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New Emerging Team on Fetal Alcohol Syndrome:Oxidative Stress and Innovative Therapies

Leader: James F. Brien, Queen’s University

Canadian Institutes of Health Research

2BiomarkersB

Antioxidant Therapy

AOxidative Stress

C

CIHR NEW EMERGING TEAM ON FAS

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Rationale

FAS is a NATIONAL RESEARCH PRIORITY.Speech from the Throne, January 30, 2001

CIHR Initiative for New Emerging Teams of Scientists in Focused Research Areas, July 2001

Institute of Neurosciences, Mental Health & Addictionresearch focus on :

Neurodevelopment and Early Life Events including FAS

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BiomarkersB I II IVAI II

Oxidative Stress

C I IIIII IV

Basic Biomedical (I)

Health Services & Systems (III)

Applied Clinical (II)

Population Health (IV)

A to C represent the Research Objectives.I to IV denote the four CIHR “Pillars”:

CIHR NEW EMERGING TEAM ON FAS

Antioxidant Therapy

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Members of NET on FASAlan D. Bocking, obstetrics and maternal-fetal physiology,

University of Western Ontario;James F. Brien, basic developmental pharmacology &

toxicology, Queen’s University;Gideon Koren, pediatrics and clinical pharmacology &

toxicology, Hospital for Sick Children, Toronto;Stephen G. Matthews, developmental neuro-endocrinology,

University of Toronto;James N. Reynolds, developmental neuroscience, Queen’s University;Joanne Rovet, developmental neuropsychology, Hospital for Sick Children;Wendy J. Ungar, health economics and population health,

Hospital for Sick Children.

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Research Objectives

• To test the hypothesis that oxidative stress is an important mechanism of the brain injury of FAS;

• To identify and validate reliable biomarkers for fetal ethanol exposure at critical periods of vulnerability during gestation and for the magnitude of fetal ethanol exposure;

• To discover and develop innovative antioxidant treatment strategies for preventing or attenuating ethanol-induced oxidative stress in fetal life and decreasing its impact on brain function in postnatal life.

7FAS

Proposed Mechanisms of FAS

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Objective ATo determine whether oxidative stress is a mechanism

of the brain injury of FAS.

Definition of Oxidative StressOxygen radicals: highly reactive molecules generated

during cell metabolism.

Cell production

of O2 radicals

Cell degradation

of O2 radicals

Overabundance of O2 radicals/Oxidative Stress

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Proposed Mechanism of Brain Injury of FASMaternal Ingestion of Ethanol

Fetal Brain Exposure to Ethanol

Damage to Key Cell Molecules(DNA, Proteins, Membrane Phospholipids)

Fetal Brain Nerve Cell Death

Oxidative Stress / Increased Reactive Oxygen SpeciesH2O2 O2

– OH

Brain Injury of FAS

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Coronal Section of the Brain

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Measures of Oxidative Stress

Products of chemical reactionreactive oxygen + membrane

species phospholipids

2. Neuroimaging of brain:magnetic resonance imaging - structural changes.magnetic resonance spectroscopy - oxidative stress.

1. F2-isoprostanes:

lipid peroxidation

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Investigation of Occurrence of Oxidative Stress

1. Guinea pig study (fetus, neonate and juvenile) of key brain areas: F2-isoprostanes.

2. Human study of neonatal umbilical cord blood and amniotic fluid: F2-isoprostanes.

3. Study of FAS children: neuroimaging of brain for evidence of oxidative stress and relationship to structural changes.

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Objective B

To identify biochemical markers in meconium (first stool passed by neonate) as measure of: gestational time and magnitude of fetal ethanol exposure resulting from maternal drinking.

Fatty acid ethyl esters (FAEEs)(family of chemical compounds)

Products of enzymatic reactionFatty acids + Ethanol in in body alcoholic beverages

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Investigation of FAEEs as Biomarkers of Fetal Ethanol Exposure

1. Pregnant sheep study:identification of members of FAEEs family that constitute biomarkers of gestational time and magnitude of fetal ethanol exposure.

2. Human meconium lab study:validation of FAEEs as reliable biomarkers of fetal ethanol exposure.

3. Human meconium clinical study:elucidation of prevalence of alcohol consumption by pregnant women in Canada.

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Objective C

To determine therapeutic efficacy and cost-effectiveness of antioxidant therapy for prevention/attentuation of brain injury of FAS

Vitamin C + Vitamin E(pharmacological doses)

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Investigation of Antioxidant Therapy

1. Guinea pig study:evaluation of efficacy of vitamin C + vitamin E to prevent/attenuate brain injury produced by chronic fetal ethanol exposure.

2. Human study:evaluation of therapeutic efficacy and cost-effectiveness of vitamin C + vitamin E in preventing/attenuating brain injury of FAS.

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BiomarkersB I II IV

Prevention-Intervention

TrainingD

I IIIII IV

AI IIOxidative Stress

C I IIIII IV

Basic Biomedical (I)

Health Services & System s (III)

Applied Clinical (II)

Population Health (IV)

A to D represent the four Objectives.I to IV denote the four CIHR “Pillars”:

CIHR NEW EMERGING TEAM ON FAS

Antioxidant Therapy