Elsevier

Reproductive Toxicology

Volume 53, June 2015, Pages 10-14
Reproductive Toxicology

Major differences in the levels of redox status and antioxidant defence markers in the erythrocytes of pre- and full-term neonates with intrauterine growth restriction

https://doi.org/10.1016/j.reprotox.2015.02.008Get rights and content

Highlights

  • We examine changes in the level of free radicals and antioxidants in human neonates.

  • Mature and pre-mature neonates with intrauterine growth restriction are compared.

  • Metallothioneins are good candidates to characterize intrauterine growth restriction.

  • Hemoxigenases are good candidates to characterize intrauterine growth restriction.

Abstract

Intrauterine growth restriction (IUGR) is a pleiotropic complication of pregnancy. Prematurity and growth abnormalities are common risk factors for perinatal morbidity and mortality. Free radical damage has been recognized as a common pathogenic mechanism of many neonatal diseases. The aim of the present study was to characterize the possible links between the level of maturity, the birthweight and the antioxidant status of neonates born with IUGR. Our data suggest that the stress markers measured on the cord blood of neonates with IUGR and mature, healthy neonates do not necessarily reflect the extent of oxidative stress. However, significant correlations were found between the maturity of the neonates with IUGR and the oxidative damage. The mature IUGRs exhibited ONOO accumulation and increased lipid peroxidation more frequently as compared with the pre-term group. The results suggest that the oxidative injury in IUGR may depend on the level of maturity and the birthweight.

Introduction

Pregnancy is a physiological state associated with an enhanced metabolism and an increased demand for oxygen. Premature infants are at particular risk from oxidative stress, as neither the endogenous nor the passively acquired exogenous antioxidant defence system accelerates in maturation until late in the third trimester [1], [2]. Intrauterine growth restriction (IUGR) is one of the major complications of pregnancy and accounts for significant neonatal mortality and morbidity [3]. The development of IUGR may be a consequence of various factors, including an abnormal fetomaternal blood circulation, genetic disorders, pregnancy-induced hypertension, pregestational diabetes, a lean umbilical cord, previous intrauterine infections, a poor nutritional state of the mother, frequent cigarette smoking [4] and toxin or drug exposure [5]. However, in the vast majority of the cases the cause remains idiopathic.

IUGR is often complicated by intrauterine hypoxia and may induce the generation of reactive oxygen species (ROS) and foetal oxidative stress, resulting in serious consequences for the foetus, such as low birthweight and prematurity [6]. Neonates with IUGR are more susceptible to ROS-induced oxidative damage because their enzymatic and non-enzymatic antioxidant defence systems and the ability to undergo induction during a hyperoxic challenge are impaired [7].

To eliminate the harmful effects of ROS, cells are equipped with an efficient antioxidant defence system, including enzymes such as superoxide dismutase (SOD), catalase (CAT), hemeoxygenases (HOs), and low-molecular weight antioxidants such as glutathione (GSH) and metallothioneins (MTs) [8], [9]. SOD catalyses the reduction of the superoxide anion (O2̇−) to hydrogen peroxide (H2O2). In a subsequent step, CAT stimulates the degradation of H2O2 to molecular oxygen and water [10]. The MTs are small proteins with unusually high cysteine content. This confers their high metal-binding and ROS-reducing properties [11]. The HOs play roles in heme degradation, yielding equimolar quantities of biliverdin, carbon monoxide (CO) with important free radical-scavenging properties and free Fe ions. In mature neonates, a considerable proportion of the plasma total antioxidant capacity originates from bilirubin [12]. HO-2 is a constitutive, and HO-1 an inducible isoform of HO, an antioxidative, anti-inflammatory and cytoprotective enzyme that is induced in response to cellular stress, including oxidative stress [13].

Nitric oxide (NO) may be an important factor for the regulation of blood pressure and oxygen delivery to the foetus [14]. Umbilical cord blood vessels lack innervations, and endothelial cells must therefore play a major role in the local control of blood flow [15]. NO derived from endothelial nitric oxide synthase (eNOS) is considered the main vasodilator agent in fetoplacental vessels [16]. The simultaneous generation of NO and O2̇− in sufficiently high concentrations in the same compartment favours the production of a toxic reaction product, peroxynitrite anion (ONOO). ONOO and other reactive nitrogen species can affect the cell functions through the oxidation or nitration of various cellular targets [17].

Under stress conditions, genes coding for molecules involved in biological defence and cellular repair are markedly upregulated, and the changes in gene expression can be characteristic, sensitive and measurable endpoints [18]. Members of this antioxidant defence system are useful biomarkers of the oxidant–antioxidant status of neonates with IUGR. The aim of the present study was to characterize the possible links between the level of maturity, the birthweight and the antioxidant status of neonates born with IUGR. We report data on macromolecular damage, the accumulation of powerful oxidants such ONOO, H2O2, the activities of the antioxidant enzymes SOD and CAT, and the expressions of a set of genes coding for members of antioxidant defence system (sod1, sod2, cat, mt-1, mt-2, ho-1, ho-2 and enos) from the aspects of the level of maturity and the birthweight of neonates with IUGR.

Section snippets

Human subjects

The blood samples were obtained from the Department of Obstetrics and Gynaecology at the University of Szeged, Hungary. The Ethics Committee of the Department of Obstetrics and Gynaecology approved the study protocol (149/2012). 24 mature neonates with normal weight and 28 mature and 28 premature neonates with IUGR of either sex were examined. The neonates were considered premature if they were born before the gestational age of 37 weeks and full-term if the delivery occurred after 37 weeks.

Comparative studies of mature, healthy neonates and neonates with IUGR

The levels of oxidant molecules (H2O2 and ONOO) and thiobarbituric acid-reactive substances (TBARS) and the activity of the H2O2-degrading CAT did not differ significantly between the IUGR and control groups (Fig. 1).

As concerns the mRNA levels of genes coding for antioxidant molecules, significantly lower amounts were measured for cat (∼20%), ho-1 (∼40%) and ho-2 (∼50%) in the IUGR group than in the controls. The mt-2 mRNA level was approximately 1.5-fold higher in the neonates with IUGR than

Discussion

Since IUGR is postulated to be a pleiotropic complication of pregnancy, the identification of unit marker molecules or reaction pathways connected with this disorder poses a number of difficulties. Various studies have focused on the antioxidant status of IUGR or premature neonates, but only brief accounts have been given as concerns the comparison of premature and full-term neonates with IUGR from any aspect. The major finding of the present study is the importance of the age-based grouping of

Conclusions

Our data furnish evidence that there is extreme heterogeneity in ROS production and in the activation of the antioxidant defence system within neonates with IUGR, which is blunted by the use of mean measurements. Intergrouping based on gestational age and birthweight, yielded evidence that the molecular results in the pre-term IUGR group were often similar to those for the mature, appropriate-for-age neonates. However, the background of the IUGR phenotype is pleiotropic, and measurements of

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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