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Oxidative Stress in Fetal Alcohol Spectrum Disorders – Insights for the Development of Antioxidant-Based Therapies

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Systems Biology of Free Radicals and Antioxidants

Abstract

Alcohol consumption during pregnancy can have severe consequences for the developing fetus, and depending on the pattern of consumption, the dose, and the period of exposure to alcohol, a myriad of functional deficits can be observed. These are grouped under the umbrella term fetal alcohol spectrum disorders (FASD) and can range from subtle behavioral abnormalities to severe cases of fetal alcohol syndrome (FAS). The mechanisms responsible for the long-lasting effects of alcohol exposure are just now beginning to be clarified, and alterations in various intracellular pathways and neuronal circuits are thought to contribute for the neuroanatomical and functional deficits that have been observed in children affected with FASD. Among these, the alcohol-induced generation of reactive oxygen and nitrogen species (ROS and RNS, respectively) and the consequent oxidative damage to lipids, proteins, and DNA are thought to contribute to these deficits. In this chapter, we will review the evidence supporting the involvement of oxidative stress in FASD, giving particular relevance to the pathways of alcohol-induced ROS generation. Given the overwhelming evidence pointing toward the involvement of oxidative stress in the neuropathology of FASD, various in vivo and in vitro studies have been devised in order to test the potential beneficial effects of antioxidant treatment in mitigating the effects of alcohol-induced neurotoxicity. Thus, in this chapter we will also review the evidence indicating that antioxidants such as vitamin E, silymarin, and melatonin can be potential therapeutic candidates for the treatment of some of the functional and behavioral deficits that can be observed in both rodent models of FASD and children afflicted with these neurodevelopmental disorders.

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Abbreviations

ARBD:

Alcohol-related birth defects

ARND:

Alcohol-related neurological disorders

BAC:

Blood alcohol concentration

BBB:

Blood-brain barrier

BDNF:

Brain-derived neurotrophic factor

CAT:

Catalase

CNS:

Central nervous system

FAS:

Fetal alcohol syndrome

FASD:

Fetal alcohol spectrum disorders

GD:

Gestational day

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSH:

Reduced glutathione

GSSG:

Glutathione disulfide (oxidized glutathione)

GST:

Glutathione-S-transferase

H2O2 :

Hydrogen peroxide

HO• :

Hydroxyl radical

NADPH:

Reduced nicotinamide adenosine dinucleotide phosphate

NO• :

Nitric oxide

NOX:

NADPH-oxidase

NT-3:

Neurotrophin-3

O2 •− :

Superoxide anion

ONOO-:

Peroxinitrite

PND:

Postnatal day

PNEE:

Prenatal ethanol exposure

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TNF-α:

Tumor necrosis factor-α, γ-GCSyn, γ-glutamyl-cysteine synthetase

γ-GTP:

γ-glutamyltranspeptidase

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Acknowledgments

A.P. is funded by a Graduate Award from the University of Victoria and a Pacific Century Scholarship. P.S.B. was supported by a postdoctoral fellowship from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)- Program Science without Borders. J.G.M. acknowledges postdoctoral funding from Natural Sciences and Engineering Research Council of Canada (NSERC) and Michael Smith Foundation for Health Research (MSFHR). B.R.C. is a Michael Smith Senior Scholar and is supported by grants from the Canadian Institutes of Health Research (CIHR), NSERC, MSFHR, and the Canada Foundation for Innovation (CFI).

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Authors and Affiliations

  1. Division of Medical Sciences, Island Medical Program, University of Victoria, Victoria, BC, Canada

    Anna Patten, Patricia S. Brocardo, Joana Gil-Mohapel & Brian R. Christie

  2. Department of Biology, University of Victoria, Victoria, BC, Canada

    Anna Patten & Brian R. Christie

  3. Brain Research Centre and Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada

    Brian R. Christie

  4. Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada

    Brian R. Christie

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  1. Anna Patten
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  2. Patricia S. Brocardo
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  3. Joana Gil-Mohapel
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  4. Brian R. Christie
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Correspondence to Brian R. Christie .

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  1. Department of Pharmacology and Therapeutics, University of British Colombia, Vancouver, British Columbia, Canada

    Ismail Laher

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Patten, A., Brocardo, P.S., Gil-Mohapel, J., Christie, B.R. (2014). Oxidative Stress in Fetal Alcohol Spectrum Disorders – Insights for the Development of Antioxidant-Based Therapies. In: Laher, I. (eds) Systems Biology of Free Radicals and Antioxidants. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30018-9_37

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