The role of oxidative stress in congenital syndromes

Children born with various syndromes caused by genetic or acquired factors have been the focus of many clinical and research studies. It is important to both understand the underlying mechanism and ameliorate the condition when possible.

A recent Antioxidants review addresses the role of oxidative stress in genetic conditions such as trisomy 21 (Down syndrome, DS), Marfan syndrome (MFS), and fetal alcohol spectrum disorders (FASD). This information has the potential to support the development of more specific and effective preventative and/or therapeutic strategies in the future.

Study: The Impact of Oxidative Stress on Pediatrics Syndromes. Image Credit: SciePro / Shutterstock.com

Introduction

Oxidative stress refers to the state in which antioxidant activity is unable to buffer the activity of oxidizing species in the body. This is largely due to the overproduction of oxidizing species, including radical oxygen species (ROS); however, it could also arise due to low ROS levels as well.

Oxidizing species

ROS mediate a host of useful functions, including killing pathogens during inflammatory responses or regulating cardiovascular function and protein activation. However, when inadequately regulated by cellular antioxidants, ROS can cause tissue damage and organ dysfunction.

ROS include superoxide (O2^–), hydroxyl (OH^–), and hydrogen peroxide (H₂O₂). O2^– is the most stable and primary ROS from which the other two are derived. The most damaging ROS is OH^–, as it is capable of injuring DNA, proteins, lipids, and carbohydrates.

Superoxide anions are produced within the mitochondria by a misstep in the electron transport chain (ETC) that is responsible for the formation of the high-energy molecule adenosine triphosphate (ATP).

The production of O2^– during this process is more likely when the cell produces excess ATP, with subsequent reduction in ETC activity, or with stress-induced decoupling of some parts of the ETC. ROS may also arise from smoking, exposure to ozone or ionizing radiation, ultraviolet rays, and some heavy metals.

The effects of ROS production include DNA breaks and other types of damage that can lead to cancer, accelerated aging, neurodegenerative diseases, autoimmune conditions, or cardiovascular disease. Epigenetic changes that alter DNA repair may also occur.

Antioxidants

Antioxidants belong to enzymatic and non-enzymatic groups. Enzymatic antioxidants include superoxide dismutase (SOD) within the mitochondria, reducing superoxide ions, catalases, glutathione peroxidase (GTPx), and glutathione transferase (GSTs), among others. GTPx is well-known for its action in detoxifying lipid peroxides and breaking down H₂O₂ into two water molecules.

Non-enzymatic antioxidants include vitamin E or alfa-tocoferol, carotenoids, and vitamin C, which partners with vitamin E, resveratrol, and other plant polyphenols.

Pediatric syndromes

Several syndromes involve oxidative stress, including DS, MFS, FASD, Gaucher syndrome, ataxia-telengiectasia (AT), Fanconi’s anemia, autism spectrum disorders (ASD), and primitive immunodeficiencies (PIs).

FASD

FASD denotes a spectrum of cognitive and behavioral abnormalities in the neonate related to maternal alcohol use during pregnancy. Fetal alcohol syndrome (FAS) is the major cause of mental retardation worldwide and the primary cause of preventable neurodevelopmental abnormalities. As a result, alcohol at any dose is completely prohibited in pregnancy, pending the establishment of a safe minimum.

The mechanism of damage in FASD is the oxidative stress on the developing hippocampus that is triggered by alcohol. This is mediated by the inability of the fetus to efficiently metabolize over half of the maternally ingested alcohol.

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The resulting generation of ROS, in response to the overexpression of the enzymes NOX₂ and NOX₄, damages the brain, specifically because of its rich content of fatty acids, which is the ideal substrate for ROS activity.

Antioxidant therapy for women who drink during pregnancy might prevent such harmful effects, as suggested by several mouse experiments using vitamin E, vitamin C, astaxanthine, and omega-3 fatty acids.

AT

AT is a purely genetic syndrome with multiple clinical manifestations in the first 20 years of life. Of these, the most disabling are T-cell tumors and cerebellar ataxia. The pathology lies in the Ataxia Telangiectasia Mutated (ATM) gene, which is key to initiating DNA repair.

Like many other genetic disorders, many of the defects are also secondary to increased ROS activity through mitochondrial dysfunction and the upregulation of other ROS sources. Oxidized low-density lipoprotein (ox-LDL) is a trigger of immune cell-mediated inflammation and vascular changes with enhanced DNA fragmentation.

DS

In DS, the extra 21^st chromosome is the site of the key enzymatic antioxidant SOD-1, which converts superoxide to H₂O₂ for further metabolism to water by catalase or GTPx. The overexpression of SOD-1 by 50% in these patients, without a corresponding increase in the other two enzymes, could explain the accumulation of H₂O2 and resulting oxidative stress.

The Amyloid Beta A4 Precursor Protein is triplicated, thus leading to an excess of beta-amyloid (Aβ), which is characteristic of Alzheimer's disease (AD). DS is the leading cause of early-onset AD, which is linked to oxidative stress, as the latter prevents normal cellular elimination of abnormal proteins. The accumulation of Aβ aggregates could drive lipid peroxidation.

Several other proteins and transcription factors involved in regulating antioxidant responses have been reported to be affected in DS. The oxidative stress associated with these changes could account for the cognitive and intellectual disabilities associated with DS, as well as the heart anomalies often found in these children.

Antioxidant supplements and physical exercise might be helpful in limiting or improving the neurological manifestations of DS.

Other pediatric syndromes

With ASD, reduced brain antioxidant activity in the brain has been observed. Ongoing studies are investigating the extent to which therapy with exogenous antioxidants could help these patients.

Similar findings have been reported in many other genetic syndromes, such as the accumulation of toxic metabolites with resulting ROS production in Gaucher’s disease, as well as the overproduction of H₂O₂ and nitric oxide (NO) driven by the aneurysmal dilation of the aorta in MFS that leads to the overexpression of ROS-producing enzyme NOX₄ and SOD.

Conclusions

The current review reports that oxidative stress can mediate many anatomical and physiological abnormalities in several pediatric syndromic illnesses. While this is the primary cause of FASD, it is secondary to the disease condition in genetic syndromes.

Clinically, this shows how FASD is completely preventable by avoiding exposure to oxidative stress in pregnancy. In genetic pediatric syndromes, the accumulation of oxidizing species secondary to the dysregulation of multiple pathways could potentially be counteracted by the judicious supplementation of antioxidants.

Along with such supplements, the benefits of regular exercise and a healthy diet in terms of reducing oxidative stress should also be emphasized. Additional studies are needed to determine how clinicians can appropriately recommend these strategies to their patients.​​​​​​​

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.