In vivo evidence for the existence of a threshold for hyperglycemia-induced major fetal malformations: relevance to the etiology of diabetic teratogenesis.
The present study was carried out to evaluate whether hyperglycemia-induced major fetal anomalies are thresholded phenomena. Streptozotocin (STZ)-treated female ICR mice were examined on day 19 of pregnancy by methods routinely used in Segment II teratological studies. Simultaneously, the glucose and hemoglobin A1c (HbA1c) levels in maternal-blood were measured and mice with glucose levels > 9.5 mmol/l (mean + 3 SD) were considered to be diabetic. The occurrence of litters with fetuses having gross structural anomalies was clearly associated with glucose levels > 27.8 mmol/l. A wide range of HbA1c levels (between 6 and 18 SD above the mean) were observed, within which only single malformed fetuses were found in the litters of diabetic females. A decreased pregnancy rate in diabetic ICR mice was associated with glucose levels > 16.7 mmol/l and with HBA1c levels > 6 SD above the mean. The results of this study suggest that there is a threshold glucose level associated with a clear increase of the number of litters with severely malformed fetuses in diabetic ICR mice. Results of this study also suggest the existence of HbA1c-associated factors determining, along with glucose, the teratogenic response of ICR mice to diabetes. The interpretation of results obtained in terms of the multifactorial/threshold model leads to the hypothesis that the teratogenic potential of diabetes may consist of two components; one associated with 'direct' teratogens perturbing developmental processes in embryos at a 'critical moment' in organogenesis, and a second component, associated with a direct or indirect influence of the diabetic environment on developmental processes in the preimplantation embryos.
Torchinsky
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A
Department of Embryology and Teratology, Sackler School of Medicine, Tel Aviv University, Israel.
Toder
V
V
Carp
H
H
Orenstein
H
H
Fein
A
A
D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D000013:Congenital Abnormalities / Q000453:epidemiology / Q000209:etiology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000503:physiopathology; D005314:Embryonic and Fetal Development / Q000502:physiology; D005260:Female; D006442:Glycated Hemoglobin / Q000009:adverse effects / Q000032:analysis / Q000502:physiology; D006943:Hyperglycemia / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D015994:Incidence; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D011256:Pregnancy Outcome; D018873:Pregnancy Rate; D011254:Pregnancy in Diabetics / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D011270:Pregnancy, Animal / Q000097:blood* / Q000502:physiology; D013311:Streptozocin
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D013311:Streptozocin