Genetic and environmental influence on diabetic rat embryopathy

Abstract

Ejdesjö A, Wentzel P, Eriksson UJ. Genetic and environmental influence on diabetic rat embryopathy. Am J Physiol Endocrinol Metab 300: E454 -E467, 2011. First published November 30, 2010 doi:10.1152/ajpendo.00543.2010We assessed genetic and environmental influence on fetal outcome in diabetic rat pregnancy. Crossing normal (N) and manifestly diabetic (MD) Wistar Furth (W) and Sprague-Dawley (L) females with W or L males yielded four different fetal genotypes (WW, LL, WL, and LW) in N or MD rat pregnancies for studies. We also evaluated fetal outcome in litters with enhanced or diminished severity of maternal MD state, denoted MD ϩ WL and MD Ϫ LW. The MDWW litters had less malformations and resorptions (0 and 19%) than the MDLL litters (17 and 30%). The MDWL litters (0 and 8%) were less maldeveloped than the MDLW litters (9 and 22%), whereas the MD ϩ WL (3 and 23%) and MD Ϫ LW (1 and 17%) litters showed increased and decreased dysmorphogenesis (compared with MDWL and MDLW litters). The pregnant MDW rats had lower serum levels of glucose, fructosamine, and branched-chain amino acids than the pregnant MDL rats, whereas the pregnant MD ϩ W and MD Ϫ L rats had levels comparable with those of the MDL and MDW rats, respectively. The 8-iso-PGF2␣ levels of the malformed MDLW offspring were increased compared with the nonmalformed MDLW offspring. Diabetes decreased fetal heart Ret and increased Bmp-4 gene expression in the MDLW offspring and caused decreased GDNF and Shh expression in the malformed fetal mandible of the MDLW offspring. We conclude that the fetal genome controls the embryonic dysmorphogenesis in diabetic pregnancy by instigating a threshold level for the teratological insult and that the maternal genome controls the teratogenic insult by (dys)regulating the maternal metabolism. diabetes in pregnancy; congenital abnormalities; teratology; animal experimentation; aldose reductase; glyceraldehyde-3-phosphate dehydrogenase; sonic hedgehog homolog; ret proto-oncogene; glial-derived neurotrophic factor; antioxidative enzymes THE INCIDENCE OF CARDIOVASCULAR, skeletal, urinary, gastrointestinal, and caudal dysgenesis-related defects is higher in offspring of women with preexisting diabetes compared with infants of nondiabetic women (4,18,27,38). Despite extensive research and optimized clinical care, diabetic embryopathy has remained etiologically enigmatic and difficult to prevent (40). The diabetes-induced alterations in embryonic development are similar to changes caused by several other teratogens, suggesting that the mechanism of diabetic dysmorphogenesis is multifactorial.The maternal environment and the fetal-maternal genotypes have been implicated in the teratogenicity of diabetic pregnancy. Thus, in diabetic women, the metabolic control (Hb A 1c levels) during the proximal part of the first trimester (29) is a strong predictor of the risk for congenital malformation (28). In experimental work, maternal metabolic deregulation has been confirmed as an important teratogenic factor (14,17,25), and a teratog...

Influence of maternal metabolism and parental genetics on fetal maldevelopment in diabetic rat pregnancy

“…In our previous work with WL and LW F 1 offspring, a combination of embryonic susceptibility and maternal milieu appeared as the most plausible explanation for differences in fetal outcome (19), a notion applicable also on the results in the present study.…”

“…As discussed above, different polymorphism in W and L mitochondria might lead to disturbed mitochondrial function in a hyperglycemic environment. The influence of parental genotype and maternal diabetes on gene expression patterns of ROS scavenging enzymes and key developmental genes are similar in the F 2 offspring in this present work compared with F 1 offspring in previous experiments (19). Furthermore, MD-WLWL offspring show a decreased mandibular gene expression of CuZnSOD, MnSOD, ECSOD, and Gpx1 compared with MD-LWLW offspring.…”

“…The malformation rate was 4 and 5% in MD-WLWL and MD-LWLW offspring. In earlier work, MD-WL and MD-LW offspring had 0 and 9% malformations, whereas parental MD-WW and MD-LL diabetic pregnancies presented with 0 and 17% malformation rates (19). The protection from diabetes-induced malformations in MD-WL offspring (compared with MD-LW offspring) was hypothesized to be caused mainly by maternal protective factors, i.e., the W uterine milieu.…”

“…From these regions, 20 candidate genes, and 2 candidate proteins, AR (chromosome 4) and Gapdh (chromosome 10), were chosen for further studies. In earlier experimental work, we have shown that the severity of the diabetic state is important but not completely decisive for the development of malformations in rat diabetic pregnancy (19). The fetal genotype as well as derangements in the uterine environment, i.e., overload of glucose and lipid compounds, disturbed amino acid levels, and enhanced oxidative stress, play different roles in the induction and direction of dysmorphogenetic pathways.…”

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

“…Outbred strains, such as ICR, appear to be susceptible to diabetes-induced neural tube defects [Oyama et al, 2009; Wu et al, 2012], with NTD incidence as high as 75% in ICR mice, although non-diabetic controls also showed a high rate of defects (24%) in one study [Phelan et al, 1997]. In the rat, genetic background also appears to modulate the susceptibility to craniofacial defects in diabetic pregnancies [Ejdesjo et al, 2011; Nordquist et al, 2012], although the molecular mechanisms underlying differential susceptibility are unknown at present. In the mouse, strain-specific differences in the position of the rostral closure site [Juriloff et al, 1991] have been suggested to influence the susceptibility to anterior neural tube defects.…”