Malformations induced in cultured rat embryos by enzymically generated active oxygen species

Jenkinson, P.C.; Anderson, Diana; Gangolli, S.D.

doi:10.1002/tcm.1770060608

Cited by 42 publications

(16 citation statements)

References 17 publications

(7 reference statements)

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“…However, the potential for damage is substantial. It is well documented that the fetus or embryo is exquisitely sensitive to oxidative stress, the generation of which can cause a spectrum of responses ranging from structural malformations to embryonic death (Hiranruengchok and Harris, 1993;Jenkinson et al, 1986;Martensson et al, 1991). Recent studies in our laboratory have illustrated that a product of lipid oxidation (HNE) may mediate some of the toxic responses to ethanol .…”

Section: Ethanol-mediated Hne Production As An Initiator Of Cell Deatmentioning

confidence: 97%

In Utero Ethanol Exposure Causes Mitochondrial Dysfunction, Which Can Result in Apoptotic Cell Death in Fetal Brain: A Potential Role for 4‐Hydroxynonenal

Vinitha

Pérez

Chen

et al. 2001

Alcoholism Clin & Exp Res

147

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These studies illustrate that in utero ethanol exposure can elicit a cascade of events in the fetal brain that are consistent with mitochondrially mediated apoptotic cell death. Additionally, the increase in mitochondrial content of HNE after ethanol intake and the ability of HNE added to fetal brain mitochondria to mimic these effects of in vivo ethanol exposure support a potential role for HNE in the proapoptotic responses to ethanol.

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Section: Ethanol-mediated Hne Production As An Initiator Of Cell Deatmentioning

confidence: 97%

In Utero Ethanol Exposure Causes Mitochondrial Dysfunction, Which Can Result in Apoptotic Cell Death in Fetal Brain: A Potential Role for 4‐Hydroxynonenal

Vinitha

Pérez

Chen

et al. 2001

Alcoholism Clin & Exp Res

147

View full text Add to dashboard Cite

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“…Increased ROS production (20,21) and lipid peroxidation (22) have subsequently been found in rat embryos cultured in high glucose and in embryos of diabetic rat mothers. Enzymatically produced ROS can disturb embryo development in vitro similarly to the effect of high glucose (23), and the resulting maldevelopment can be blocked by vitamins E and C separately (24). Apart from increased production, the putative ROS excess can be attributed to impaired embryonic defense in response to an oxidative environment.…”

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confidence: 99%

Combined Treatment with Vitamin E and Vitamin C Decreases Oxidative Stress and Improves Fetal Outcome in Experimental Diabetic Pregnancy

2001

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The aim was to investigate whether dietary supplementation of a combination of the two antioxidants, vitamin E and vitamin C, would protect the fetus in diabetic rat pregnancy at a lower dose than previously used. Normal and streptozotocin-induced diabetic rats were mated and given standard food or food supplemented with either 0.5% vitamin E ϩ 1% vitamin C or 2% vitamin E ϩ 4% vitamin C. At gestational d 20, gross morphology and weights of fetuses were evaluated. Vitamins E and C and thiobarbituric acid reactive substances were measured in maternal and fetal compartments. In addition, protein carbonylation was estimated in fetal liver. Maternal diabetes increased the rate of malformation and resorption in the offspring. High-dose antioxidant supplementation decreased fetal dysmorphogenesis to near normal levels. The low-dose group showed malformations and resorptions at an intermediate rate between the untreated and the high-dose groups. Thiobarbituric acid reactive substances were increased in fetal livers of diabetic rats and reduced to normal levels already by low-dose antioxidative treatment. Protein carbonylation rate was also increased in fetal liver of diabetic rats; it was normalized by high-dose treatment but only partially reduced by low-dose antioxidants. We conclude that combined antioxidative treatment with vitamins E and C decreases fetal malformation rate and diminishes oxygen radicalrelated tissue damage. However, no synergistic effect between the two antioxidants was noted, a result that may influence future attempts to design antiteratogenic treatments in diabetic pregnancy. Oxidatively modified proteins may be teratogenically important mediators in diabetic embryopathy. Maternal type-1 diabetes during pregnancy causes an increased rate of malformation in the fetus despite insulin treatment and glucose monitoring (1-3). The incidence of fetal malformations in type-1 diabetic pregnancies is estimated to be 5-10% in recent studies (4 -8). Several clinical studies have demonstrated that high maternal HbA1c levels during early pregnancy are associated with an increased risk for malformations (4, 9, 10). It is, however, likely that the pathogenesis of diabetic embryopathy is multifactorial (11), and in experimental work not only maternal serum levels of glucose but also levels of triglycerides, ␤-hydroxybutyrate, branched-chain amino acids, and creatinine correlate positively with increased resorption and malformation rates (12). Also, genetic factors may predispose for the development of malformations in maternal diabetes (13,14).The putative role of ROS in the development of diabetic complications has been investigated for several decades (15-17). Evidence of ROS involvement in hyperglycemia-induced embryopathy was first obtained in studies in which antioxidant enzymes proved to be protective in vitro (18,19). Increased ROS production (20, 21) and lipid peroxidation (22) have subsequently been found in rat embryos cultured in high glucose and in embryos of diabetic rat mothers. Enzymatically prod...

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“…First, diabetes in vivo (25) and hyperglycemia in vitro (26,27) cause an increase in lipid peroxides and free radicals in the offspring (28). Second, developmental defects similar to those seen in diabetic rat pregnancies in vivo and in high-glucose embryo cultures in vitro can be induced by enzymatic production of superoxide ions in embryo culture systems (29). Third, several different scavengers of free oxygen radicals added to the diet (18, [30][31][32] decrease the malformation rate in diabetic rat pregnancy.…”

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confidence: 99%

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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Malformations induced in cultured rat embryos by enzymically generated active oxygen species

Cited by 42 publications

References 17 publications

In Utero Ethanol Exposure Causes Mitochondrial Dysfunction, Which Can Result in Apoptotic Cell Death in Fetal Brain: A Potential Role for 4‐Hydroxynonenal

In Utero Ethanol Exposure Causes Mitochondrial Dysfunction, Which Can Result in Apoptotic Cell Death in Fetal Brain: A Potential Role for 4‐Hydroxynonenal

Combined Treatment with Vitamin E and Vitamin C Decreases Oxidative Stress and Improves Fetal Outcome in Experimental Diabetic Pregnancy

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

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