title: Thoracic skeletal defects and cardiac malformations: a common epigenetic link?
abstract: Congenital heart defects (CHDs) are the most common birth defects in humans. In addition, cardiac malformations represent the most frequently identified anomaly in teratogenicity experiments with laboratory animals. To explore the mechanisms of these drug-induced defects, we developed a model in which pregnant rats are treated with dimethadione, resulting in a high incidence of heart malformations. Interestingly, these heart defects were accompanied by thoracic skeletal malformations (cleft sternum, fused ribs, extra or missing ribs, and/or wavy ribs), which are characteristic of anterior-posterior (A/P) homeotic transformations and/or disruptions at one or more stages in somite development. A review of other teratogenicity studies suggests that the co-occurrence of these two disparate malformations is not unique to dimethadione, rather it may be a more general phenomenon caused by various structurally unrelated agents. The coexistence of cardiac and thoracic skeletal malformations has also presented clinically, suggesting a mechanistic link between cardiogenesis and skeletal development. Evidence from genetically modified mice reveals that several genes are common to heart development and to formation of the axial skeleton. Some of these genes are important in regulating chromatin architecture, while others are tightly controlled by chromatin-modifying proteins. This review focuses on the role of these epigenetic factors in development of the heart and axial skeleton, and examines the hypothesis that posttranslational modifications of core histones may be altered by some developmental toxicants.
authors.affiliation: Developmental and Reproductive Toxicology Center of Emphasis, Drug Safety Research, and Development, Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Weston
authors.forename: Terence R S
authors.initials: TR
authors.lastname: Ozolins
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Brown
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000015:Abnormalities, Multiple / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities*; D002868:Chromosomal Proteins, Non-Histone; D044127:Epigenesis, Genetic; D005260:Female; D006330:Heart Defects, Congenital / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D008954:Models, Biological; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D012272:Ribs / Q000002:abnormalities; D013249:Sternum / Q000002:abnormalities; D013723:Teratogens / Q000633:toxicity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D035683:MicroRNAs; C491649:SMARCD3 protein, human; D013723:Teratogens; D014157:Transcription Factors