blood flow and heartbeat. Cardiovascular function impairments were accompanied by morphological developmental defects, characterized by shrunken atria and ventricles, altered cardiac looping and defects in angiogenesis. Molecular analysis of DTG-induced cardiovascular mechanisms of those effects revealed the DTG-induced impairment of genes that are crucial in cardiac myofibrillar organization, cardiomyocyte contractility and vascular morphogenesis and function ( myh6/amhc , myl7/cmlc2 , vegfaa , kdrl/vegfr2a , flt1/vegfr1 , hif1aa , runx1 and gata1a ). Our exploratory findings suggest that exposure of zebrafish embryos to 1 µM DTG results in embryonic cardiovascular functional and morphological impairments, mechanistically could be linked to the disturbed regulation of key genes involved in cardiovascular development.