Exposure of neural crest cells to elevated glucose leads to congenital heart defects, an effect that can be prevented by N-acetylcysteine.
BACKGROUND
Diabetes mellitus during pregnancy increases the risk for congenital heart disease in the offspring. The majority of the cardiovascular malformations occur in the outflow tract and pharyngeal arch arteries, where neural crest cells are essential for normal development. We studied the effects of specific exposure of neural crest cells to elevated glucose on heart development. Antioxidants reduce the damaging effect of glucose on neural crest cells in vitro; therefore, we investigated the effect of supplementing N-acetylcysteine in vivo.


METHODS
Cardiac neural crest of HH 8-12 chicken embryos was directly exposed by a single injection in the neural tube with 30 mM D-glucose (or 30 mM L-glucose as a control). To examine the effect of a reduction in oxidative stress, we added 2 mM N-acetylcysteine to the injected D-glucose.


RESULTS
Exposure of neural crest cells to elevated D-glucose-induced congenital heart malformations in 82% of the embryos. In the embryos injected with L-glucose, only 9% developed a heart malformation. As expected, all malformations were located in the outflow tract and pharyngeal arch arteries. The frequency of heart malformations decreased from 82% to 27% when 2 mM N-acetylcysteine was added to the injected D-glucose.


CONCLUSIONS
These data are the first to confirm that the vulnerability of neural crest cells to elevated glucose induces congenital heart malformations. The fact that N-acetylcysteine limits the teratogenicity of glucose implies that its damaging effect is mediated by an increase of oxidative stress in the neural crest cells.
Roest
Pauline A M
PA
Department of Anatomy and Embryology, Leiden University Medical Centre, Leiden, The Netherlands.
van Iperen
Liesbeth
L
Vis
Shirley
S
Wisse
Lambertus J
LJ
Poelmann
Rob E
RE
Steegers-Theunissen
Regine P M
RP
Molin
Daniel G M
DG
Eriksson
Ulf J
UJ
Gittenberger-De Groot
Adriana C
AC
D000111:Acetylcysteine / Q000627:therapeutic use*; D000818:Animals; D002642:Chick Embryo; D005947:Glucose / Q000633:toxicity*; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D009432:Neural Crest / Q000166:cytology / Q000187:drug effects* / Q000196:embryology
D005947:Glucose; D000111:Acetylcysteine