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

Abstract

The purpose of this study was to investigate the influence of parental transgenerational genetics and maternal metabolic state on fetal maldevelopment in diabetic rat pregnancy. Rats from an inbred malformation-resistant (W) strain, and an inbred malformation-prone (L) strain, were cross-mated to produce two different F(1) hybrids, WL and LW. Normal (N) and manifestly diabetic (MD) WL and LW females were mated with normal males of the same F(1) generation to obtain WLWL and LWLW F(2) hybrids. Maternal diabetes increased malformation and resorption rates in both F(2) generations. MD-WLWL offspring had higher resorption rate but similar malformation rate compared with the MD-LWLW offspring. Malformed MD-WLWL offspring presented with 100% agnathia/micrognathia, whereas malformed MD-LWL offspring had 60% agnathia/micrognathia and 40% cleft lip and palate. The MD-WL dams showed increased β-hydroxybutyrate levels and alterations in concentrations of several amino acids (taurine, asparagine, citrulline, cystine, glutamic acid, leucine, tyrosine, and tryptophan) compared with MD-LW dams. Fetal glyceraldehyde-3-phosphate dehydrogenase (Gapdh) activity and gene expression were more altered in MD-WLWL than MD-LWLW. Fetal gene expression of reactive oxygen species (ROS) scavenger enzymes was diminished in MD-WLWL compared with MD-LWLW. Glial cell line-derived neurotrophic factor and Ret proto-oncogene gene expression was decreased in both MD-WLWL and MD-LWLW fetuses, whereas increased bone morphogenetic protein 4 and decreased Sonic hedgehog homolog expression was found only in MD-LWLW fetuses. Despite identical autosomal genotypes, the WL and LW dams gave birth to offspring with markedly different malformation patterns. Together with fetal differences in enzymatic activity and expression of Gapdh, ROS scavengers, and developmental genes, these results may suggest a teratological mechanism in diabetic pregnancy influenced by maternal metabolism and parental strain epigenetics.

Maternal obesity is a risk factor for orofacial clefts: a meta-analysis

“…These malformations are related to defects in the fetal expression of developmental genes such as bone morphogenetic protein 4 and the sonic hedgehog gene and those that encode enzymes for the management of reactive oxygen species, which shows that glucose has a teratogenic effect at several levels. 18 However, there have been some controversial results. Some reports have found that diabetic mothers have an increased risk of having a child with cleft lip and palate compared with non-diabetic mothers.…”

Investigating the Mechanism of Hyperglycemia-Induced Fetal Cardiac Hypertrophy

“…Pregnant women with either pre-gestational diabetes mellitus (PGDM) or gestational diabetes mellitus are at high risk (2–5 times higher than non-diabetic pregnancies) of carrying a fetus with congenital anomalies, such as phocomelia, cardiac malformations, macrosomia and central nervous system malformations [ 1 , 2 ]. Among those congenital malformations induced by hyperglycemia, congenital heart disease [ 3 ] and anomalies of the nervous system are prominent [ 4 ] because both the cardiovascular and nervous systems start to develop during the early embryonic developmental stage, the period that is vulnerable to external harmful factors.…”

Autophagy is involved in high glucose-induced heart tube malformation

“…There is no doubt that fetal cardiac defects are closely associated with maternal hyperglycemia because they occur up to 5 times more often in pre-gestational diabetic mothers compared to those without diabetes. 1 There are many types of rodent animal models that have been employed to date to explore the mechanism of diabetic teratogenesis. Based on the characteristics Figure 5.…”

“…The incidence of congenital malformations in diabetic pregnancy has been reported to be 2-5 times higher than in non-diabetic pregnancy. 1 Therefore, pregnant women with preexisting diabetes mellitus or gestational diabetes are at high risk of carrying a fetus with congenital anomalies such as neural phocomelia, cardiac malformations, macrosomia and central nervous system malformations. 2 Macintosh et al reported that the increased risk of congenital anomalies was predominantly for congenital heart disease (3.4 times higher risk) and anomalies of the nervous system (2.7 times higher risk) in their study.…”