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Background: Hyperglycemia-related oxidative stress and hypoxia are important mechanisms responsible for diabetes-induced embryopathy and other complications. High sucrose low copper diet (HSD), but not regular diet (RD), induces type 2 diabetes in the inbred Cohen diabetic sensitive (CDs) rats but not in the Sabra control rats. We recently demonstrated long-term changes of DNA methylation and gene expression in various groups of genes, including genes involved in oxidant-antioxidant activity in the liver of 2-4-week-old CDs offspring of diabetic dams. We now studied the postnatal effects of diabetes and/or HSD on several liver metabolic parameters in these offspring., Methods: we studied lipid peroxidation, activity of the antioxidants enzymes superoxide dismutase (SOD) and Catalase (CAT). By immunohistochemistry: protein oxidation by nitrotyrosine staining, hypoxia inducing factor1α (HIF1α), apoptosis [caspase 3, bcl-2-like protein (BAX)], proliferation [proliferating cell nuclear antigen (PCNA)] and NF-κB., Results: In the Sabra rats fed HSD only few, early and transitional changes were observed in lipid peroxidation, SOD and CAT activity. In the CDs fed HSD more significant changes in lipid and protein oxidation, HIF1α, apoptosis and proliferation were observed, persisting for longer., Conclusions: The changes in the Sabra rats HSD were attributed to the pro-oxidant effects of the diet and those in the diabetic CDs to the HSD and maternal diabetes. In light of the DNA methylation changes in the liver of the CDs HSD, we presume that changes in gene expression are responsible for our findings, and that similar changes may lead to the metabolic syndrome at adulthood., (© 2018 Wiley Periodicals, Inc.)

Fetal Growth Restriction (FGR) is a leading cause for long term morbidity. The Cohen diabetic sensitive rats (CDs), originating from Wistar, develop overt diabetes when fed high sucrose low copper diet (HSD) while the original outbred Sabra strain do not. HSD induced FGR and fetal oxidative stress, more prominent in the CDs, that was alleviated more effectively by copper than by the anti-oxidant vitamins C and E. Our aim was to evaluate the impact of copper or the anti-oxidant Tempol on placental size, protein content, oxidative stress, apoptosis and total DNA methylation. Animals were mated following one month of HSD or regular chow diet and supplemented throughout pregnancy with either 0, 1 or 2 ppm of copper sulfate or Tempol in their drinking water. Placental weight on the 21st day of pregnancy decreased in dams fed HSD and improved upon copper supplementation. Placental/fetal weight ratio increased among the CDs. Protein content decreased in Sabra but increased in CDs fed HSD. Oxidative stress biochemical markers improved upon copper supplementation; immunohistochemistry for oxidative stress markers was similar between strains and diets. Caspase 3 was positive in more placentae of dams fed HSD than those fed RD. Placental global DNA methylation was decreased only among the CDs dams fed HSD. We conclude that FGR in this model is associated with smaller placentae, reduced DNA placental methylation, and increased oxidative stress that normalized with copper supplementation. DNA hypomethylation makes our model a unique method for investigating genes associated with growth, oxidative stress, hypoxia and copper., (Copyright © 2014 Elsevier Inc. All rights reserved.)

High sucrose low copper diet induces fetal growth restriction in the three strains of the Cohen diabetic rats: an inbred copper deficient resistant (CDr), an inbred copper deficient sensitive (CDs that become diabetic on high sucrose low copper diet -HSD) and an outbred Wistar derived Sabra rats. Although those growth restricted fetuses also exhibit increased oxidative stress, antioxidants do not restore normal growth. In the present study, we evaluated the role of copper deficiency in the HSD induced fetal growth restriction by adding to the drinking water of the rats 1 ppm or 2 ppm of copper throughout their pregnancy. Fetal and placental growth in correlation with fetal liver copper content and anti-oxidant capacity was evaluated on day 21 of pregnancy. HSD compared to regular chow induced fetal growth restriction, which was most significant in the Cohen diabetic sensitive animals. The addition of 1 ppm and 2 ppm copper to the drinking water normalized fetal growth in a dose dependent manner and reduced the degree of hyperglycemia in the diabetes sensitive rats. The CDs fetuses responded to the HSD with lower catalase like activity, and less reduced superoxide dismutase levels compared to the Sabra strain, and had high malondialdehyde levels even when fed regular chow. Immunostaining was higher for nitrotyrosine among the CDr and higher for hypoxia factor 1 α among the CDs. We conclude that in our model of dietary-induced fetal growth restriction, copper deficiency plays a major etiologic role in the decrease of fetal growth and anti-oxidant capacity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Hyperglycemia and hypoxia are well-known teratogens that may affect many animal species, including man. We hypothesize that a combination of hypoxia and hyperglycemia will increase embryonic damage produced by either factor individually. We investigated the interrelationship between hyperglycemia and hypoxia and their effects on genes involved in the balance of embryonic redox status., Methods: Rat embryos (10.5-day-old) were cultured for 28 hr in culture medium with about 6 mg/ml of glucose and 20% oxygen (hyperglycemia), with 10% oxygen (hypoxia) and 2.4 g/ml glucose (normal) or a combination of both 6 mg/ml glucose and 10% oxygen. Antioxidant capacity was determined by activity and gene expression of antioxidant enzymes: Cu/Zn SOD, Mn-SOD, CAT, and GSH-px using real time PCR., Results: Hyperglycemia, hypoxia, or their combination, decreased embryonic growth and induced a high rate (62-78%) of anomalies mainly of the nervous system, heart, and limbs. CAT mRNA and GSH-px mRNA were decreased in the malformed embryos exposed to hyperglycemia, to hypoxia or their combination. CAT mRNA was also decreased in the nonmalformed embryos subjected to hyperglycemia and hypoxia. Cu/Zn SOD mRNA was increased in all experimental embryos whether malformed or not, whereas Mn-SOD was drastically decreased. Total SOD and CAT like activity were changed very little in the experimental embryos compared to controls., Conclusions: Both hyperglycemia, hypoxia, and their combination reduce embryonic growth and development, induce embryonic anomalies, and modify the expression of the principle antioxidant genes. However, hypoxia does not seem to enhance the damaging effects of hyperglycemia except its effects of embryonic growth., (© 2011 Wiley-Liss, Inc.)

Intrauterine hyperglycemic environment could harm the fetus making it more susceptible to develop postnatal glucose intolerance. A possible mechanism is compromise of the fetal pancreatic development. We previously found that a high sucrose low copper diabetogenic diet induces type 2 diabetes in the Cohen diabetic sensitive rats, but not in the Sabra control rats. However, oxidative stress was observed in the placenta and term fetal liver of diabetic and nondiabetic controls. We now investigated whether the fetal pancreas is affected by this diet and whether the effects result from oxidative stress, maternal hyperglycemia, or both. Term fetal pancreases were evaluated for morphology, beta cells, oxidative stress, apoptosis, and DNA methylation. There were no microscopic changes in hematoxylin and eosin stained sections and beta cells immunostaining in the pancreas of fetuses of both strains. Fetuses of the sensitive strain fed diabetogenic diet had significantly higher activity of superoxide dismutase and catalase, elevated levels of low molecular weight antioxidants, and more intense immunostaining for nuclear factor kappa-B and hypoxia inducing factor-1α. Both strains fed diabetogenic diet had increased immunostaining for Bcl-2-like protein and caspase 3 and decreased immunostaining for 5-methylcytosine in their islets and acini. Our data suggest that maternal diabetogenic diet alters apoptotic rate and epigenetic steady states in the term fetal pancreas, unrelated to maternal diabetes. Maternal hyperglycemia further increases pancreatic oxidative stress, aggravating the pancreatic damage. The diet-induced insults to the fetal pancreas may be an important contributor to the high susceptibility to develop diabetes following metabolic intrauterine insults [ABSTRACT FROM AUTHOR]

Abstract Introduction A common animal model of ASD is the one induced by valproic acid (VPA), inducing epigenetic changes and oxidative stress. We studied the possible preventive effect of the methyl donor for epigenetic enzymatic reactions, S-adenosine methionine (SAM), on ASD like behavioral changes and on redox potential in the brain and liver in this model. Methods ICR albino mice were injected on postnatal day 4 with one dose of 300 mg/kg of VPA, with normal saline (controls) or with VPA and SAM that was given orally for 3 days at the dose of 30 mg/kg body weight. From day 50, we carried out neurobehavioral tests and assessment of the antioxidant status of the prefrontal cerebral cortex, liver assessing SOD and CAT activity, lipid peroxidation and the expression of antioxidant genes. Results Mice injected with VPA exhibited neurobehavioral deficits typical of ASD that were more prominent in males. Changes in the activity of SOD and CAT increased lipid peroxidation and changes in the expression of antioxidant genes were observed in the prefrontal cortex of VPA treated mice, more prominent in females, while ASD like behavior was more prominent in males. There were no changes in the redox potential of the liver. The co-administration of VPA and SAM alleviated most ASD like neurobehavioral symptoms and normalized the redox potential in the prefrontal cortex. Conclusions Early postnatal VPA administration induces ASD like behavior that is more severe in males, while the redox status changes are more severe in females; SAM corrects both. VPA-induced ASD seems to result from epigenetic changes, while the redox status changes may be secondary. Highlights • Administration of valproic acid (VPA) to neonatal mice induced autistic like behavior. • The administration of S-Adenosyl methionine (SAM) following the VPA injection prevents these autistic like behaviors. • Enhanced oxidative stress in the VPA treated mice was found in the cerebral cortex but not in the liver. It was normalized by SAM. • We suggest that the changes induced by VPA result from epigenetic modifications. [ABSTRACT FROM AUTHOR]