TY - JOUR
T1 - Maternal diabetes triggers DNA damage and DNA damage response in neurulation stage embryos through oxidative stress
AU - Dong, Daoyin
AU - Yu, Jingwen
AU - Wu, Yanqing
AU - Fu, Noah
AU - Villela, Natalia Arias
AU - Yang, Peixin
N1 - Funding Information:
This research is supported by NIH R01DK083243, R01DK101972, and R01DK103024 (to P. Y) and an American Diabetes Association Basic Science Award (1-13-BS-220).
Funding Information:
This research is supported by NIH R01DK083243 , R01DK101972 , R01DK103024 and an American Diabetes Association Basic Science Award ( 1-13-BS-220 ).
Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
PY - 2015/11/13
Y1 - 2015/11/13
N2 - 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.
AB - 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.
KW - DNA damage
KW - DNA damage response
KW - Diabetic embryopathy
KW - Embryo
KW - High glucose
KW - Maternal diabetes
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U2 - 10.1016/j.bbrc.2015.09.137
DO - 10.1016/j.bbrc.2015.09.137
M3 - Article
C2 - 26427872
AN - SCOPUS:84944395759
VL - 467
SP - 407
EP - 412
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -