The 1986 McCollum award lecture. Fuel-mediated teratogenesis during early organogenesis: the effects of increased concentrations of glucose, ketones, or somatomedin inhibitor during rat embryo culture

In an attempt to define the pathogenesis of congenital malformations in diabetic pregnancy, a number of serum factors were determined in normal and diabetic pregnant rats and correlated to the outcome of gestation with the aid of multivariate linear regression analysis. The animals were from two different lines of Sprague-Dawley rats with documented differences in rates of fetal dysmorphogenesis in diabetic pregnancy. The diabetic rats increased less in body weight than the normal rats, yet displayed increased liver and kidney weights. The serum concentrations of glucose, P-hydroxybutyrate, triglycerides, the branched-chain amino acids, and asparagine, proline, alanine, citrulline, tyrosine, and ornithine were increased by diabetes. In contrast, IGF-I, glutamic acid, glutamine, cystine, and lysine were decreased in the serum of the diabetic pregnant rats. The maternal metabolic imbalance exerted profound effects on embryonic development. Thus, the embryos of the diabetic rats were smaller, had fewer somites, and contained less DNA and protein than the control embryos. In addition, the resorption and malformation rates were increased in the embryos of the diabetic rats. The regression analysis of the data revealed significant interrelationships between adverse embryonic outcome (rates of malformations and resorptions) and the maternal serum concentrations of glucose, triglycerides, P-hydroxybutyrate, branched-I---Diabetic pregnancy is associated with an increased risk of fetal maldevelopment (1-3). The pathogenesis of congenital malformations in the offspring of diabetic mothers is unknown. In previous clinical and experimental studies, strict metabolic control of the mother has been shown to diminish the risk of fetal maldevelopment, especially if the improved control is initiated in early pregnancy (4-7) or before conception (8).chain amino acids, and creatinine. This suggests that the maternal metabolism of the three major classes of nutrients covariates with the embryonic development in diabetic rat pregnancy. The monitoring of only one of these maternal parameters, e.g. the serum glucose concentration, may therefore not adequately predict the developmental status of the offspring. Our results suggest that the pathogenesis of fetal malformations in diabetic pregnancy is multifactorial. Thus, maintaining metabolites from all nutrient classes at a normal level may be important in preventing adverse fetal outcome. Maintenance of normal serum glucose levels alone, however, does not seem to completely protect the fetus from malformations (9). Other disturbed metabolic processes in the mother, reflected by alterations in serum levels of associated metabolites, may therefore have pathogenic roles in the teratogenicity of diabetic pregnancy. In previous studies of an animal model for diabetic pregnancy, w e found increased rates of fetal malformations and resorptions among the offspring of streptozotocin-diabetic rats

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“…Altogether these data would support the notion of a multiple origin of the embryonic maldevelopment in diabetic pregnancy (23,48,50,51).…”

Section: Ud Hn Hdsupporting

confidence: 76%

Correlations between Maternal Metabolism and Deranged Development in the Offspring of Normal and Diabetic Rats

et al. 1995

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“…The earliest detection of receptor for somatomedin C has been at day 10 for mouse embryo [37] and for epidermal growth factor receptors at day 12 [38]. The findings that somatomedin inhibitors from diabetic rat serum retarded growth and development in rat [36] and mouse [35] embryos suggest a possible role of somatomedin in early embryonic development. We can not exclude the possibility that decreased activity of somatomedin [34] and increased counterregulatory hormones [33] in insulin-induced hypoglycaemic serum may have been involved as well.…”

Section: Discussionmentioning

confidence: 99%

Effects of hypoglycaemia on early embryogenesis in rat embryo organ culture

Akazawa

Hashimoto

et al. 1987

Diabetologia

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Summary.As congenital malformations may be caused by perturbations of glycolytic flux on early embryogenesis [16], effects of hypogtycaemia were investigated by using rat embryo organ culture. Nine and one-half day old rat embryos were grown in vitro for 48 h (day 9 89 to 11 89 in the presence of hypoglycaemic serum for different hours during the culture period. Hypoglycaemic serum was obtained from rats given insulin intraperitoneally. On exposure to hypoglycaemic serum during the first 24 h of culture (day 9 89 to 10 89 embryos showed marked growth retardation and had increased frequencies of neural lesions (42.7% versus 0%, p < 0.01), in contrast to hypoglycaemic exposure during the second 24 h of culture (day 10~A to 11%), where only minor growth retardation and low frequencies of neural lesions (2.4% versus 0%, NS) were seen. Even exposure to hypoglycaemic serum for a relatively short period (8 h) during the first 24 h of culture resulted in neural lesions at the frequency of 9.3-13.3%. The embryos exposed to hypoglycaemia demonstrated decreased glucose uptake and lactic acid formation, indicating decreased energy production via glycolysis that constitutes the pnncipal energy pathway at this stage of embryonic development. These results suggest that hypoglycaemia during critical periods of embryogenesis has adverse effects on the development of the embryo and these effects might be mediated through metabolic interruption of embryogenesis.Key words: Hypoglycaemia, rat embryo culture, congenital malformation, growth retardation.It is generally accepted that infants of insulin-dependent diabetic mothers have a higher incidence of congenital malformations [1][2][3][4]. A number of experiments of streptozotocin-induced diabetic animals [5,6] and studies in humans [7,8] have suggested that metabolic abnormalities such as hyperglycaemia in early pregnancy may be important factors causing congenital malformations. Whole embryo organ culture techniques in rodents, in which the embryo can develop from early head-fold stage to tail-bud stage with 26-30 somites have been developed [9,10]. The morphogenetic events that occur in cultured embryos correspond to periods observed in human embryos during the 3rd-6th weeks of gestation which is the most susceptible period of teratogenesis in diabetic patients. It has been shown that the addition of excess glucose [11,12] or ketone bodies [13,14] to the culture medium have had teratogenic effects on cultured rat or mouse embryos.On the other hand, effects of hypoglycaemia, during early embryogenesis remain to be evaluated. Since the embryo during the early phase of organogenesis is critically dependent on glycolysis and inhibition of glycolytic flux during the early periods resulting in dysmorphogenesis [15,16], maternal hypoglycaemia during the vulnerable periods could be harmful to the embryo. Therefore, rat embryo organ culture was employed to test whether hypoglycaemia was associated with demonstrable abnormalities even during early embryogenesis and to determine its tempor...

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“…Environmental insults during this developmental window lead to defects in the cardiovascular system, which subsequently affect the development of several embryonic organs. An in vitro whole embryo culture model permits study of this crucial developmental period and has shown that short exposure to hyperglycemia is teratogenic, causing dose dependent growth retardation, neural tube lesions and yolk sac failure (Cockroft and Coppola, 1977;Pinter et al, 1999;Reece et al, 1996;Rashbass and Ellington, 1988;Sadler, 1980a;Sadler, 1980b;Freinkel et al, 1986). Additionally, this model system mimics the morphological and biochemical vascular defects in the embryo and yolk sac observed in vivo (New et al, 1976;Mills et al, 1979;Sadler and Warner, 1984).…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide modulates murine yolk sac vasculogenesis and rescues glucose induced vasculopathy

et al. 2004

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Nitric oxide (NO) has been demonstrated to mediate events during ovulation,pregnancy, blastocyst invasion and preimplantation embryogenesis. However,less is known about the role of NO during postimplantation development. Therefore, in this study, we explored the effects of NO during vascular development of the murine yolk sac, which begins shortly after implantation. Establishment of the vitelline circulation is crucial for normal embryonic growth and development. Moreover, functional inactivation of the endodermal layer of the yolk sac by environmental insults or genetic manipulations during this period leads to embryonic defects/lethality, as this structure is vital for transport, metabolism and induction of vascular development. In this study, we describe the temporally/spatially regulated distribution of nitric oxide synthase (NOS) isoforms during the three stages of yolk sac vascular development (blood island formation, primary capillary plexus formation and vessel maturation/remodeling) and found NOS expression patterns were diametrically opposed. To pharmacologically manipulate vascular development,an established in vitro system of whole murine embryo culture was employed. During blood island formation, the endoderm produced NO and inhibition of NO(L-NMMA) at this stage resulted in developmental arrest at the primary plexus stage and vasculopathy. Furthermore, administration of a NO donor did not cause abnormal vascular development; however, exogenous NO correlated with increased eNOS and decreased iNOS protein levels. Additionally, a known environmental insult (high glucose) that produces reactive oxygen species(ROS) and induces vasculopathy also altered eNOS/iNOS distribution and induced NO production during yolk sac vascular development. However, administration of a NO donor rescued the high glucose induced vasculopathy, restored the eNOS/iNOS distribution and decreased ROS production. These data suggest that NO acts as an endoderm-derived factor that modulates normal yolk sac vascular development, and decreased NO bioavailability and NO-mediated sequela may underlie high glucose induced vasculopathy.

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The 1986 McCollum award lecture. Fuel-mediated teratogenesis during early organogenesis: the effects of increased concentrations of glucose, ketones, or somatomedin inhibitor during rat embryo culture

Cited by 92 publications

References 38 publications

Correlations between Maternal Metabolism and Deranged Development in the Offspring of Normal and Diabetic Rats

Correlations between Maternal Metabolism and Deranged Development in the Offspring of Normal and Diabetic Rats

Effects of hypoglycaemia on early embryogenesis in rat embryo organ culture

Nitric oxide modulates murine yolk sac vasculogenesis and rescues glucose induced vasculopathy

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