Oxidative stress and DNA damage in the mechanism of fetal alcohol spectrum disorders

Abstract

This review covers molecular mechanisms involving oxidative stress and DNA damage that may contribute to morphological and functional developmental disorders in animal models resulting from exposure to alcohol (ethanol, EtOH) in utero or in embryo culture. Components covered include: (a) a brief overview of EtOH metabolism and embryopathic mechanisms other than oxidative stress; (b) mechanisms within the embryo and fetal brain by which EtOH increases the formation of reactive oxygen species (ROS); (c) critical embryonic/fetal antioxidative enzymes and substrates that detoxify ROS; (d) mechanisms by which ROS can alter development, including ROS-mediated signal transduction and oxidative DNA damage, the latter of which leads to pathogenic genetic (mutations) and epigenetic changes; (e) pathways of DNA repair that mitigate the pathogenic effects of DNA damage; (f) related indirect mechanisms by which EtOH enhances risk, for example by enhancing the degradation of some DNA repair proteins; and, (g) embryonic/fetal pathways like NRF2 that regulate the levels of many of the above components. Particular attention is paid to studies in which chemical and/or genetic manipulation of the above mechanisms has been shown to alter the ability of EtOH to adversely affect development. Alterations in the above components are also discussed in terms of: (a) individual embryonic and fetal determinants of risk and (b) potential risk biomarkers and mitigating strategies. FASD risk is likely increased in progeny which/who are biochemically predisposed via genetic and/or environmental mechanisms, including enhanced pathways for ROS formation and/or deficient pathways for ROS detoxification or DNA repair.

Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin

“…A recent study confirmed that oxidative stress in ethanol-treated rats brings about damage to mitochondria (essential in regulation of apoptosis), and results in the production of intracellular reactive oxygen [58]. Our data confirm the involvement of oxidative stress, but the limitation of the study is a lack of data on apoptosis and autophagy-which are also mTOR dependent.…”

Effects of DNA Damage and Oxidative Stress in Human Bronchial Epithelial Cells Exposed to PM2.5 from Beijing, China, in Winter

“…The overproduction of ROS may attack and destroy various cellular macromolecules including DNA, proteins, peptides, and lipids [ 35 ]. It is well known that ROS are capable of interacting with DNA molecules to induce DNA strand breaks and cause oxidative DNA damage [ 36 ].…”

Impact of Alcohol Abuse on Susceptibility to Rare Neurodegenerative Diseases

“…Fetal alcohol exposure also impairs autophagy ( Girault et al, 2017 ), and activation of TLR4 is necessary to generate the neurodevelopment changes and behavioral symptoms of fetal alcohol exposure ( Shukla et al, 2018 ). These changes impact neuroinflammation ( Pascual et al, 2017 ; Noor and Milligan, 2018 ), oxidative stress ( Bhatia et al, 2019 ; Brocardo et al, 2011 ), and cognition. At the same time, fetal alcohol exposure has been shown to permanently disrupt the endogenous hypothalamus-pituitary-adrenal (HPA) rhythm mediating cyclic cortisol release, suggesting a long-term alteration in stress reactivity and signaling ( Ouellet-Morin et al, 2011 ).…”