New Emerging Team on Fetal Alcohol Syndrome:Oxidative Stress, Biomarkers and

Antioxidant Therapy

New Emerging Team on Fetal Alcohol Syndrome:Oxidative Stress, Biomarkers and

Antioxidant Therapy

Leader: James F. Brien, Queen’s UniversityLeader: James F. Brien, Queen’s University

Fetal Alcohol SyndromeFetal Alcohol Syndrome

• Growth deficiency• Facial characteristics• Brain injury (structural and functional)

Alcohol-Related Neurodevelopmental Disorder

Alcohol-Related Neurodevelopmental Disorder

• Brain injury (structural and functional)

Fetal Alcohol Spectrum DisorderFetal Alcohol Spectrum Disorder

• All-inclusive term for the different manifestations of alcohol-induced birth defects (teratogenic effects).

Coronal Section of the BrainCoronal Section of the Brain

Critical Periods of Human DevelopmentCritical Periods of Human Development

K.L. Moore. The Developing Human, Clinically Oriented Embryology (1988).

Biomarkers

B

Antioxidant Therapy

AOxidative Stress

C

CIHR NEW EMERGING TEAM ON FASCIHR NEW EMERGING TEAM ON FAS

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

University of Toronto

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

Research ObjectivesResearch Objectives

A. To test the hypothesis that oxidative stress is an important mechanism of the brain injury of FAS.

B. To identify and validate reliable biomarkers for fetal alcohol exposure at critical periods of vulnerability

during gestation and for the magnitude of fetal alcohol exposure.

C. To discover and develop innovative antioxidant treatment strategies for preventing or attenuating the brain injury of FAS.

Objective AObjective ATo determine whether oxidative stress is a mechanism of

the brain injury of FAS.

Definition of Oxidative StressDefinition 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

Proposed Mechanism of Brain Injury of FASProposed Mechanism of Brain Injury of FAS

Maternal Ingestion of Alcohol

Fetal Brain Exposure to Alcohol

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

Fetal Brain Nerve Cell Death

Oxidative Stress / Increased Reactive Oxygen Species

H2O2 O2– OH

Brain Injury of FAS

Depletion of Glutathione(a peptide that protects against Oxidative Stress)

G. Weaver, University of Colorado at Denver

Measures of Oxidative StressMeasures of Oxidative Stress

Products of chemical reaction:reactive oxygen + membrane

species phospholipids

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

2. F2-isoprostanes:

lipid peroxidation

8-iso-Prostaglandin F2

1. Glutathione (GSH):Small intracellular protein (peptide) localized in mitochondria (energy -producing organelles) and other sites within the cell.

Investigation of Occurrence of Oxidative StressInvestigation of Occurrence of Oxidative Stress

1. Guinea pig study (fetus and neonate) of key brain areas: GSH and 8-iso-PGF2.

Following chronic prenatal alcohol exposure:• Decreased mitochondrial GSH content in

fetal hippocampus (learning and memory).• No change in 8-iso-PGF2 content in fetal or neonatal

hippocampus or other key brain areas.

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

Objective BObjective B

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

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

Products of enzymatic reaction:Fatty acids + Ethanol in in body alcoholic beverages

FAEEs

Investigation of FAEEs as Biomarkers ofFetal Alcohol Exposure

Investigation of FAEEs as Biomarkers ofFetal Alcohol Exposure

1. Pregnant guinea pig study:identification of members of FAEEs family that constitute biomarkers of gestational time and magnitude of fetal alcohol exposure.

• FAEEs measurable in meconium of term fetus following chronic prenatal alcohol exposure.

• No measurable FAEEs in meconium of non-alcohol-exposed fetus.

• Five different FAEEs identified for chronic prenatal alcohol exposure; ethyl linoleate most common.

Investigation of FAEEs as Biomarkers ofFetal Alcohol Exposure

Investigation of FAEEs as Biomarkers ofFetal Alcohol Exposure

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

• 6x Increase in FAEEs in neonatal meconium for heavy prenatal alcohol exposure compared with control.

• Seven different FAEEs identified for prenatal alcohol exposure; four FAEEs most common, including ethyl linoleate.

Objective CObjective C

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

Vitamin C + Vitamin E(pharmacological doses)

Investigation of Antioxidant TherapyInvestigation of Antioxidant Therapy

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

2. Human studies:• evaluation of therapeutic efficacy and

cost-effectiveness of vitamin C + vitamin E in preventing/attenuating brain injury of FAS.

• investigation of determinants of recruitment and retention of pregnant alcohol-using women in preventative treatment.

Biomarkers

B

Antioxidant Therapy

Training

D

AOxidative Stress

C

CIHR NEW EMERGING TEAM ON FASCIHR NEW EMERGING TEAM ON FAS

2 PDF

3 PhD

3 MSc