Developmental cardiotoxicity effects of four commonly used antiepileptic drugs in embryonic chick heart micromass culture and embryonic stem cell culture systems.
Antiepileptic drugs (AEDs) are commonly used drugs in pregnant women with epilepsy. Prenatal exposure to AEDs increases the risk of major or minor congenital malformation during embryonic development. The precise mode of action and intracellular mechanisms of these AEDs during embryonic development remains unclear. To determine relative teratogenic risk of AEDs, four AED drugs including valproic acid (VPA), phenytoin (PHT), phenobarbital (PB), and trimethadione (TMD) were tested using two in vitro systems (the embryonic chick heart micromass (MM) culture and the in vitro differentiating mouse embryonic stem cells into cardiomyocytes culture systems). Cardiomyocyte cultures (the heart MM and ES cell-derived cardiomyocytes) were treated with or without different concentrations of PHT, PB, TMD (10-100 μM), and VPA (100-2000 μM). 5-Fluorouracil (5-FU) (1-10 μM) and l-ascorbic acid (10-1000 μM) were used as positive and negative controls. It was found that these four commonly used AEDs and 5-FU tested have the potential to inhibit embryonic heart cell differentiation (p<0.05) without inducing any cytotoxicity. VPA at higher concentrations (≥800 μM), and 5-FU at all doses proved to be cytotoxic in the differentiating ES cell culture system. The results demonstrated in this study suggest that the use of these four commonly prescribed AEDs during pregnancy may have an effect on embryonic heart development, and may be associated with congenital cardiovascular defects.
National Center for Computational Toxicology (B205-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Bhavesh K
BK
Ahir
School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. Electronic address: margaret.pratten@nottingham.ac.uk.
Margaret K
MK
Pratten
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D066126:Cardiotoxicity; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D053595:Embryonic Stem Cells / Q000166:cytology*; D006321:Heart / Q000187:drug effects* / Q000196:embryology; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*
D000927:Anticonvulsants
Antiepileptic drugs (AEDs); Cardiotoxicity; Chick heart micromass (MM) culture; Congenital heart defects; D3 Mouse embryonic stem cell (ESC) culture