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Dr. Wargowski: Welcome. This is the fourth
in a series of podcasts on fetal alcohol spectrum
disorders presented by the Great Lakes FASD
Regional
Training Center through a grant from the CDC.
My name
is David Wargowski. This podcast is titled
biological
effects of alcohol on the developing embryo
and fetus.
The first consideration in regard to the
effects of alcohol on the developing embryo
and
fetus is how alcohol is distributed within
the body
once it's consumed. Alcohol, as many of you
are
aware, is a solvent, a nearly universal solvent
and
can pass through both water compartments and
lipid
compartments very easily. It's also one of
only
two compounds that is rapidly absorbed directly
through the stomach and so it is readily
distributed throughout most areas of the body,
enters water compartments and tissue very
quickly
and passes through cell membranes somewhat
less
quickly, but still much more rapidly than
many
other compounds. Alcohol metabolism primarily
occurs in the liver. It's a fairly simple
enzymatic pathway that occurs at a predictable
rate
and so it can be mathematically estimated.
There
is a small amount of alcohol metabolism that
occurs
in the kidneys with subsequent elimination
in the
urine and some alcohol is expired through
the lungs
which facilitates the use of breathalyzers.
But
again the vast majority of it occurs in the
liver,
it's a two step enzymatic pathway, it's a
first
time alcohol dehydrogenase or ADH, converts
alcohol
to acid aldehyde, the second enzyme, ALDH
or acid
aldehyde dehydrogenase converts acid aldehyde
to
carbon dioxide and water. Variants in the
enzyme
activities can contribute to blood alcohol
concentration and also determine the blood
acid
aldehyde concentration. Acid aldehyde is
responsible for some of the unpleasant effects
of
alcohol intoxication including nausea and
flushing.
Variance in enzyme activity are, in part,
determined by variations in the genes that
produce
the enzymes. So there is, at least, some
theoretical basis for genetic contributions
to
variations in alcohol sensitivity. We can't
talk
about alcohol exposure to the developing embryo
and
fetus without mentioning what is known about
alcohol metabolism in women. We do know, from
observation, that there are variations in
alcohol
metabolism between men and women. Women tend
to
achieve higher blood alcohol content with
the same
level of alcohol use compared to men, partly
because body water volume is smaller than
that of
men and also because women, as a group, tend
to
have higher rates of alcohol absorption from
the
stomach than men. Alcohol exposure on the
brain
has affects on the structure and several aspects
of
the brain function. We know that from observation
that prenatal alcohol exposure can have effects
on
any region or all regions of the brain. MRI
and
other imaging technologies have allowed
visualization of some of these effects, most
notable, is overall reduction in the brain
size
among individuals with alcohol exposure.
Particular structures that show demonstrable
effects of alcohol exposure include the corpus
callosum, cerebellum, and vasoganglia. In
this
series of MRI images, we can make comparisons
between the corpus callosum in exposed and
unexposed individuals. In the image on left
there
is a nice white arc of normal appearing corpus
callosum tissue. In the middle image, we see
disruption of the corpus callosum with an
incomplete formation of that structure, and
then
the image on the right, there is very little
developed corpus callosum tissue visible.
The
other finding to note on these images is the
size
of the cranium relative to the face is much
smaller
in the images from the exposed individuals
than in
the unexposed individual on the left. This
is a
result of the overall reduction and brain
volume.
Facial effects that allow us to identify
characteristics that help in the diagnosis
are
likely to be secondary to effects on the developing
brain, at least in part. This is because the
developing forebrain induces several processes
involved in normal development of the midline
facial structures. Also, eyes develop primarily
as
outgrowths of the developing brain, so it
makes
sense that if the brain volume is reduced
as a
result of alcohol exposure that the eye volume
would also be reduced, and the way we see
that
manifest on an exam of a individual's face
is in
the form of small palpebral fissures. Alcohol
is
nearly unique as a teratogen in the respect
that it
can cause problems by exposure throughout
gestation. There are multiple periods of
sensitivity to alcohol exposure. Early in
embryonic life, which is the first two weeks
or so
after conception, alcohol exposure can lead
to loss
of the embryo, but it is very unlikely that
alcohol
exposure, at that time, would lead to the
birth of
a child with manifestations of prenatal alcohol
exposure. Exposure later, but still in the
first
trimester, during the period of organogenesis,
roughly three to nine weeks after conception,
is
the period of time during which exposures
are most
likely to lead to significant congenital anomalies
including the facial structures that we recognize
in individuals with fetal alcohol syndrome
but also
congenital anomalies to the brain, heart,
eyes,
pallet and limbs. Later exposures during the
second and third trimesters are less likely
to lead
to these types of congenital structural
abnormalities except in the brain because
brain
development continues during this time and
it
remains vulnerable to the effects of alcohol
exposure. These effects primarily manifest
themselves in growth impairment and cognitive
and
behavioral problems, which for most families
taking
care of individuals with effects of prenatal
alcohol exposure, are among the most significant
challenges that they face. When we look at
the
cellular biology of effects of prenatal alcohol
exposure, we can identify several important
processes that are disrupted by these effects.
Neurogenesis, the original formation of nerve
cells, can be interrupted, growth and
differentiation of neurons is affected in
a number
of ways, migration of neurons to their proper
location within the cerebral architecture
is also
impaired, this process is very important to
the
normal development of intercellular connections
and
cellular relationships within the brain and
has
significant functional implications. Alcohol
exposure can also disrupt the formation of
synapses, the normal communication channels
between
nerve cells, and also alters the process of
apoptosis or programmed cell death which is
important for the normal structural and functional
development of the brain. The brain is also
unique
in its ability to adapt to abnormalities in
its
development as regions take up the function
of
other regions that are not developing properly.
This plasticity or adaptability is also impaired
by
the effects of prenatal alcohol exposure.
In
addition to the structural effects, we know
that
alcohol can have affects on several other
functional and neurochemical processes including
neurotransmitter production and function.
The most
demonstrable effects are on neurotransmitter
receptors. Alcohol exposure prenatally makes
the
receptors more sensitive to neurotransmitters
especially those involved in excitation. Cells
that contain neurotransmitter receptors also
seem
to be particularly sensitive to alcohol in
terms of
increased cell death, and we also see altered
cellular responses to neurotransmitters in
cells
that have been exposed to alcohol during brain
development. Within the cells, there are complex
signaling pathways that are important for
normal
neuronal responses to neurotransmitters and
also to
cell processing of the messages that
neurotransmitters deliver and many of these
processes within cells are also disrupted
after
prenatal exposure to alcohol. All of these
processes result in a number of effects on
cognitive development and behavior that are
manifest in individuals who are affected by
prenatal alcohol exposure. Cognitive development
is impaired, often resulting in intellectual
disability. In fact, there has been some dose
response relationships developed in regard
to this
particular effect of prenatal alcohol exposure.
A
wide range of psychiatric and behavioral problems
also result, particularly difficulties with
social
interaction and executive functioning. For
more
information on the biological effects of prenatal
alcohol exposure, contact the Great Lakes
FASD
Regional Training Center at the number or
address
on the slide. If you're outside the great
lakes
region, the link on this slide will connect
you to
a list of other regional training centers
and allow
you to identify the center closest to you.
Thank
you.
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