The first presentation on FASD and Epigenetics in Ontario, Canada. Aboriginal FASD and CNP Workshop. Toronto, 6th March, 2013.

1. Aboriginal
FASD
and
CNP
Workshop
Toronto,
6th.
March,
2013
Barry
Stanley.
www.barrystanleyfasd.com

2. PRENATAL
–
ExisMng
or
Occurring
Before
Birth
Phenotype
-­‐
The
observable
physical
or
biochemical
characterisMcs
of
an
organism,
as
determined
by
both
geneMcs
and
environment
Diagnosis
–
The
idenMficaMon
of
the
nature
of
a
disease
or
injury
by
history,
examinaMon
and
laboratory
data.
Genotype
–
The
geneMc
makeup
of
an
organism
or
a
group
of
organisms.
GENETICS
–
The
study
of
heredity
and
the
variaMon
of
inherited
characterisMcs.
EPIGENETICS
–
The
study
of
changes
in
gene
funcMon
[expression]
That
do
not
involve
changes
in
DNA
sequence.
STEM
CELL
–
develop
into
specialized
cells
or
replenish
some
specialized
cells-­‐
can
replicate
[
reproduce]
indefiniMely.
PROGINATOR
CELL
-­‐
more
specialized-­‐
can
only
replicate
a
few
Mmes.
Nucleic
Acids
–
DNA
and
RNA
NucleoMdes
–
are
what
the
Nucleic
Acids
are
formed
from.
DEFINITIONS

3. ALCOHOL
-­‐use
–
12,000
Years
-­‐ NegaMve
effects
–individual
and
society.
Rare
references
to
effects
of
PAE
–
4,000
years,
unMl
the
last
300
years
GeneraMons
–
approx.
600
-­‐
12,000
years
200
–
4,000
years

4. 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

5. ALCOHOL
–
2013
Reflects
the
historical
perspecMve
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
sMll
largely
ignored
by
the
alcohol
research
community
the
medical
profession
and
governments.
Pubmed
-­‐
138,000
results
for
“publicaMons
on
alcohol”
-­‐
35,300
results
for
“publicaMons
on
alcoholism
-­‐
397
results
for
“publicaMons
on
Fetal
Alcohol
Spectrum
Disorder
-­‐
2,550
results
for
“publicaMons
on
Fetal
Alcohol
Syndrome”
-­‐
2,320
results
for
“publicaMons
on
Prenatal
Alcohol
Exposure”.
”

6. 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
nucleo@des.
Each
nucleo@de
contains
one
base,
one
phosphate
molecule
and
the
sugar
molecule
deoxyribose.
The
bases
in
DNA
nucleo@des
are
adenine,
thymine,
cytosine
and
guanine.
GeneMcs
–
D.N.A.

7. GeneMcs
–
R.N.A.
Ribonucleic
acid
[RNA]
is
a
ubiquitous
family
of
large
biological
Molecules
that
perform
mulMple
vital
roles
in
the
coding,
decoding,
RegulaMon,
and
expression
of
genes.
Together
with
DNA,
RNA
Comprises
the
nucleic
acids,
which
along
with
proteins,
consMtute
Three
major
macromolecules
essenMal
for
all
known
forms
of
life.

8. Increasing
awareness
of
the
Consequences
of
Prenatal
Alcohol
Exposure
• BEFORE
our
understanding
of
EpigeneMcs
• >
Clinical
presentaMon
and
Psychological
Assessments
• >
Gross
anatomy
and
imaging.
• >
Female
consumpMon
>
FASD
[FAS,
pFAS,
ARND]
• Now
with
our
understanding
of
EpigeneMcs
• >
Micro-­‐anatomy
and
advanced
imaging.
• >
Cellular
level
studies
–
animal
models
• >
GeneMcs
and
EpigeneMcs
• >
Female
and
Male
alcohol
consumpMon,
• present
and
previous
generaMons.

9. PLASTICITY
AND
SOME
OF
THE
REGIONS
OF
THE
BRAIN
EFFECTED
BY
PAE

10. Brain
Size
and
CorMcal
Thickness
and
the
Glial
Cell

11. Corpus
Callosum
Human brain
The corpus callosum, a nerve bundle connecting the two cerebral hemispheres, with the
lateral ventricles directly below
The two cer
connected by a
called the co
crosses the mi
the thalamus. T
smaller conn
commissure
commissure,
subcortical con
midline. The
main avenue

12. Amygdalae

13. Thalamus

14. Hypothalamus

15. Hypothalamic-­‐Pituitary-­‐Adrenal
Axis

16. Hippocampus

17. Prefrontal
Cortex

18. Cerebellum

19. Basal
Ganglia

20. Thymus

21. Cell
Structure,
FuncMon
and
Neurotransmifers
-­‐some
of
the
effects
of
PAE

22. MethylaMon,
AcetylaMon
leading
to

impaired
IGF
receptor
funcMon

glial
and
astrocyte
cell
dysfuncMon
>
impaired
neuron
migraMon

impaired
development
of
neurotransmifer
receptors

glucose
uptake
and
transport

suppression
of
anMoxidants
-­‐accumulaMon
of
free
radicles

impaired
cell
membrane
funcMon
>
calcium
ion
exchange

abnormal
protein
formaMon
>
ubiquitous
effects
on
brain
funcMon

reduced
proliferaMon
of
neural
progenitor
cells

abnormaliMes
of
endocrine
funcMon
and
neuroendocrine
regulaMon

impaired
immune
funcMon
and
stress
response
>
deficiencies
in
number
and
funcMon
of
white
blood
cells

cell
death
>
impaired
apoptosis
and
necrosis

23. Neurotransmifers,
Neuromodulator
Systems
and
Hormones
-­‐
DysregulaMon
of
Insulin
Growth
Factors
-­‐
NMDA
glutamate
receptors
>
synapMc
plasMcity
and
memory
systems
-­‐ GABA
[a,b,c]
gamma-­‐aminobutyric
acid
>
C.N.S.
inhibitory
[and
excitatory
during
development]
neurotransmifer
>
cell
membrane
funcMon
-­‐ -­‐
Reduced
Choline
Acetyltransferase
>
decreased
acetylcholine
>
Hippocampus
>
memory
–
Neuromodulator
>
plaMcity,
arousal,
reward,
sensory
percepMons
and
sustained
afenMon.
Hydroxylase
>
mood,
appeMte,
sleep,
memory,
learning
-­‐
Decreased
Dopamine
receptor
funcMon
>
reward
learning,
reward
seeking.
Decreased
levels
of
Dopamine
in
the
Prefrontal
Cortex.
-­‐
Hypothalamic-­‐Pituitary
Axis
>
differing
acMvaMon
>
stress
responsiveness.
Male/Female
differenMal
stress
responsiveness
>
protecMve
role
of
estrogens.
-­‐ InhibiMon
of
Serotonin
synthesis
and
expression
of
serotonin
precursor,
tryptophan

24. Neurotrophic
Factors
and
Adult
Neurogenesis
Proteins
that
control
the
development,
survival
and
funcMon
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.

25. FASD
and
COMORBIDITY
and
Diagnosis
AfenMon,
Mood
and
Personality
Disorders
AddicMons
Cancer
InfecMous
Diseases

26. EPIGENETICS
and
FASD

27. EPIGENETICS
and
FASD

28. EPIGENETICS
and
FASD

29. PreconcepMon
-­‐
paternal,
9
weeks
exposure
and
maternal
-­‐
10
weeks
exposure
PreimplantaMon
–
ferMlized
egg
>
implantaMon
>
first
two
weeks
of
pregnancy
-­‐
>
placenta
>
growth
retardaMon
GastrulaMon
–
3rd
to
8th
week
of
pregnancy
>
most
sensiMve
–
stem
cells
>
cellular
differenMaMon
–
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

30. Perinatal
AdaptaMon
–
fetal
suscepMbility
and
protecMon
 second
and
third
trimesters
–
 separate
from
early
embryogenesis
AdapMon
increases
fetus
survival
but
leads
to
adult
disease
–
through
the
epigeneMc
regulaMon
of
gene
expression
–
rheostat
effect,
rather
than
off/on
switch
effect.
Fetal
insults
–
anoxia,
nutriMonal
>
maternal
or
utero-­‐placental
insufficiency
>
Adult
metabolic
disorders,
cardiovascular
disease,
insulin
resistance
and
obesity.
 Consequently
the
later
effects
of
PAE
will
tend
to
vary
?

31. more
likely
to
be
mechanisMcally
important
in
the
epigeneMc
regulaMon
of
perinatal
adaptability.
CANDIDATE
GENES
AND
MARKERS

32. >
The
brain
is
a
complex
system
PAE
creates
a
complex
chaoMc
system
ManipulaMon
of
a
complex
system
by
a
simple
system
leads
to
unintended
consequences
The
more
complex
the
system
is
the
greater
the
unintended
consequences

33.  EpigeneMcs
explains
the
many
puzzling
and
contradictory
observaMons
about
FASD.
 The
brain
dysfuncMons
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
generaMons.

The
nomenclature
of
FASD
needs
to
be
changed
to
reflect
our
understanding
of
epigeneMcs
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
manipulaMon
of
gene
expression
will
result
in
harmful
unintended
consequences.
CONCLUSIONS