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A role for DNA mutations in diabetes-associated teratogenesis in transgenic embryos
1Picower Institute for Medical Research, Manhasset, New York 11030.
Abstract:
Congenital malformations are the leading cause of death in infants of insulin-dependent diabetic mothers. Although there are data to suggest that hyperglycemia itself is teratogenic, few mechanisms have been proposed to explain diabetic embryopathy. To address the possibility that DNA mutations play a role in the fetal malformations associated with diabetes, we developed a transgenic mouse model system to measure the mutation frequency of a neutral target gene, lacI, during embryonic development in a maternal hyperglycemic environment. Despite the short 21-day gestational period of the mouse, we observed a twofold increase in the mutant frequency of the lacI transgene in fetuses that developed in a mild diabetic environment (blood glucose > 8.3 mmol/l) compared with those that developed under normoglycemic conditions (blood glucose < 8.3 mmol/l). These data provide the first direct evidence of the genotoxic effect of diabetes in vivo and suggest a mechanism for the teratogenicity of the maternal diabetic environment.
Insights
Maternal diabetes during pregnancy increases the risk of birth defects. This study found that hyperglycemia in diabetic mothers causes DNA mutations in developing fetuses, explaining a key mechanism of diabetic embryopathy.
Area of Science:
- Reproductive biology
- Genetics
- Endocrinology
Background:
- Congenital malformations are a primary cause of infant mortality in offspring of mothers with insulin-dependent diabetes.
- Hyperglycemia is suspected to be teratogenic, but the underlying mechanisms for diabetic embryopathy remain largely unknown.
Purpose of the Study:
- To investigate the role of DNA mutations in fetal malformations associated with maternal diabetes.
- To establish a transgenic mouse model for quantifying mutation frequency during embryonic development in a hyperglycemic environment.
Main Methods:
- Development of a transgenic mouse model to assess mutation frequency of the neutral lacI target gene.
- Monitoring mutation frequency in fetuses exposed to maternal hyperglycemic versus normoglycemic conditions throughout gestation.
Main Results:
- A twofold increase in lacI transgene mutant frequency was observed in fetuses from mildly diabetic mothers (blood glucose > 8.3 mmol/l) compared to controls (blood glucose < 8.3 mmol/l).
- This increase occurred despite the short 21-day mouse gestational period.
Conclusions:
- This study provides the first in vivo evidence of diabetes-induced genotoxicity.
- The findings suggest that DNA damage is a significant mechanism contributing to the teratogenic effects of maternal diabetes.