Polymorphic Susceptibility to the Molecular Causes of Neural Tube Defects During Diabetic Embryopathy

Abstract

Previously, we demonstrated that neural tube defects (NTDs) are significantly increased in a mouse model of diabetic pregnancy. In addition, expression of Pax-3, a gene encoding a transcription factor required for neural tube development, is significantly decreased. This suggests that diabetic embryopathy results from impaired expression of genes regulating essential morphogenetic processes. Here, we report that in one mouse strain, C57Bl/6J, embryos are resistant to the effects of maternal diabetes on NTDs and Pax-3 expression, in contrast to a susceptible strain, FVB, in which maternal diabetes significantly increases NTDs (P ‫؍‬ 0.02) and inhibits Pax-3 expression (P ‫؍‬ 0.01). Resistance to NTDs caused by diabetic pregnancy is a dominant trait, as demonstrated by heterozygous embryos of diabetic or nondiabetic mothers of either strain. There was no significant difference between strains in expression of genes that regulate free radical scavenging pathways, suggesting that susceptibility to oxidative stress does not account for the genetic differences. Understanding the genetic bases for differential susceptibility to altered gene expression and NTDs in diabetic mice may be important in delineating the mechanisms by which maternal hyperglycemia interferes with embryo gene expression. Moreover, if susceptibility to diabetic embryopathy is variable in humans as well as in mice, it may be possible to screen individuals at increased risk for this complication of diabetes. Diabetes 51: 2871-2874, 2002

Relationship of antioxidant enzyme activities with myelomeningocele

“…In addition, multiple studies have demonstrated that the genetic susceptibility plays a key role in MM (2,5,20,21). Patients with genetically low FRSE activity are more susceptible to FRinduced damage (21).…”

“…Also, MM that is FR-mediated can be attributed to an increased FRs and decreased FRSE activity in the developing embryo. Many studies have demonstrated that antioxidants can prevent congenital malformations (2,20). Recent studies have shown that the addition of SOD or antioxidants to diet in culture helps to reduce the rate of embryonic anomalies (26).…”

“…Considerable advances have been made regarding the etiology of MM. The common mechanisms for MM include folate deficiency, genetic susceptibility, environmental factors, in utero drug exposure and biochemical factors (2,5,20,21,22,29). Numerous reports have described free radicals (FRs)-mediated congenital defects (2,3,12,18,22,26).…”

“…However, FR-mediated cellular damage can occur if there is a genetic deficiency in free radical scavenging enzyme (FRSE) activity (22). Evidences that have been presented so far suggest that an imbalance between diminished host antioxidant defenses and increased formation of FRs creates a state of oxidative stress (12,16,20,22,25). FRs play a crucial role in MM and there is a direct relationship between antioxidant enzymes and the development of MM (21,22).…”

Expression of the gene encoding the high-K m glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy

“…The Glut2 knockout strain was originally generated on a mixed C57Bl/6J×129/Sv background. C57Bl/6J embryos are resistant to diabetic embryopathy [36]. Therefore, a congenic strain was generated to place the Glut2 +/− allele on a 129/SvJ background [37].…”