Genetic basis for developmental toxicity due to statin intake using embryonic stem cell differentiation model

Abstract

<jats:p> The in utero environment is a key factor controlling the fate of the growing embryo. The deleterious effects of statins during the fetal development are still not very well understood. Data from animal studies and retrospective studies performed in pregnant women give conflicting reports. In this study, using in vitro differentiation model of embryonic stem cells, which mimic the differentiation process of the embryo, we have systematically exposed the cells to lipophilic statins, simvastatin, and atorvastatin at various doses and at critical times during differentiation. The analysis of key genes controlling the differentiation into ecto-, meso- and endodermal lineages was assessed by quantitative polymerase chain reaction. Our results show that genes of the mesodermal lineage were most sensitive to statins, leading to changes in the transcript levels of brachyury, Flk-1, Nkx2.5, and α/β-myosin heavy chain. In addition, changes to endodermal marker α-fetoprotein, along with ectodermal Nes and Neurofilament 200 kDa, imply that during early differentiation exposure to these drugs leads to altered signaling, which could translate to the congenital abnormalities seen in the heart and limbs. </jats:p>

The effect of statins exposure during pregnancy on congenital anomalies and spontaneous abortions: A systematic review and meta-analysis

“…Conversely, preclinical studies exposing mouse embryonic stem cells to statins showed changes in genes expression such as NKX 2.5 andα/β-myosin heavy chain, which potentially can affect embryonic cardiac development. ( Jyoti and Tandon, 2015 ). The studies in our meta-analysis reported various cardiac malformations, including coarctation of the aorta, cardiomegaly, atrial septal defect, ventricular septal defect, and cardiac arrhythmia.…”

Dyslipidaemia as a target for atherosclerotic cardiovascular disease prevention in children with type 1 diabetes: lessons learned from familial hypercholesterolaemia

“…One final aspect of initiating statin treatment in adolescents is the contraindication to statins during pregnancy. Cholesterol plays an important role in embryogenesis and in animal studies high doses of statins have shown teratogenic effects [ 50 ]. There are not enough data from human studies to conclude that lower doses of statins during pregnancy are safe.…”