8-hydroxy-2--deoxyguanosine and Fetal-Growth-Retardation

Pregnancy complications including pre-eclampsia, gestational-diabetes mellitus, preterm birth and intrauterine growth restriction can cause acute and chronic health problems for the mother and lead to fetal loss or dysregulation of infant physiology. The human placenta is susceptible to oxidative stress and oxidative damage in early gestation contributes to the onset of these conditions later in pregnancy. Current methods of predicting pregnancy complications are limited and although a large number of factors are associated with disease progression, few biomarkers have been used to aid in disease diagnosis early in gestation. This review discusses the detection of oxidative stress markers in biological fluids and highlights the need for further studies to validate their use in the prediction or diagnosis of pregnancy disorders.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Deoxyguanosine; Diabetes, Gestational; Female; Fetal Growth Retardation; Glycation End Products, Advanced; Humans; Lipoproteins, LDL; Oxidative Stress; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Protein Carbonylation; Tyrosine

Rats with a normal birth weight (NBW) or intra-uterine growth retardation (IUGR) were fed basic diets (NBW and IUGR groups) or basic diets supplemented with curcumin (NC and IC groups) from 6 to 12 weeks. The body weight of IUGR rats was lower (P<0·05) than that of the controls. Rats with IUGR showed higher (P<0·05) concentrations of TNF-α, IL-1β and IL-6; higher (P<0·05) activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in their serum; and increased (P<0·05) concentrations of malondialdehyde (MDA), protein carbonyl (PC) and 8-hydroxy-2'-deoxyguanosine (8-OHDG) in the liver compared with the NBW rats. The livers of IUGR rats exhibited a lower (P<0·05) superoxide dismutase activity and decreased (P<0·05) metabolic efficiency of the hepatic glutathione redox cycle compared with those of the NBW rats. In response to dietary curcumin supplementation, concentrations of inflammatory cytokines and activities of AST and ALT in the serum and MDA, PC and 8-OHDG in the liver were lower (P<0·05), and the hepatic glutathione redox cycle in the liver was improved (P<0·05) in the IC group than in the IUGR group. These results were associated with lower (P<0·05) phosphorylated levels of the NF-κB pathway and Janus kinase 2 (JAK2) and higher (P<0·05) mRNA expression of genes involved in the nuclear factor, erythroid 2-like 2 (Nfe2l2)/antioxidant response element (ARE) pathway in the liver of the IC rats than that of the IUGR rats. Maternal undernutrition decreased birth weight and led to inflammation, oxidative damage and injury in rats. Curcumin appeared to be beneficial in preventing IUGR-induced inflammation, oxidative damage and injury by activating the expression of the NF-κB, JAK/STAT and Nfe2l2/ARE pathways in the liver.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine Transaminase; Animals; Animals, Newborn; Aspartate Aminotransferases; ATP-Binding Cassette Transporters; Birth Weight; Caenorhabditis elegans Proteins; Curcumin; Cytokines; Deoxyguanosine; Dietary Supplements; Disease Models, Animal; Female; Fetal Growth Retardation; Gene Expression; Inflammation; Liver; Liver Diseases; Oxidation-Reduction; Oxidative Stress; Pregnancy; Rats

To estimate the levels of malondialdehyde (MDA) and 8-hydroxy-2-deoxyguanosine (8-OH-dG) in cord blood plasma of newborns born through meconium-stained amniotic fluid (MSAF) and also to find out the correlation between their levels with birth weight and gestation, we measured the cord blood plasma levels of MDA and 8-OH-dG in 59 newborns born through MSAF and 50 newborns born through clear liquor. The levels of cord blood plasma MDA and 8-OH-dG were significantly higher in full-term and late-preterm newborns born through MSAF. On further comparison, it was found that both full-term and late-preterm intrauterine growth restricted (IUGR) neonates had higher levels of these markers as compared to babies born as appropriate for gestational age (AGA) through MSAF. Plasma levels of MDA and 8-OH-dG were significantly correlated with birth weight even after controlling the relationship with gestational age for all cases as well as all full-term cases. These markers are also significantly correlated to each other.. The present study suggest that the neonates born through MSAF experience higher degrees of oxidative stress, as evidenced by increased levels of cord blood plasma MDA and 8-OH-dG. What is known: • Aspirated meconium has been found to induce free radical generation and cellular damage in animal studies. • Its role in free radical generation and oxidative damage in human neonates is scarce. What is new: • Neonates born through meconium-stained amniotic fluid experience significant oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Amniotic Fluid; Biomarkers; Birth Weight; Chi-Square Distribution; Cross-Sectional Studies; Delivery, Obstetric; Deoxyguanosine; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Malondialdehyde; Meconium; Oxidative Stress; Pregnancy

Oxidative stress is a key factor in the pathogenesis of intra-uterine growth restriction in singleton. However, its role in selective intra-uterine growth restriction (sIUGR) in monochorionic twins (MCT) is still unknown. This study explored the characteristics of oxidative stresses in the placenta shares of MCT and analyzed their possible connections with sIUGR.. The placental levels of hypoxia inducible factor-1α gene (HIF1A)mRNA, malondialdehyde (MDA), and 8-hydroxydeoxyguanosine (8-OHdG) were evaluated in normal MCT (Group A) and sIUGR MCT (Group B). The results were compared between the placental shares of the larger twins (A1/B1) and smaller twins (A2/B2).. Placental HIF1A mRNA level significantly increased in Group B. Particularly, HIF1A mRNA level was elevated in the placenta share of the growth-restricted fetus (B2) than the co-twin (B1) (P = 0.036). More discordant HIF1A mRNA level was detected in Group B than Group A with larger inter-twin difference (P = 0.021). The levels of MDA and 8-OHdG were significantly higher in B2 than B1 in sIUGR MCT (P < 0.05). Both the inter-twin differences of MDA and 8-OHdG were also significantly larger in Group B (P < 0.05), indicating that discordant oxidative stress existed in the placental shares of sIUGR pregnancies. Finally, MDA concentration was found inversely correlated with neonatal birth weight, in both sIUGR (r = -0.650, P = 0.022) and normal MCT (r = -0.632, P = 0.027) pregnancies.. The elevation of HIF1A mRNA, and MDA/8-OHdG levels in placenta shares of sIUGR MCT suggests that oxidative stress may be involved in the pathogenesis of sIUGR.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Birth Weight; Deoxyguanosine; Diseases in Twins; Female; Fetal Growth Retardation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Infant, Newborn; Infant, Small for Gestational Age; Lipid Peroxidation; Male; Malondialdehyde; Oxidative Stress; Placenta; Pregnancy; Pregnancy, Twin; RNA, Messenger; Up-Regulation

To investigate the relation between the severity of hypoxic changes and oxidative DNA damage in the placenta of early and late-onset preeclampic women and fetal growth restriction (FGR), serum parameters of oxidative stress, placental hypoxic change, and oxidative DNA damage were determined.. We examined 10 participants with uncomplicated pregnancies, 13 with early-onset and 12 with late-onset preeclampsia. Maternal and umbilical plasma derivatives of reactive oxygen metabolites (d-ROMs) were measured as markers of oxygen free radicals. Immunohistochemical analysis was performed to measure the proportion of placental trophoblast cell nuclei staining positive for 8-hydroxy-2'-deoxyguanosine (8-OHdG), redox factor-1 (ref-1), and hypoxia-induced factor-1α (HIF-1α), which are markers of oxidative DNA damage, repair functions, and hypoxia status, respectively.. 8-OHdG was higher in both preeclamptic groups, but significantly higher in the early-onset preeclamptic group. Ref-1 was higher in the late-onset preeclamptic group. HIF-1α was higher in both preeclamptic groups, with a tendency towards a higher in the early-onset preeclamptic group.. Our findings indicate that the severity of hypoxic changes and oxidative DNA damage are greater in the placenta of women with early-onset preeclampsia, and that the prolonged preeclamptic conditions may reduce placental blood flow, ultimately leading to FGR.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Cell Hypoxia; Deoxyguanosine; DNA Damage; DNA-(Apurinic or Apyrimidinic Site) Lyase; Female; Fetal Growth Retardation; Gestational Age; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Oxidation-Reduction; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Reactive Oxygen Species; Umbilical Arteries

Oxidative damage to placental DNA can result in negative pregnancy outcomes, including intrauterine growth restriction (IUGR) and low birth weight (LBW).. We investigated associations between the levels of 8-oxo-7,8-dihydro-2´-deoxyguanosine (8-oxodG), a marker of oxidative DNA damage, in placental DNA, exposure to air pollutants during pregnancy, genetic polymorphisms in 94 selected genes, and pregnancy outcomes.. We studied 891 newborns who were IUGR- or LBW-affected or normal weight and were born between 1994 and 1999 in the Czech Republic in two districts with different levels of air pollution.. We found nonsignificantly elevated 8-oxodG levels in the IUGR-affected group compared with the non-IUGR group (p = 0.055). Similarly, slightly elevated 8-oxodG levels were found in the LBW-affected group compared with the non-LBW group (p < 0.050). In univariate analyses, we identified single nucleotide polymorphisms associated with 8-oxodG levels, IUGR, and LBW. Exposure to particulate matter < 2.5 µm was associated with increased 8-oxodG levels in placental DNA and LBW. However, multivariate-adjusted logistic regression revealed that above-median 8-oxodG levels were the only factor significantly associated with IUGR [OR = 1.56; 95% confidence interval (CI), 1.07-2.37; p = 0.022]. Above-median levels of 8-oxodG were associated with LBW (OR = 1.88; 95% CI, 1.15-3.06; p = 0.011). Other variables associated with LBW included sex and gestational age of the newborn, maternal smoking, and haplotypes in the promoter region of the gene encoding mannose-binding lectin 2 (MBL2). The role of air pollutants in the risk of adverse pregnancy outcomes seemed to be less important.. Levels of 8-oxodG in placental DNA were associated with the risk of IUGR as well as LBW. Newborn's sex, gestational age, maternal smoking, and genetic polymorphisms in the promoter region of the MBL2 gene were associated with LBW incidence.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Case-Control Studies; Deoxyguanosine; DNA; Female; Fetal Growth Retardation; Humans; Infant, Low Birth Weight; Infant, Newborn; Particulate Matter; Pregnancy; Pregnancy Outcome

Preeclampsia is frequently accompanied by fetal growth restriction (FGR). Preeclampsia increases oxygen free radical production, and the resulting oxidative stress impairs placental blood flow. To determine whether placental oxidative stress is associated with FGR in preeclamptic women, we evaluated placental oxidative DNA damage and its repair in 13 preeclamptic women with FGR, 10 preeclamptic women without FGR, and 11 healthy pregnant women without complications. We measured maternal and umbilical serum derivatives of reactive oxygen metabolites (d-ROMs), as a marker of oxygen free radicals, and pulsatility index (PI) of uterine and umbilical arteries, and performed an immunohistochemical analysis to measure the proportion of nuclei in the placental trophoblast that stained positive for 8-hydroxy-2'-deoxyguanosin (8-OHdG), an indicator of oxidative DNA damage, and redox factor-1 (ref-1), indicative of the repair function towards oxidative DNA damage. D-ROMs were increased in the maternal blood of both preeclamptic groups (with FGR, 687.3 ± 50.4 CARR U, p < 0.01; without FGR, 750.4 ± 87.2 CARR U, p < 0.001) compared with controls (504.7 ± 25.0 CARR U). In contrast, d-ROM levels in the umbilical artery were elevated in preeclamptic women with FGR (134.9 ± 13.3 CARR U, p < 0.01), but not in preeclamptic women without FGR (44.0 ± 7.3 CARR U) compared with controls (38.2 ± 5.0 CARR U). Mean PI for uterine arteries was significantly increased in both preeclamptic groups, and the PI in preeclamptic women with FGR was significantly greater than that in women without FGR (0.94 ± 0.07 vs. 1.31 ± 0.07, p < 0.001). The PI for umbilical arteries was significantly increased in preeclamptic women with FGR (0.90 ± 0.05vs. 1.19 ± 0.07, p < 0.001), but not in preeclamptic women without FGR. The proportion of nuclei positive for 8-OHdG was higher in both groups of preeclamptic women than in the control group, but was higher in preeclamptic women with FGR (0.21 ± 0.05 vs. 0.87 ± 0.01, p < 0.001). The proportion of nuclei positive for ref-1 was higher in preeclamptic women without FGR (0.54 ± 0.06, p < 0.001) than in the control group, whereas the proportion did not differ significantly between normal and preeclamptic women with FGR. Our findings indicate that increased oxidative stress and disrupted compensatory reaction against placental oxidative DNA damage may be associated with FGR in preeclamptic women.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Case-Control Studies; Deoxyguanosine; DNA Damage; DNA-(Apurinic or Apyrimidinic Site) Lyase; Female; Fetal Blood; Fetal Growth Retardation; Free Radicals; Humans; Oxidative Stress; Oxygen; Placenta; Pre-Eclampsia; Pregnancy

The aim of this study was to investigate the influence of cigarette smoking on the pro/antioxidant balance in pregnant women with intrauterine growth restriction (IUGR). The studies have shown a 2-fold increase of Cd concentration in blood of women with IUGR in labour and a 10-fold increase in smoking pregnant women with IUGR. The increase of malondialdehyde concentration in plasma and 8-hydroxydeoxyguanosine in serum and Cu/Zn superoxide dismutase activity in erythrocyte lysate of pregnants with IUGR, reinforced by smoking, was revealed. We observed a decrease in the concentration of glutathione in blood and glutathione peroxidase activity in plasma and in erythrocyte lysate. A 4-fold higher metallothionein concentration in the plasma of women with IUGR in labour suggests that metallothionein may be one of the IUGR markers. Metallothionein concentration was intensified by smoking up to 7-fold in comparison to the controls. The pro/antioxidant balance during pregnancy is significantly affected by smoking.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Antioxidants; Cadmium; Copper; Cotinine; Deoxyguanosine; Environmental Pollutants; Female; Fetal Blood; Fetal Growth Retardation; Glutathione; Glutathione Peroxidase; Humans; Lead; Malondialdehyde; Metallothionein; Pregnancy; Smoking; Superoxide Dismutase; Young Adult; Zinc

Investigation of increased oxidative stress in early pregnancy and association with an increased risk of small-for-gestational-age (SGA) fetus.. Longitudinal case-control study.. University Hospitals of Leicester NHS Trust, Leicester, UK.. Low-risk pregnant women with no current or pre-existing medical illness were recruited at a large teaching hospital from 2004 to 2006.. Recruitment performed at the time of the dating ultrasound scan (12+/-2 weeks of gestation). Spot urine samples collected at 12+/-2 and 28+/-2 weeks of gestation were analysed for 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) by liquid chromatography with tandem mass spectrometry). SGA was defined as birthweight <10th centile based on customised centile calculator (www.gestation.net). This identified the cases (n=55), whereas controls (n=55) were mothers whose babies were appropriate for gestational age (AGA, birthweight 10th-90th centile). Statistical analysis was performed using GraphPad Prism v.5. The relationship between maternal urinary 8-oxodG at different gestations and customised SGA was investigated by nonparametric tests.. Customised SGA and AGA pregnancies.. Urinary 8-oxodG concentrations were significantly increased in pregnancies with subsequent SGA compared with concentrations in normal pregnancies; 12 weeks: 2.8 (interquartile range [IQR] 1.96-3.67) versus 2.2 (IQR 1.26-3.28) pmol 8-oxodG/micromol creatinine (P=0.0007); 28 weeks: 2.21 (IQR 1.67-3.14) versus 1.68 (IQR 1.16-2.82) pmol 8-oxodG/micromol creatinine (P<0.0002). Concentrations decreased significantly between week 12 and 28 (P=0.04 and P=0.02 for controls and cases).. In this study, urinary 8-oxodG at 12 and 28 weeks were elevated in SGA compared with AGA pregnancies. This may reflect early placental changes predating clinical features of SGA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Biomarkers; Birth Weight; Case-Control Studies; Cotinine; Deoxyguanosine; Female; Fetal Growth Retardation; Follow-Up Studies; Humans; Oxidative Stress; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Prospective Studies; Risk Assessment; Saliva; Smoking; Statistics, Nonparametric

We have previously demonstrated that melatonin protects against ischemia/reperfusion-induced oxidative damage to mitochondria in the fetal rat brain. The purpose of the present study was to evaluate the effects of maternally administered melatonin on ischemia/reperfusion-induced oxidative placental damage and fetal growth restriction in rats. The utero-ovarian arteries were occluded bilaterally for 30 min in rats on day 16 of pregnancy to induce fetal ischemia. Reperfusion was achieved by releasing the occlusion and restoring circulation. Melatonin solution (20 microg/mL) or the vehicle alone was administered orally during pregnancy. A sham operation was performed in control rats, which were treated with vehicle alone. Laparotomy was performed on day 20 of pregnancy and the number and weight of fetal rats and placentas were measured. Placental mitochondrial respiratory control index (RCI), a marker of mitochondrial respiratory activity, was also calculated for each group. Using immunohistochemistry, we investigated the degree of immunostaining of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and redox factor-1(ref-1), which repairs DNA damage and acts as a redox-modifying factor in rat placenta. Predictably, the ischemia/reperfusion operation significantly decreased the weight of fetal rats and placentas and the RCI. Melatonin prevented ischemia/reperfusion-induced changes in RCI (1.55 +/- 0.05 to 1.83 +/- 0.09, P < 0.05) and fetal growth (3.04 +/- 0.17 to 3.90 +/- 0.1, P < 0.0001). Immunohistochemistry revealed significant positive staining for 8-OHdG and ref-1 following ischemia/reperfusion; these effects were also reduced by melatonin treatment. Results indicated that ischemia/reperfusion-induced oxidative placental DNA and mitochondrial damage and fetal growth restriction can be prevented by maternally administered melatonin.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Deoxyguanosine; DNA Damage; DNA-(Apurinic or Apyrimidinic Site) Lyase; Female; Fetal Development; Fetal Growth Retardation; Immunohistochemistry; Melatonin; Mitochondria; Nitrosation; Oxidation-Reduction; Oxidative Stress; Placenta; Pregnancy; Rats; Reperfusion Injury

Recent evidence suggests that oxidative stress is involved in the pathophysiology of preeclampsia. Using immunohistochemistry and Western blotting, we investigated the oxidative stress- and redox-related molecules, such as 8-hydroxy-2'-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), thioredoxin (TRX) and redox factor-1 (ref-1) in the placenta in preeclampsia, intrauterine growth restriction (IUGR), preeclampsia + IUGR and in normal pregnancy. Using immunohistochemistry, the level of 8-OHdG was significantly higher in IUGR ( P=0.012) or preeclampsia + IUGR (P=0.0021) than in normal pregnancy, while TRX expression was significantly higher in preeclampsia (P=0.045), and ref-1 expression was significantly higher in preeclampsia (P=0.017), IUGR (P=0.016) and preeclampsia + IUGR (P=0.0038) than in normal pregnancy. The levels of 4-HNE did not differ significantly between either preeclampsia or IUGR and normal pregnancy. A significant positive correlation was observed between TRX and ref-1 expressions in both normal (rho=0.52) and complicated (rho=0.43) pregnancies. Using Western blotting, ref-1 expression tended to be higher in complicated pregnancies than in normal pregnancy (P=0.09). These results suggest that oxidative DNA damage is increased in IUGR and that redox function is enhanced in both preeclampsia and IUGR compared with normal pregnancy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Blotting, Western; Deoxyguanosine; DNA Damage; DNA-(Apurinic or Apyrimidinic Site) Lyase; Female; Fetal Growth Retardation; Gestational Age; Humans; Immunohistochemistry; Oxidation-Reduction; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Thioredoxins

Placental oxidative stress was suggested to play a role in the pathogenesis of pre-eclampsia (PE). In this study, levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), a well-established marker of oxidative DNA damage, were analysed in placental cellular DNA from normal (group NP) and pre-eclamptic (group PE) pregnancies as well as from PE pregnancies complicated by intrauterine growth restriction (group PE-IUGR). Placental samples obtained immediately after delivery were frozen at -80 degrees C until analysis. Cellular DNA was isolated, hydrolysed and analysed using high-performance liquid chromatography. Native nucleosides were monitored at 254 nm and 8-OH-dG using electrochemical detection. Concentrations of 8-OH-dG were expressed as micro mol/mol 2'-deoxyguanosine. In group NP, mean concentration of 8-OH-dG reached 179.97+/-80.58 (+/-SEM; micro mol/mol dG). 8-OH-dG levels were higher in group PE (273.44+/-110.14 micro mol/mol), but the difference was not significant in comparison with group NP. Highest concentrations of 8-OH-dG were found in group PE-IUGR (428.97+/-141.40 micro mol/mol), with levels significantly higher than in group NP, but not group PE. The results indicate a positive correlation between the severity of PE and the degree of oxidative stress and corroborate previous studies suggesting reactive oxygen species to be involved in the pathophysiology of PE.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; DNA Damage; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Oxidation-Reduction; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy

DNA is susceptible to oxidation and is constantly being damaged and repaired in living cells. The most abundant of the nucleoside oxidation products is 8-oxo-7,8 dihydro-2 deoxyguanosine (8 OH-dG). Our objective was to determine whether oxidative damage to DNA, as measured by 8 OH-dG, is increased with poor pregnancy outcome.. We utilized a case-control design to study oxidative damage to DNA during an ongoing prospective study. Cases (n = 18) included all women giving birth to a low-birth-weight (< 2500 g) or growth-restricted (< 10th centile) or preterm infant (< 37 completed weeks). Controls (n = 34) were selected at random from women with normal pregnancies. Urine samples were obtained early in the third trimester (28 +/- 2 weeks) and normalized to creatinine. Diet was assessed at three points during pregnancy.. Cases had significant (p < 0.05) increases in maternal urinary 8 OH-dG excretion at week 28, when all cases were considered and when cases were defined as those who delivered a low-birth-weight infant. 8OH-dG excretion, in turn, correlated positively with saturated fat in the maternal diet.. This study suggests that gravidas with poor pregnancy outcome have increased oxidative damage to their DNA early in the third trimester of pregnancy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Case-Control Studies; Deoxyguanosine; DNA Damage; Female; Fetal Growth Retardation; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Nutritional Physiological Phenomena; Oxidative Stress; Pregnancy; Pregnancy Outcome; Prospective Studies; Socioeconomic Factors; Urban Population