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

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New Emerging Team on Fetal Alcohol
SyndromeOxidative Stress and Innovative
Therapies
Leader James F. Brien, Queens University
Canadian Institutes of Health Research
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CIHR NEW EMERGING TEAM ON FAS
Antioxidant Therapy
C
B
A
Biomarkers
Oxidative Stress
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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
Addiction research focus on Neurodevelopment
and Early Life Events including FAS
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CIHR NEW EMERGING TEAM ON FAS
Antioxidant Therapy
C
I
III
II
IV
A to C represent the Research Objectives.
I to IV denote the four CIHR Pillars
Basic Biomedical (I)
Applied Clinical (II)
Health Services Systems (III)
Population Health (IV)
B
A
I
II
I
II
IV
Biomarkers
Oxidative Stress
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Members of NET on FAS
Alan D. Bocking, obstetrics and maternal-fetal
physiology, University of Western Ontario James
F. Brien, basic developmental pharmacology
toxicology, Queens 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,
Queens 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.

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Proposed Mechanisms of FAS
FAS
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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 of O2 radicals
Cell production of O2 radicals
Overabundance of O2 radicals/Oxidative Stress
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Proposed Mechanism of Brain Injury of FAS
Maternal Ingestion of Ethanol
Fetal Brain Exposure to Ethanol
Damage to Key Cell Molecules (DNA, Proteins,
Membrane Phospholipids)
Fetal Brain Nerve Cell Death
Brain Injury of FAS
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Coronal Section of the Brain
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Measures of Oxidative Stress
1. F2-isoprostanes
Products of chemical reaction reactive
oxygen membrane species
phospholipids
lipid peroxidation
2. Neuroimaging of brain magnetic resonance
imaging - structural changes. magnetic
resonance spectroscopy - oxidative stress.
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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
reaction Fatty 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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CIHR NEW EMERGING TEAM ON FAS
Antioxidant Therapy