title: Maternal diabetes triggers DNA damage and DNA damage response in neurulation stage embryos through oxidative stress.
abstract: DNA damage and DNA damage response (DDR) in neurulation stage embryos under maternal diabetes conditions are not well understood. The purpose of this study was to investigate whether maternal diabetes and high glucose in vitro induce DNA damage and DDR in the developing embryo through oxidative stress. In vivo experiments were conducted by mating superoxide dismutase 1 (SOD1) transgenic male mice with wild-type (WT) female mice with or without diabetes. Embryonic day 8.75 (E8.75) embryos were tested for the DNA damage markers, phosphorylated histone H2A.X (p-H2A.X) and DDR signaling intermediates, including phosphorylated checkpoint 1 (p-Chk1), phosphorylated checkpoint 2 (p-Chk2), and p53. Levels of the same DNA damage markers and DDR signaling intermediates were also determined in the mouse C17.2 neural stem cell line. Maternal diabetes and high glucose in vitro significantly increased the levels of p-H2A.X. Levels of p-Chk1, p-Chk2, and p53, were elevated under both maternal diabetic and high glucose conditions. SOD1 overexpression blocked maternal diabetes-induced DNA damage and DDR in vivo. Tempol, a SOD1 mimetic, diminished high glucose-induced DNA damage and DDR in vitro. In conclusion, maternal diabetes and high glucose in vitro induce DNA damage and activates DDR through oxidative stress, which may contribute to the pathogenesis of diabetes-associated embryopathy.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Daoyin
authors.initials: D
authors.lastname: Dong
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Fu
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Natalia Arias
authors.initials: NA
authors.lastname: Villela
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: pyang@fpi.umaryland.edu.
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
mesh_terms: D000818:Animals; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004249:DNA Damage; D016640:Diabetes, Gestational / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D054261:Neurulation / Q000235:genetics*; D018384:Oxidative Stress; D010766:Phosphorylation; D011247:Pregnancy; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013113:Spin Labels; D013311:Streptozocin; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D003497:Cyclic N-Oxides; D005947:Glucose; D006657:Histones; D011494:Protein Kinases; D013113:Spin Labels; D013311:Streptozocin; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D016159:Tumor Suppressor Protein p53; C000606291:Sod1 protein, mouse; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; C001803:tempol; C475961:gamma-H2AX protein, mouse
keywords: DNA damage; DNA damage response; Diabetic embryopathy; Embryo; High glucose; Maternal diabetes