Altered Levels of Scavenging Enzymes in Embryos Subjected to a Diabetic Environment

Forsberg, Henrik; Borg, Lisa; Cagliero, Enrico; Eriksson, UJ

doi:10.3109/10715769609088044

Cited by 53 publications

(31 citation statements)

References 46 publications

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“…The catalase result for the U embryos is in line with earlier studies showing no differences in mRNA levels between embryos of normal and diabetic U rats (43). Intere s t i n g l y, in the previous study, Mn-SOD tended to be increased in embryos of diabetic rats (43), similar to the result in the present investigation. It may be speculated, therefore, that maternal diabetes could induce a small increase in U-strain mRNA levels of Mn-SOD.…”

Section: Discussionsupporting

confidence: 92%

Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain.

et al. 2000

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Previous studies have suggested that reactive oxygen species (ROS) are mediators in the teratogenic process of diabetic pregnancy. In an animal model for diabetic p r e g n a n c y, offspring of the H rat strain show minor dysmorphogenesis when the mother is diabetic, whereas the offspring of diabetic rats of a sister strain, U, display major morphologic malformations. Earlier studies have shown that embryonic catalase activity is higher in the H than in the U strain, and maternal diabetes increases this difference in activity. The aim of this study was to characterize the influence of genetic predisposition on diabetic embryopathy by comparing the mRNA levels of ROS-metabolizing enzymes in the two strains. We determined the mRNA levels of catalase, glutathione peroxidase, -g l u t a m y l c y s t e i n -s y n t h e t a s e , glutathione reductase, and superoxide dismutase (CuZn-SOD and Mn-SOD) in day 11 embryos of normal and diabetic H and U rats using semiquantitative reverse transcription-polymerase chain reaction. The mRNA levels of catalase and Mn-SOD were increased in H embryos as a response to maternal diabetes, and no d i fferences were found for the other genes. Sequence analysis of the catalase promoter indicated that the d i fference in mRNA levels may result from diff e r e n t regulation of transcription. Sequence analysis of the catalase cDNA revealed no differences between the two strains in the translated region, suggesting that the previously observed difference in the electrophoretic mobility in zymograms is due to posttranslational modifications. An impaired expression of scavenging enzymes in response to ROS excess can thus be an integral part of a genetic predisposition to embryonic dysmorphogenesis. D i a b e t e s 4 9 :1 0 1-107, 2000 M aternal type 1 diabetes during pregnancy has been known for many years to be associated with an increased risk for congenital malformations in the offspring (1-4). Clinical studies have estimated the risk for a malformed fetus in a t y p e 1 diabetic pregnancy to be in the range of 5-10% (5-9). The malformations are induced before the 7th postconceptional week in human diabetic pregnancy (10). In rats, the teratogenic process is believed to occur during organogenesis (11). Recent reports, however, indicate that a diabetic environment may decrease the inner cell mass (12) and that a high glucose concentration can lead to increased apoptosis already in the preimplantation embryo (13). The teratogenic process and its predisposing factors are not known in detail. In pregnancies with poorly controlled diabetes, however, there is a correlation between the level of H b A 1 c in maternal blood and the risk for having a malformed child (5,14,15).The hypothesis has been put forward that an excess of reactive oxygen species (ROS) mediates the teratogenicity of diabetic pregnancy (16)(17)(18)(19). The oxygen radicals may be harmful to the cell and its functions by reacting with unsaturated fatty acids in membranes, yielding lipid peroxides and causing decreased membran...

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Section: Discussionsupporting

confidence: 92%

Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain.

et al. 2000

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“…Therefore, the increase in Mn-SOD, if present, may have been undetected when measured as total SOD activity. This explanation is supported by the studies of Cederberg and colleagues [5,36] showing that the increased activity of SOD in embryos of the malformation-resistant strain, as a result of maternal diabetes, was mainly due to increase in Mn-SOD and not to CuZn-SOD.…”

Section: Discussionmentioning

confidence: 75%

The Role of Reactive Oxygen Species in Diabetes‐Induced Anomalies in Embryos of Cohen Diabetic Rats

Zangen

Yaffe

Shechtman

et al. 2002

Journal of Diabetes Research

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The role of the antioxidant defense mechanism in diabetesinduced anomalies was studied in the Cohen diabetes-sensitive (CDs) and -resistant (CDr) rats, a genetic model of nutritionally induced type 2 diabetes mellitus. Embryos, 12.5-day-old, of CDs and CDr rats fed regular diet (RD) or a diabetogenic high-sucrose diet (HSD) were monitored for growth retardation and congenital anomalies. Activity of superoxide dismutase (SOD) and catalaselike enzymes and levels of ascorbic acid (AA), uric acid (UA), and dehydroascorbic acid (DHAA) were measured in embryonic homogenates. When fed RD, CDs rats had a decreased rate of pregnancy, and an increased embryonic resorption. CDs embryos were smaller than CDr embryos; 46% were maldeveloped and 7% exhibited neural tube defects (NTDs). When fed HSD, rate of pregnancy was reduced, resorption rate was greatly increased (56%; P < .001), 47.6% of the embryos were retrieved without heart beats, and 27% exhibited NTD. In contrast, all the CDr embryos were normal when fed RD or HSD. Activity of SOD and catalase was not different in embryos of CDs and CDr rats fed RD. When fed HSD, levels of AA were significantly reduced, the ratio DHAA/AA was significantly increased, and SOD activity was not sufficiently increased when compared to embryos of CDr. The reduced fertility of the CDs rats, the growth retardation, and NTD seem to be genetically determined. Maternal hyperglycemia seems to result in The increased rate of fetal malformations in diabetic pregnancy despite better glycemic control represents a clinical problem and a research challenge. The exact mechanism behind the elevated rate of malformations is presently unknown. It has, however, been suggested that both intrauterine (maternal) environment as well as genetic background may be important [1][2][3][4][5][6][7] in the teratogenic process. As of today, the literature describes 3 main pathways by which diabetes may affect the normal development of the embryos: disturbed inositol uptake, yielding lowered intracellular inositol concentration [8]; diminished flow in the arachidonic acid-prostaglandin pathway, yielding decreased PGE2 concentration [9]; and excess amount of reactive oxygen species, resulting in decreased amount of low-molecular-weight antioxidants, such as vitamin C, uric acid, glutathione, and vitamin E [5,6,10,11]. The reactive oxygen species pathway seems to be the most important pathway because antioxidants may protect against the disturbances of both the inositol and the arachidonic pathways. The proposed mechanisms for increased reactive oxygen species generation at higher glucose concentrations include nonenzymatic protein glycosylation [12][13][14], enhanced mitochondrial electron transport chain flow [15], autooxidation [16], and changes in the redox potential. The relative 247

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“…The role of oxidative stress as an etiologic factor in diabetic teratogenesis has recently been supported by in vivo and in vitro studies: Forsberg et al [25] found altered levels of scavenging enzymes both in embryos cultured in diabetic conditions and in embryos obtained from diabetic mothers, and different antioxidant agents have been tested with positive results: butylated hydroxytoluene [25,26], vitamin E [27,28], vitamin C [29], and N-acetylcysteine [30].…”

Section: Introductionmentioning

confidence: 99%

Development of Rat Embryos Cultured in Serum from Diabetic Rats

Menegola¹,

Broccia²,

Giavini³

1998

Neonatology

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Experimental studies carried out in vitro suggest a role of oxidative stress in diabetes-induced embryopathies. Glutathione is the main defense against free radicals in embryonic as it is in adult tissues. In this experiment, using postimplantation whole-embryo culture, we analyze: (1) the effects of serum from streptozotocin-induced diabetic rats on embryonic development and on glutathione distribution between the yolk sac and embryonic tissues and (2) the role of glutathione in preventing embryopathies (using the inhibitor of glutathione synthesis buthionine sulfoximine). Our data show that in rat embryos cultured in diabetic serum, the only observed effects are at the yolk sac level. No effects on the glutathione content were observed. The addition of buthionine sulfoximine reduced the glutathione content and produced signs of developmental delay in embryos cultured in diabetic serum, suggesting a role of the oxidative stress in producing diabetes-related embryotoxicity.

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Altered Levels of Scavenging Enzymes in Embryos Subjected to a Diabetic Environment

Cited by 53 publications

References 46 publications

Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain.

Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain.

The Role of Reactive Oxygen Species in Diabetes‐Induced Anomalies in Embryos of Cohen Diabetic Rats

Development of Rat Embryos Cultured in Serum from Diabetic Rats

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