Aboriginal FASD and CNP Workshop Toronto, 6th. March, 2013

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Aboriginal FASD and CNP WorkshopToronto, 6th.
March, 2013
Barry Stanley. www.barrystanleyfasd.com
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DEFINITIONS
PRENATAL Existing or Occurring Before
Birth Phenotype - The observable physical or
biochemical characteristics of an organism, as
determined by both genetics and
environment Diagnosis The identification of the
nature of a disease or injury by history,
examination and laboratory data. Genotype The
genetic makeup of an organism or a group of
organisms. GENETICS The study of heredity and
the variation of inherited characteristics. EPIGEN
ETICS The study of changes in gene function
expression That do not involve changes in DNA
sequence. STEM CELL develop into specialized
cells or replenish some specialized cells- can
replicate reproduce indefinitiely. PROGINATOR
CELL - more specialized- can only replicate a
few times. Nucleic Acids DNA and
RNA Nucleotides are what the Nucleic Acids are
formed from.


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• ALCOHOL
• -use 12,000 Years
• Negative effects individual and
• society.
• Rare references to effects
• of PAE 4,000 years, until
• the last 300 years

Generations approx. 600 - 12,000 years 200
4,000 years
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Epigenetcs, Alcohol and FASD

• Now is not the end. It is not even
• the beginning of the end. But it is,
• perhaps, the end of the beginning.
• Winston Churchill

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• ALCOHOL 2013
• Reflects the historical perspective
• Research on alcohol and alcohol related issues
• cost millions annually.
• all related to the developed brain.
• negligibly less on PAE exposure.
• the role of PAE still largely ignored by the
  alcohol research community the medical profession
  and governments.
• Pubmed
• - 138,000 results for publications
  on alcohol
• - 35,300 results for
  publications on alcoholism
• - 397 results for publications
  on Fetal Alcohol Spectrum Disorder
• - 2,550 results for
  publications on Fetal Alcohol Syndrome
• - 2,320 results for
  publications on Prenatal Alcohol Exposure.

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Genetics D.N.A.
DNA Structure The long, stringy DNA that makes up
genes is spooled within chromosomes inside the
nucleus of a cell. (Note that a gene would
actually be a much longer stretch of DNA than
what is shown here.) DNA consists of two long,
twisted chains made up of nucleotides. Each
nucleotide contains one base, one phosphate
molecule and the sugar molecule deoxyribose. The
bases in DNA nucleotides are adenine, thymine,
cytosine and guanine.
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Genetics R.N.A.
Ribonucleic acid RNA is a ubiquitous family of
large biological Molecules that perform multiple
vital roles in the coding, decoding, Regulation,
and expression of genes. Together with DNA, RNA
Comprises the nucleic acids, which along with
proteins, constitute Three major macromolecules
essential for all known forms of life.
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Increasing awareness of the Consequences of
Prenatal Alcohol Exposure

• BEFORE our understanding of Epigenetics
• gt Clinical presentation and Psychological
  Assessments
• gt Gross anatomy and imaging.
• gt Female consumption gt FASD FAS, pFAS, ARND
• Now with our understanding of Epigenetics
• gt Micro-anatomy and advanced imaging.
• gt Cellular level studies animal models
• gt Genetics and Epigenetics
• gt Female and Male alcohol consumption,
• present and previous generations.

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PLASTICITY AND SOME OF THE REGIONS OF THE
BRAIN EFFECTED BY PAE
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Brain Size and Cortical Thicknessand the Glial
Cell
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Corpus Callosum

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Amygdalae
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Thalamus
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Hypothalamus
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Hypothalamic-Pituitary-Adrenal Axis
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Hippocampus
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Prefrontal Cortex
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Cerebellum
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Basal Ganglia
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Thymus
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Cell Structure, Function andNeurotransmitters-s
ome of the effects of PAE
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Methylation, Acetylationleading to

• impaired IGF receptor function
• glial and astrocyte cell dysfunction gt
  impaired neuron migration
• impaired development of neurotransmitter
  receptors
• glucose uptake and transport
• suppression of antioxidants -accumulation of
  free radicles
• impaired cell membrane function gt calcium ion
  exchange
• abnormal protein formation gt ubiquitous effects
  on brain function
• reduced proliferation of neural progenitor cells
• abnormalities of endocrine function and
  neuroendocrine regulation
• impaired immune function and stress response gt
  deficiencies in number
• and function of white blood cells
• cell death gt impaired apoptosis and necrosis

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• Neurotransmitters, Neuromodulator Systems and
  Hormones
• - Dysregulation of Insulin Growth Factors
• - NMDA glutamate receptors gt synaptic plasticity
  and memory systems
• GABA a,b,c gamma-aminobutyric acid gt C.N.S.
  inhibitory and excitatory during development
  neurotransmitter gt cell membrane function
• - Reduced Choline Acetyltransferase gt decreased
  acetylcholine gt Hippocampus gt memory
  Neuromodulator gt platicity, arousal, reward,
  sensory perceptions and
• sustained attention.
• Hydroxylase gt mood, appetite, sleep, memory,
  learning
• - Decreased Dopamine receptor function gt reward
  learning, reward seeking. Decreased levels of
  Dopamine in the Prefrontal Cortex.
• - Hypothalamic-Pituitary Axis gt differing
  activation gt stress responsiveness. Male/Female
  differential stress responsiveness gt protective
  role of estrogens.
• Inhibition of Serotonin synthesis and expression
  of serotonin precursor, tryptophan

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Neurotrophic Factors and Adult Neurogenesis Pro
teins that control the development, survival and
function of nerve cells neurons They trigger
the development of neurons from progenitor cells
Neuronal progenitors persist in the adult brain,
but die. Neurotrophic factors might be used to
develop those cells for repair of damaged nerve
cells.
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FASD and COMORBIDITY and Diagnosis
Attention, Mood and Personality
Disorders Addictions Cancer Infectious Diseases
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EPIGENETICS and FASD
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EPIGENETICS and FASD
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EPIGENETICS and FASD
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Preconception - paternal, 9 weeks exposure and
maternal - 10 weeks exposure Preimplantation
fertilized egg gt implantation gt first two weeks
of pregnancy - gt placenta gt growth
retardation Gastrulation 3rd to 8th week of
pregnancy gt most sensitive stem cells gt
cellular differentiation birth defects.
transient exposure to alcohol during the
pre-implantation and early gastrulation periods
of development may have permanently altered gene
expression patterns in basic cell-signaling
pathways involved in limbic/ neuroendocrine
development, resulting in reprogramming of the
hypothalamic-pituitary-adrenal (HPA) axis and
stress- related autonomic and behavioral
reactivity in these infants. On/off switch effect

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• Perinatal Adaptation fetal susceptibility and
  protection
• second and third trimesters
• separate from early embryogenesis
• Adaption increases fetus survival but leads to
  adult disease through the
• epigenetic regulation of gene expression
  rheostat effect, rather than off/on
• switch effect.
• Fetal insults anoxia, nutritional gt maternal or
  utero-placental insufficiency
• gt Adult metabolic disorders, cardiovascular
  disease, insulin resistance and obesity.
• Consequently the later effects of PAE will tend
  to vary ?

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more likely to be mechanistically
important in the epigenetic regulation of
perinatal adaptability.
CANDIDATE GENES AND MARKERS

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gt The brain is a complex system PAE creates a
complex chaotic system Manipulation of a complex
system by a simple system leads to unintended
consequences The more complex the system is the
greater the unintended consequences
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• Epigenetics explains the many puzzling and
  contradictory observations about FASD.
• The brain dysfunctions of PAE are only part of
  the disease effect of PAE
• The factor of the mother drinking in a pregnancy
  no longer stands alone.
• The term prenatal for any given pregnancy has
  to include alcohol exposure from both parents,
  including previous generations.
• The nomenclature of FASD needs to be changed to
  reflect our understanding of epigenetics without
  diminishing acknowledgment and treatment of FASD,
  as occurs at present.
• Disorders of mood and personality need to be
  redefined in the context of environmental factors
  that cause changes in gene expression- alcohol
  being a major factor.
• Society needs to be aware that the manipulation
  of gene expression will result in harmful
  unintended consequences.

CONCLUSIONS