The Molecular Basis for the Link between Maternal Health and the Origin of Fetal Congenital Abnormalities: An Overview of Association with Oxidative Stress

Full text available

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the principal cause of early death in developing countries. The acceleration of the epidemic of early CVD is thought to include genetic factors as well as demographic factors such as lifestyle changes and nutritional transitions. CVD prevalence is a consequence of the interaction between the distribution of relative genotype frequencies and environmental exposures of a particular population. Although, the biological determinants of CVD and metabolic disorders in low and middle income countries are likely to be similar to those in affluent countries, the drivers of these determinants are likely to differ. In accordance with the developmental origin of health and disease (DOHaD) hypothesis adverse intrauterine influences such as poor maternal nutrition lead to impaired fetal growth, resulting in low birth weight, short birth length, and small head circumference. These adverse influences are postulated to also induce the fetus to develop adaptive metabolic and physiological responses. These responses, however, may lead to disordered reactions to environmental challenges as the child grows, with an increased risk of glucose intolerance, hypertension, and dyslipidaemia in later life and adult CVD as a consequence. This chapter discusses some of the possible links between programmed development and oxidative stress as one of the underlying mechanisms involved in the DOHaD phenomenon.

The effects of adult lifestyle and environmental chemicals are important factors affecting the fertility of men and women. Many studies have shown that nutritional and hormonal status during fetal development is decisive for long-term control of energy metabolism. Obesity, type 2 diabetes (T2D) and hypertension may take root during early development, throughout gestation and lactation, as stated in the “Developmental Origins of Health and Disease” (DOHaD) hypothesis. Recent data demonstrated that adult lifestyle factors can also impact the fertility of offspring. Among these factors, nutrition plays a major role. In humans, links between birthweight and fertility have been established, but little data on the relationship between maternal nutrition and fertility of offspring are yet available. In animals, studies have shown that both maternal undernutrition and maternal overnutrition can affect the reproductive function of offspring. Maternal nutrition can influence the development of the fetal reproductive system at all stages of development. Indeed, maternal body composition before conception may influence oocyte maturation. Preimplantation embryos are sensitive to environmental conditions that can affect future growth and developmental potential. Furthermore, embryogenesis, cellular differentiation, placentation and organ maturation can be affected by a wide range of mechanisms involved in metabolic programming. Maternal nutrition may affect circular and local concentrations of endogenous hormones that are essential during fetal development and may also affect oxidative balance with consequences on oocyte maturation, follicular steroidogenesis, implantation, embryo cell function and further development. Various exposures to altered maternal nutrition are associated with epigenetic modifications in the offspring, inducing long-term changes in gene expression, potentially leading to disease in later life and infertility. Finally, micronutrient unbalance, alcohol and tobacco exposure during gestation are known to have detrimental effects on offspring development and further studies are required to establish links with fertility. Whereas the role of the maternal environment has been so far mostly studied, it now becomes clearly evident from very recent work that metabolic effects can also be mediated through the paternal gametes.

Major physiological systems, such as the hypothalamic-pituitary-adrenal (hpa) axis, are susceptible to certain intrauterine exposures of the fetus. These exposures may lead to long-term programming, with potential consequences for the individual throughout life. One such exposure is the administration of synthetic glucocorticoids that are commonly used in different medical fields. This chapter focuses on fetal programming of hpa axis by synthetic glucocorticoids. It introduces the pharmacological and physiological background of this topic, summarizes major findings from human and animal studies, and addresses potential biological mechanisms and the clinical relevance of such programming. In humans, exposure to synthetic glucocorticoids in utero reduces fetal and, in some cases, postnatal hpa activity under basal conditions, and following stress. Data from animal studies indicate that lifelong hpa axis dysregulation, rather than either static hypoactivity or hyperactivity of hpa axis, is a common consequence of early exposure to synthetic glucocorticoids. The mechanisms of glucocorticoid-induced changes in hpa axis function are complex, including possible alterations at subcortical and cortical levels of the brain. Emerging evidence indicates that early dysregulation of hpa axis is adverse, possibly leading to compromised development and health in the short term. It is as yet unclear as to whether long-term health disturbances are to be expected. More randomized human follow-up studies are needed to better understand the short- and long-term effects of intrauterine exposure to synthetic glucocorticoids on hpa axis and potential short- and long-term consequences on health and development.

Epigenetics is a heritable transcriptional regulation mechanism independent of DNA sequence. Epigenetic transcriptional control is achieved by regulation of chromatin conformation. The molecular mechanisms of epigenetics include post-translational modifications of histone and DNA methylation. Histone acetylation is the mostly studied epigenetic regulation. Histone deacetylase (HDAC) deacetylates histones and induce chromatin condensation, which prevent the approach of transcriptional regulating proteins. Methylated DNA is recognized by methyl-CpG binding protein (MBD) which recruits HDAC to the methylated region. Epigenetic status is known to be affected by oxidative stress condition via altering metabolic pathway associated with methylation reaction, and epigenetic abnormality on the developmental stage can influence brain and mental development. These suggest that oxidative stress condition affects brain and mental development via altering epigenetic regulation. In some mental retardation, such as Rett syndrome (RTT) and fetal alcohol syndrome (FAS), patients show microcephaly which may be caused by glial growth abnormality. The responsible gene of RTT is one of the MBDs, MeCP2. We discovered that knock down of MeCP2 in astrocytes reduced the growth rate, and DNA methyltransferase (DNMT) and HDAC inhibitors also did the same. Thus, epigenetic dysregulation induced mental disorder may be, at least partly, caused by abnormality of glial cells.

Endothelial dysfunction as a consequence of a variety of common cardiovascular disease risk factors is thought to be associated with increased reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO). In this article we give a detailed discussion of evidence of the impact of oxidative-nitrosative stress during maternal pregnancy on fetal development in animal models and also the association with the onset of cardiovascular conditions in adult humans. We highlighted specifically the presence of ROS in circulating blood as the key intermediary related to vascular injury and organ dysfunction. In addition, the evidence that red blood cells regulate the arteriolar microcirculation, coupling oxygen delivery with blood flow, highlighting their role in NO bioavailability. The unique natures of relationship between cell-signalling, transcriptional mechanisms and oxidative-nitrosative stress in the progression of coronary heart disease have also been discussed in greater detail. We have also discussed the emerging concepts that pharmacological prevention of cardiovascular events in the future might consists of the control of classical risk factors with specific interventions targeting oxidative stress while simultaneously improving NO production.

Fetal and neonatal programming is a phenomenon produced by deviations from the normal development during prenatal or early postnatal life. These deviations can increase risk for different diseases later in life and are an example of phenotypic plasticity throughout the nature. For instance, infants born with low birth weight, as a marker of an unfavorable intrauterine environment, are programmed differently and face additional challenges in adulthood; thereby encountering more risks for coronary artery diseases, diabetes, hypertension, metabolic syndrome, imbalanced immune response, renal insufficiency, and suboptimal cognition. Advances in research in the last decade significantly improved the understanding of underlying mechanisms. Once these mechanisms are understood it is very tempting to implicate them into management. However, the risk and benefit of each new implication into clinical practice need to be considered carefully and evaluated by randomized controlled trials. This chapter will propose and discuss some of the possible clinical implications of fetal and neonatal programming which can lead to possible changes in current clinical management in reflection of latest knowledge on this topic.

Oxidative stress, occurring as a consequence of imbalance between the production of oxygen free radicals and inactivation of these species by antioxidant defense system, seems to play a pivotal role in the pathophysiology of several diseases. In fact, there are numerous cellular biochemical targets for oxidative stress, all susceptible to long-lasting dangerous effects, especially if they take place early during infancy. Therefore, it is fundamental to obtain data starting in prepuberty to fully explore the intriguing relationship between precocious impairment of the oxidant-antioxidant status and organic alterations, and to preserve prepubertal children to the tracking of disease from infancy to adulthood. Nowadays the identification of children with a highly altered oxidant-antioxidant status is possible through accurate analysis. Much work still needs to be done to offer appropriate treatments aiming to guarantee a good quality of life for the young patients.

Molecular mechanisms are increasingly being reported allowing a better understanding of the mother health and fetal metabolic abnormalities in pregnancies that are affected by diseases. Most aspects of cellular function are regulated by a tuned equilibrium between the ability of cells to synthesize oxidants and antioxidants, and preventing the formation or blocking the actions of antioxidants. Oxidative and nitrative stresses are causative agents in human pregnancy-related disorders, including preeclampsia, intrauterine growth restriction, pre-gestational and gestational diabetes and premature delivery. An equilibrium between abundance and/or activity of reactive oxygen (ROS) and nitrogen (RNS) derived species, and antioxidant and nitrative enzyme systems are crucial in gestation. Hydrogen peroxide and superoxide radicals as well as NADPH oxidase and nitric oxide synthases (NOS) play significant contributions to maintain this physiological equilibrium in the human fetoplacental endothelium. Alterations in this relationship lead to abnormal cell function, where the endothelium is one of the targeted cells affected by these pathological conditions. Thus, altered ROS and RNS production, i.e., over the physiological permitted levels, leads to altered endothelial function, a phenomenon associated with endothelial dysfunction in pregnancy diseases. This chapter briefly reviews general aspects of oxidative and nitrative stress in the vasculature in diseases of pregnancy, and a role to NADPH oxidase, NOS and adenosine is summarized.

Incidence of Type 2 diabetes mellitus (T2DM) is increasing worldwide. Diabetes during pregnancy, as adverse intrauterine environment, has been shown to induce long term effects and play a crucial role in developmental programming in offspring. In utero exposure to increased maternal blood glucose concentrations is associated with cardio-vascular alterations, including hypertension and increased risk for obesity and T2DM at adulthood. Early programming of later dysfunction and disease in offspring may result from a combination of mechanisms acting at organ, tissue, cellular and molecular levels. Impaired glucose-insulin metabolism programmed during the critical window of perinatal development may contribute to epigenetic changes in gene expression. This disadvantageous intrauterine environment has been recently emphasised by the role of genetic pathways and in particular, perinatal disturbance of the oxidative state. This chapter examines the epidemiologic and mechanistic issues involved in the developmental programming of long term consequences in offspring of diabetic mothers, with a particular focus on oxidative stress. It also emphasises the mechanisms of hypertension, obesity and insulin resistance. In that considerable concern and because maternal diabetes may be a contributor to the current worldwide epidemic of T2DM, interventions aimed at optimizing maternal blood glucose concentrations during pregnancy should significantly impact T2DM epidemiology.

Full text available