New Emerging Team on Fetal Alcohol Syndrome:
Oxidative Stress, Biomarkers and
Antioxidant Therapy
Leader: James F. Brien, Queen’s University
Fetal Alcohol Syndrome
• Growth deficiency
• Facial characteristics
• Brain injury (structural and functional)
Alcohol-Related Neurodevelopmental
Disorder
• Brain injury (structural and functional)
Fetal Alcohol Spectrum Disorder
• All-inclusive term for the different manifestations of
alcohol-induced birth defects (teratogenic effects).
Coronal Section of the Brain
Critical Periods of Human Development
K.L. Moore. The Developing Human, Clinically Oriented Embryology (1988).
CIHR NEW EMERGING TEAM ON FAS
Antioxidant Therapy
C
A
Oxidative Stress
B
Biomarkers
Members of NET on FAS
Alan 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 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 A
To determine whether oxidative stress is a mechanism of
the brain injury of FAS.
Definition of Oxidative Stress
Oxygen radicals: highly reactive molecules generated
during cell metabolism.
Cell
degradation
Cell
of O2
production
radicals
of O2
radicals
Overabundance of O2 radicals/Oxidative Stress
Proposed Mechanism of Brain Injury of FAS
Maternal Ingestion of Alcohol
Fetal Brain Exposure to Alcohol
Oxidative Stress / Increased Reactive Oxygen Species
H2O2 O2– OH
Depletion of Glutathione
(a peptide that protects against Oxidative Stress)
Damage to Key Cell Macromolecules
(DNA, Proteins, Membrane Phospholipids)
Fetal Brain Nerve Cell Death
Brain Injury of FAS
G. Weaver, University of Colorado at Denver
Measures of Oxidative Stress
1. Glutathione (GSH):
Small intracellular protein (peptide) localized in mitochondria
(energy -producing organelles) and other sites within the cell.
2. F2-isoprostanes:
Products of chemical reaction:
reactive oxygen + membrane
species
phospholipids
lipid peroxidation
8-iso-Prostaglandin F2
3. Neuroimaging of brain:
magnetic resonance imaging - structural changes.
magnetic resonance spectroscopy - oxidative stress.
Investigation 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 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 of
Fetal 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-alcoholexposed fetus.
• Five different FAEEs identified for chronic prenatal
alcohol exposure; ethyl linoleate most common.
Investigation of FAEEs as Biomarkers of
Fetal 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 C
To determine therapeutic efficacy and costeffectiveness of antioxidant therapy for
prevention/attenuation of brain injury of FAS.
Vitamin C + Vitamin E
(pharmacological doses)
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 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.
CIHR NEW EMERGING TEAM ON FAS
Antioxidant Therapy
C
D
Training
2 PDF
3 PhD
3 MSc
A
B
Oxidative Stress
Biomarkers