fetal alcohol spectrum disorder this is
going to be the topic for today's
episode of SCI talks 2.0 I will be
interviewing two prominent scientists to
talk about their research on how
exposure to alcohol during pregnancy
could impact the development and growth
of the brain so stay tuned for an
exciting and informative interview
hello and welcome everybody to another
exciting episode of cytotoxicity point
now as always my name is dr. Jack
16-yard and today I'm excited to have
two very wonderful guests to talk to us
about an important topic related to
fetal alcohol syndrome disorders I will
allow them to introduce themselves and
then we'll get on with the topic of our
discussion so with that please introduce
yourselves dr. Kelly Hoffman and dr.
Olga Kazan Ian hi I'm dr. Kelly Hoffman
and I'm a professor in psychology and
environments at the University of
California Riverside and I study in my
laboratory fetal alcohol spectrum
disorders in mice and we use so we use a
rodent model to look at molecular brain
development and behavioral development
in our model of fetal octo-pete about
which is present in humans after
maternal consumption during pregnancy
okay hello so my name is Olga Kazan Ian
and I actually received my PhD from dr.
Kelly Hoffman's laboratory so on my
training my doctoral training was done
in Kelly's lab so my dissertation was
pretty much on fetal alcohol syndrome
disorders I'm currently a postdoctoral
fellow and at Scripps Research in La
Jolla and the Weiss lab and I study
alcohol addiction and relapse all right
wonderful so as you guys both have a
very strong background in this topic I
just wanted to have one of you
introduced to us and audience about what
is fetal alcohol syndrome and why they
should care about this and why it's
important to know about something like
this okay so about 40 years ago now
people started talking about the effects
of maternal drinking during pregnancy on
the offspring the baby on the child and
early on there were some significant
phenotypes that were observed in
children born to drinking mothers
typically alcoholic mothers
and what life from this was an under
Annie and really a diagnostic criteria
which was termed fetal alcohol syndrome
so that is the first term that was used
what we've learned since then is that
it's really a spectrum disorder and what
I mean by that is depending upon the
dose of the alcohol that the mother took
in during her pregnancy there's going to
be a lot of variability in how affected
the child is so you could imagine then
if a pregnant woman drinks sort of
smaller amounts or maybe has occasional
binge drinking that this would produce
some phenotype but maybe not complete
mental disability right whereas more
severe cases when you have an alcoholic
mother who's really consuming copious
amounts of alcohol during her pregnancy
maybe on a daily basis that's going to
show really what we now turn this fetal
alcohol syndrome which is really the
mower for the more severe form on that
spectrum and that will accompany itself
with facial phenotypes some problems
with actual facial development along
with a lot of behavioral problems that
the child has so you know I became
interested in this because actually you
know my mother was a neonatal nurse in a
NICU and she experienced a lot of
children who came in when their mothers
had been either doing illicit drugs or
alcohol and what was interesting to me
was that the more severe out long-term
outcomes for some of these children was
with alcohol not with heroin where they
would be born terribly addicted but then
they would be able to recover and then
having actually less long-term outcomes
than what alcohol seemed to do in
developing brain so I was really became
interested in that like what was the
mechanism by which alcohol could impact
the offspring in such a significant way
to cause really in many cases severe
mental retardation or severe mental
disability and that a lot of these
phenotypes that were last lifelong so
what was the molecular mechanism or
perhaps how our genetics impacted by
this kinds of exposure and it's
obviously really really important now
over the last and 15 years or so we've
seen an increase in maternal drinking it
used to be you know only five or six
percent of women in the United States
where we're consuming any alcohol while
pregnant now the recent CDC data shows
upwards of 18 percent of women in like
the 35 to 44 age range so typically
educated women who are being told by the
media and the internet that you know
having a little bit of wine here and
there can be relaxing and beneficial for
pregnancy and the science however does
not argue about the safety of alcohol in
pregnancy it's very clear from the
scientists point of view that it is not
safe in any amount and the CDC has
finally come forward and said that but
that's basically why we started this
whole thing about it's been about 10
years ago my laboratory started working
in this so certainly from a clinical
point of view in medical school were
we're sort of taught not to promote
drinking during pregnancy but I guess
when somebody asks a patient for example
how much could I drink usually you know
we say zero is the best answer but
sometimes when they say they have a
glass of wine or a beer you know we're
not you know shaking our fingers they
know no that's bad so what you guys are
saying now is that we should be telling
them to abstain from alcohol altogether
oh you can oh absolutely yeah so I
actually think there's a huge disconnect
between OBGYNs and scientists where a
lot of obese do tell their patients it's
okay to have a glass of wine here or
there and your second trimester in your
third trimester but what that means for
someone who is a was a regular drinker
before getting pregnant the glass mine
here there could be one for lunch one
for dinner or one every
you know or you know for someone else it
could be once a week once a month
so a lot of factors come into play here
critical periods being one the brain of
course is developing up until seven
years old and beyond
man Kelly was just talking about this up
until 20 years old really so depending
when you consumed alcohol and the
amounts you you drink really can have an
effect they may not be severe where you
display the phenotypes of facial
phenotypes or the severe learning
disabilities or the severe autism
resembling type of phenotypes but you
can have other I guess time for mental
deficits so temperament being one of
them for a judgment on colicky baby with
with the little amount that you are
drinking so yes your child may not have
mental retardation or something on the
FAS severe form but we do think as a
scientist even if you consume a little
here a little there there could be some
outcome adverse outcome associated with
that in your child do you agree with
that Harry yeah and we do have data to
support this information so there have
been studies showing really even small
amounts and this is an animal models for
example even you know a single dose of
ethanol at a certain point in the
pregnancy can induce changes in an
entire class of receptors in the brain
you know we have gaba receptors which
are very very important for inhibition
and they play a key role in brain
function in a variety of ways and there
is very clear data that maternal
consumption of alcohol even in small
doses can alter the development of this
particular class of receptors in the
brain so when people ask me the same
question which I have been asked as many
many times you know okay so let's say I
have a few drinks in my third trimester
is it's going to cause an effect and
what I might a typical response is that
most likely you are changing some
in the brain of the baby that even with
a small dose and there are a lot of
things you can intake during the
pregnancy that will also change the
brain of the baby now what whether or
not a few glasses of wine is going to
produce a very severe phenotype has to
do with a lot of other factors that
unfortunately you don't know going into
it how well does the mother herself
metabolize the ethanol you know her
alcohol dehydrogenase levels in terms of
enzymatic activity how does that impact
her being able to process and pull the
ethanol from her own blood these kinds
of things all play a role and we don't
as people we don't know about that
function in us so we there is no safe
way okay I know that I'm okay or not and
the data is really clear that you know
you will CH mean something at the baby's
brain whether or not that will read out
some kind of severe deficit most likely
not in low doses but you know you you go
to any second grade class first grade
class right now in the United States and
what you'll see are children who are
pretty off-the-hook they're they're
hyper you know they have problems paying
attention in many cases and they're not
diagnosed with autism or ADHD but along
this kind of normal within that normal
range but maybe on the edge and it's
quite possible and I would even probably
argue that some of these children who we
see having these mild dysfunctions in
terms of cognitive ability fine motor
skills or fine fine motor skill
development right temperament the
ability to emotionally regulate like
from keeping them from getting angry
that these kinds of things could be very
likely from maternal intake when it was
present you really do need to have those
higher doses to show the facial cream
the time that's give that medical
diagnosis of FAS or fetal alcohol
syndrome and it's important to mention
that unless the mother actually admits
to drinking alcohol there is no
diagnostic tool to measure okay this kid
has FAS or FAS do or partial FAS
so a lot of mothers wouldn't admit that
right so just to kind of define a couple
of terms for people that might not know
phenotype is referred to the physical
features or the behavioral outputs that
are seeing in the children so we'll talk
about the specific facial features the
other thing I wanted to ask you guys I
know from a clinical point of view we
just look at the physical features to
say whether somebody has fetal alcohol
syndrome or fetal alcohol spectrum
disorder so if maybe one of you guys
could define some of these specific
features that would be used to diagnose
this and I could jump in and give a
couple of on my end but after that I
really want to get into what you guys
have done in terms of research to
support the argument that you're making
in terms of what you found from the
animal studies and how the animal
studies correlated with the stuff that
we see with the children well we're not
clinician so we're you know we're pH DS
right so I don't I don't know all of the
details of diagnostic criteria for it I
do know that for with if we see
behavioral phenotypes that occur in the
absence of facial and facial changes or
facial they're almost like mild
deformities in the face that you have to
really have the maternal admission of
how much she drank during the pregnancy
for them to kind of identify let's say
hyperactivity as a result of fetal
alcohol rather than a result of
something like ADHD obviously there are
very very specific facial deformities if
you will instead of using the word
phenotype where we see the the eyelid
fissure which is normally you know mine
is this wide they tend to be smaller and
so it gives the appearance of a wider
set eyes there's also the dip in the
upper lip
called our philtrum and for these
children it's very very smooth almost
flat a lot of times too they have an
extended distance between the nose and
the upper lip so there are very clear
there are very clear telltale signs but
those are only there in that really
really high dose and when I that okay
just a really quick thing and you're
absolutely right those physical features
correlate with the amount of the mental
issues that you will see in other words
the higher the alcohol intake the more
prominent those facial features are in
the more severe the mental issues are so
it's the physical feature is kind of a
gauge of where the speck on the spectrum
the child lies so it's one thing that
clinicians used to kind of measure how
severe the mental issues would be when
the child is first born and obviously
the more severe form of a fetal alcohol
syndrome which is the worst end of the
spectrum is the one where the facial
features are really prominent and and
you can say okay this child was born to
a mother who had significant amounts of
alcohol during pregnancy well in one
thing that's interesting though again
it's not just like total volume of the
alcohol and that's something I think
that is important because if you you are
a pregnant woman who is fairly alcohol
naive so you're not a practicing drinker
so to speak and you have let's just say
a handful of binge experiences during
the pregnancy and even though the actual
overall volume of the alcohol is not
that much over a nine-month period and
maybe even the number of occasions is
not that much but if you're an alcohol
if your alcohol naive and your liver and
other things are not used to working
with the ethanol your system this is
going to result in higher blood alcohol
levels that are sustained for longer
which will have a greater impact on
developing fetus so you know and that's
the thing
no one really knows exactly how well
they do any of things things so if
someone tries to experiment that's what
you're truly doing you're truly
experimenting with your child's
developing brain which is why the CDC
now has really clearly come forward and
saying no amount of alcohol is safe so I
guess just clarify myself and he
absolutely made a great point
it's not about how much the mother
drinks it's the amount of exporter that
fetus gets during pregnancy and that has
multiple factors like you're mentioning
the liver enzymes of the mother the the
timing of when they're drinking and the
critical period in which the development
is happening and when he drink during
that period it's more severe than if you
were to drink it a little bit before or
later I guess but therefore you're kind
of playing a Russian roulette with your
kids development by taking in alcohol
and the best thing is not to play that
game and just stop staying from the
Train all right right I like to I like
to say that I'm having to endure myself
once you have the kid your life is
pretty much one big sacrifice to take
care of them and give them everything
anyway so you might as well just start
nine months earlier my own sacrifice in
comparison great so uh can we go into
some of the specific experiments you
guys have done to back up this data
because it's important you know we agree
on the no alcohol zero tolerance policy
and this is what I think every physician
should be promoting but at the same time
the devil's advocate in me says okay
show me the data because I think that's
what we should be basing it on right
well I'll what I'll do is I'll start off
with a little bit about our original
model in our original papers and then I
can have Olga talk about a couple of her
papers specifically that were a part of
the overall project in a laboratory so
as I mentioned once around ten years ago
I think it was around 2009 with my very
first graduate student we began this
quest to develop a mounts model other
mouse models had been made previously in
in different strains of mice we had done
a lot of work in an out bred strain
which means that the genetics of each
individual animal are not identical a
lot of people in molecular biology
prefer to use mice that have really
identical genetics and they're inbred
strains but what we've we wanted to
really create something that would be
applicable to humans and as humans we
are absolutely out bridge strains so we
wanted to use this particular strain of
mouse called the seedy one and so we
began working on that once we got the
animals to breed with the maternal
consumption of alcohol we sort of
settled on a percentage and these
animals drink 25% ethanol once they
become pregnant and that may seem like a
lot but mice metabolize ethanol at a
rate tremendously faster than humans so
when we talk about our mothers are we
called dams these Mouse pregnant mothers
the dams maintain blood alcohol what
would be equivalent to about a point oh
eight point oh seven in a human so what
that kind of means is right a couple of
drinks in your system so and it's even
though 25% ethanol sounds like a ton at
the end of the day what we're really
talking about is about a mom who's
drinking daily right keeping her blood
alcohol at some level throughout the day
when she's not sleeping and this
absolutely is with impossibility that
can happen now when we started we wanted
to hit it with as much ethanol as we
could because we wanted to see whether
what kind of phenotypes we could find
that's why we do have somewhat of a high
dose eventually we're starting to do
some work now where we're decreasing
dose limiting dose two different
trimesters and things like that but in
our original model which we have worked
with now for 10 years is this sort of
20% ethanol and in our first group of
papers we found some really very
exciting things
that we're shocking to the field
particularly that the way that the brain
particularly the neocortex which is of
course the wrinkly part of the brain
when you see an image of a human brain
it's that the wrinkly thing that sits on
top and this is the part of the brain
that makes us completely human it is its
function gives us sophisticated
behaviors complex cognition language you
know a lot of memory intensity of
emotion and everything that makes us
human uniquely human right has to do
with mostly our function at the cortex
so it's obvious this is a place where we
look at children with FAS or FAS see we
can see that they clearly have
dysfunction within this part of the
brain because we see these deficits and
fine motor skills in emotion regulation
in cognitive performance on tasks or
their ability to learn complex behaviors
so we started sorry not because just
because but just to clarify so you've
taken mothers that became pregnant and
then it gave them alcohol and then once
the offspring was born you put them
through a battery of tests that measured
all of these stuff and you also looked
at their brains to look for
morphological changes right yes yes and
and molecular changes as well so right
so in that first model we looked at how
particularly how the cortex was wired up
so in order for me for example to sit
here and be able to talk and move my
hands and to create you know lucid
thoughts and express them language
language I'm activating these many many
many circuits within my cortex and we're
doing this all day long with all of our
behaviors and our hypothesis initially
was that there would be a disruption in
the development of these circuits within
the in that part of the brain and we did
find that indeed to be true that on the
day of birth when we would you know
sacrifice these animals examine their
brains that they had this disruption in
the normal development of the prior
circuit that allows the animals to
navigate through their environment and
this was very very exciting we then
followed this up with sort of
mechanistic studies to understand okay
what is it how are these what is the
mechanism by which these connections are
mal forming and we found this to be
altered gene expression so one thing
that in terms of how the brain develops
it is patterned by genes turning on and
off in specific locations at specific
times so when we see shifts in gene
expression because of altered
programming in some way that can that
can lead to problems with development of
connections or the circuit in general
which ultimately we hypothesize would
lead to a typical behavior so that was
our first finding and it was very
exciting we were able to look in that
newborn Mouse and find these molecular
alterations in the brain meaning the
genes were not expressed in normal
patterns the connections did not form in
a normal way and then also and then at
around 20 days around weaning we tested
them on a battery behavioral assays and
found than to have abnormal behavior
particularly things that are consistent
with what we see in humans increased
anxiety like behaviors errors in motor
skills or what we call sensory motor
integration which is your ability to
integrate information coming in through
the senses as the animals like walking
on a little bark and then they have to
adjust their motor performance so they
don't fall out or fall off of the bar
those kinds of things were disrupted in
our alcohol model so that was our first
first big paper published in Journal of
Neuroscience in 2013 that's really
exciting because it really clearly
demonstrates that the alcohol affects
specific genes and genes that are
important for patterning and formation
of the brain and you could explain sort
of the behavioral outcomes based on the
molecular stuff that you're seeing so
it's definitely a very strong evidence
about the effects of alpha
during pregnancy right and and then
another you know we have we've had
several studies on this model but I went
I'm gonna have a chance to talk about a
study in order in her older mice a lot
of our work is focused on the molecular
work in a very newborn because that's
when the genes are most robustly
expressed and we can really see that
better in the newborn their patterning
genes go once the brain becomes
developed we see those things fade and
we aren't able to identify those
phenotypes as well so Olga did a really
fantastic study on air conditioning in
the adult animals that I want her to
have a chance to talk about as well
thanks Kel yeah so I was mostly I guess
interested in the long-term effects of
in utero exposure to alcohol so one
project that I worked on with you know
really interesting results is we keep
talking about children with FAS yeah
learning disabilities and and all that
so how do we actually model this in
animal models to really learn what's
going on in the brain for children to
have these learning disabilities so like
Kelly talked about we exposed our mice
to 25% alcohol when the mom was pregnant
so the child was born with FAS and then
I let my animals grow up to be P 50 this
is equivalent to about young adulthood
in human life so at P 50 that's where I
began my experiments of fear
conditioning where we actually exposed
the animal to we put him in a chamber
and we exposed them to a tone and a foot
shock within two seconds so they're
learning that if I hear this tone I'm
gonna get food shots so there's an
aversive stimuli coming my way such and
then the outcome would be freezing
behavior once they hear the tone the
expectation is for an animal to freeze
because they're afraid right so once
we're conditioning of the shock with the
freezing response right right
so once the conditioning is is finished
there the form disassociation in their
head if I hear this tone I'm gonna get
shocked that's when we do the testing so
I did testing in two developmental time
points conditioning them at p50 which is
like I said early adulthood and I tested
that my p52 which is again early
adulthood and p7d which is later on in
adulthood and both at P 52 and at P 50
where we exposed the animal to the
chamber and only give them the tone and
no fat shock at this point so like I
said they've made this sociation I hear
the tone I'm gonna get foot shocked but
they hear the tone they don't get foot
shocked the outcome is to freeze again
and we saw that these animals at P 50
and at P 72 or P 52 and peace of 82
don't freeze so compared to their
control naive counterparts where the
controls hear the tone they
automatically freeze because they're
like oh my gosh I'm gonna get this
aversive stimuli I'm gonna get a foot
shocked and that's gonna hurt these pre
animals just weren't freezing they
weren't recognizing the fact that I hear
in this tone
I'm going to get foot shocks and it's
probably gonna hurt so what is actually
happening in the brain I looked at
several I guess neuro 10 you're an
anatomical components of this one being
the amygdala the amygdala is typically
our emotion center but it's also where
we make these associations we're
learning actually occurs associations
between a tone and consolidation of the
tone and aversive stimuli coming
together so what I found is when I took
the brains at P 52 and T 70 is that at P
50 actually no I let me backtrack I took
the brains at P 50 in a separate cohort
of animals because it's a whole
different paradigm or a whole different
experiment when they actually go through
the test at P 50 when they're actually
learning the association between the
tone and the versus stimuli the amygdala
is actually a lot smaller so I can't
really speak to the functional outcomes
of that but we know that you're
anatomically speaking the amygdala isn't
I guess as developed as it should be
controlled
I mean compared to their controls so
I mean I guess this isn't a great piece
of data because it's it shows that I
guess and correct me if I'm wrong that
they're learning and association between
fear and the stimuli is is lacking and
if I remember correctly kids with FAS
have impulsivity issues and so they are
more likely to get into trouble because
they can't really control themselves so
they're not able to in some ways
associate the dangers of their actions
with the outcome and you guys can
correct me if I'm wrong right but this
does definitely translate into that kind
of you know I'm gonna if I misbehave I'm
going to get reprimanded for it but
someone who has can't make that
association if I misbehave I'm gonna get
in trouble for this they're more prone
to taking risks and just acting out and
not recognizing that they're gonna
actually get in trouble for it and so
it's smaller amygdala it kind of shows
that there is an anatomical reason why
the behavioral outcomes we're seeing
right every as well in another assay
called the elevated plus maze in our
inner mice we see what many would
identify as decreased anxiety which is
this is a little maze it's a platform
where the animal of the mouse can either
hide inside a closed tunnel or be out in
the open and we know these are rodents
their prey animals typically if they
have any kind of anxiety at all the idea
is that they will go and hide in the
enclosed tunnel what we actually saw was
the opposite in our fetal alcohol mice
in that they would spend more time out
in the open and we just you know I
thought a lot about this and and I
absolutely do not believe this indicates
that they have lower anxiety when it
indicates is that they have higher risk
taking behavior and the reason they are
having higher risk-taking behavior is
because like we saw in Olga's study they
aren't learning normal fear
responses as a normal prey animal would
and you know again how does this map out
into humans when we look at cortical
development and brain development in
human versus rodent models one thing
that the general public a lot of time
doesn't understand is that there are
tremendous similarities particularly
with how the genetics pattern the brain
early on in development a lot of the
same genes are going on and turning on
and off in these discrete locations in
the human and in the rodent brain this
is why rodents are actually a good model
for human neural biology in general
because of the similarities in genetic
patterning that goes on in development
so you know I think it is really
consistent I think when we think about
humans with a few no alcohol effects
whether it's severe or even more mild we
do see these higher risk-taking
behaviors we do see the what seems to be
the inability to learn normal fear
responses and I think it's coming down
to perhaps
this really deficit in development of
the amygdala but also you know we also
see in another study we have done with
Olga that isn't yet published where we
did more anatomical measures in older
mice as a remodel we found things like
even later on in life decreased spine
density so little spines are on the
neurons that affect their communication
and we see deficits in that that are
maintained long term also we see some
long term changes in gene expression as
well so these all of these things
together could produce work together to
produce these effects behavioral effects
whether it's decrease fear learning or
more you know being more clumsy people
having difficulty with fine motor skills
and then of course the huge different
types of cognitive dysfunction that we
see you know is most likely from this
these mechanisms that underlie brain
development that are altered with that
the alcohol exposure very very
interesting so all guys you would
talking about the two different sets of
experiments and and you said you
measured them in adulthood and can you
go a little bit more detailed in some of
the other features that you saw in Lyra
anatomically so we did publish a paper
actually where we mapped out the whole I
guess anatomical trajectory of the
cortex and subcortical areas so what
that means is the wiggly part of the
brain which has different components
that are responsible for your vision for
your senses for your decision-making but
also we looked at different subcortical
regions like areas associated with
memory like the hippocampus areas
associated with like the amygdala with
emotion and what we see is without
getting into too much detail we looked
at ages P Zero P xx and I believe page
50 which is birth early pubescent and
early adulthood where the trajectory of
development of these key brain regions
in your area is altered in FASD so
compared to their controls so when the
nuclei or the certain brain regions
should be developed at at a certain rate
either is slowed down or is accelerated
which of course can have functional
outcomes again I can't really speak to
that function as positive but because we
see a neuroanatomical change in this
trajectory it's needed to say to say
that there is some sort of maybe adverse
outcome that comes with it and sorry I
know that you know GABA is very
important during development and this is
one of the receptors that alcohol binds
to and but of course alcohol could do
many many different things in terms of
its promiscuity no pun intended but so
do you guys know in terms of molecular
lis what specifically the receptors or
the molecular changes that is doing in
that context so yes well we I mean
certainly not everything I mean I think
there's a lot of things that and
discovered still about this and and
you're right that alcohol you know
alcohol we take it in
Emily right so we're we're drinking it
it's going it's going it's affecting our
gut biology right absolutely and it's
doing a lot of your things throughout
the nervous system in other parts of the
body as well and the body is definitely
whole so I think that you know we focus
on the neurobiology of it but I would
definitely believe that especially
something like what's going on in the
gut as a result of alcohol would also
impact development or just function in
the brain in general but specifically to
answer your question after we found some
of the the early early studies where we
published these effects in gene
expression changes as a result of
prenatal alcohol exposure we started to
kind of you know groupthink about what
could be the mechanisms that would be
able to generate the change in the gene
expression right so this is RNA
expression and we wanted to find out
exactly you know what what is the
mechanism so one of our early hypotheses
which turned out to be correct was that
DNA methylation can change from
consumption of alcohol what this is you
know every one probably all the viewers
know what DNA is double helix with your
acids and basically to not get too
technical
we have little methyl groups that bind
to our DNA okay and what these things do
is they don't change the sequence of the
DNA but they change how the DNA
functions in in the body at any given
time so they control all kind of how
genes turn on and turn off and so we
know that changes in methylation or how
those methyl groups are binding to the
DNA and those changes can alter gene
expression particularly in development
so we we had our probably our biggest
paper in terms of notoriety and fame if
you will in the science world would be
our our work that were published in 2018
in the journal cerebral cortex and in
this paper we first began to investigate
DNA methylation
in these in this model and we did find
very significant that alcohol intake
which and there's a very complicated
pathway that has to do with one carbon
metabolism for example that alters the
methylation we found that in the brains
of the offspring that had been exposed
to ethanol during development during
pregnancy
they had decreased methylation and this
decreased methylation was gene specific
so when we found that it was specific
for the genes that we found to have
those altered expression patterns so we
were able to identify this mechanism
which was really fantastic and what's
really interesting about this is that
typically these changes in methylation
although they are not changing the
sequence of the DNA they changed the way
the DNA functions but making stick from
generation to generation and this is
what's really really important there had
been some studies earlier suggesting
that subsequent generations of animals
exposed to ethanol during pregnancy that
they have behavioural effects that seem
to be passed on through the generations
but that was pretty much the extent of
the knowledge in that entire area once
we discovered that the methylation which
changed leading to the change in gene
expression initiating the change in
abnormal or the abnormal development of
the connections or the circuits that's
when we created our transgenerational
model so that was really really made a
big step in the field I believe because
we were able to demonstrate that not
only are the offspring of the mom who's
drinking during pregnancy impacted but
their children and their grandchildren
are impacted by just that one single
maternal exposure so in the absence of
any other additional alcohol exposure
these animals as they pass through the
preparations are affected showing these
behavioral phenotypes showing brain
phenotypes as well that are that look a
lot like animals who have been exposed
to alcohol so this is really really one
of those things it's really exciting for
science it was different tasks
for our laboratory that we were right
and you know we all of that but it was
one of those things that was also kind
of sad for for humans right for people
because you know if you're let's say
you're someone whose mother drank during
pregnancy and you do have some deficits
because of that I mean knowing that no
matter what you do or your child does
that your child and your grandchildren
could be affected could be really
disappointing and so this is very
exciting stuff because I had made a
prior episode on transgenerational
transference of anxiety and emotional
stuff in general so now this ties in
with the alcohol consumption which
brings into the question well it's not
just the mother the father has a
contribution to if their alcohol
consumption is significant or they come
from a generation of alcoholic parents
for example right so this then brings in
a second factor that we've been talking
about maternal drinking but there's also
the paternal contribution to this whole
thing right and we just published a
paper two months ago I think on on this
very topic so when when the CDC came
forward and said this was a few years
ago no drinking in pregnancy is safe
that was great and they made this point
that if women are sexually active and
not on the birth control that they
shouldn't be drinking at all it's kind
of created a little bit of an uproar in
you know particularly feminist America
saying well what about the guys and I
still can remember I was driving my
little Fiat to work and I thought you
know this is what I need to figure this
out we need to create a paternal model
and you know we did so we did and we
just published this paper in the journal
a ser which is alcoholism clinical and
experimental research and we found
really some exciting stuff basically we
exposed the males for two weeks to the
same high-dose 25% ethanol and at the
end they are we obviously after two
weeks we remove them from
alcohol put them with the female we had
to remove the things we didn't want her
to drink anything right so anyway their
offspring were absolutely affected so it
was really really exciting to see how
some changes in most likely methylation
in the sperm which has been shown to
happen that has been shown by others
where a high dose of alcohol in a male
can affect the methylation profiles in
his firm that this could actually alter
the developmental trajectories of the
offspring he produces the moment he you
know he breeds after having this period
of about high alcohol exposure that's a
quick question in regards to that
because again to play the devil's
advocate here so we know that any kind
of fear stimuli or noxious stimuli in
animals it's been shown that it causes
anxiety and a sort of terror and so this
has been shown that they could pass it
on to several generations so in that
regard
do do mice enjoy alcohol I mean or is
this when you're exposing the male or in
the Fila it is this a noxious stimuli
that they're taking in that is being
passed on or is it is there evidence
that I mean I don't know how you would
measure if mice enjoy it but I guess if
they're addicted to a diamond stay enjoy
it right they're not beautiful for it so
I'm wondering whether the
transgenerational stuff is a relation to
a noxious stimuli or it's an actual
alcohol smell well we know that the
alcohol causes this demethylation I mean
so we do know that I I definitely don't
know whether or not you know how the
mice feel about it I don't know the mice
have that kind of sort of cognitive you
know but I don't know oh god you know
there's two to place preference what
what they would they prefer the alcohol
they do right yeah they do prefer the
alcohol but I guess in like the f1
generation so the mother that's directly
been exposed to that alcohol because we
are kind of hitting them
with this whole gestational model of
alcohol exposure they're not going to
withdrawal which comes with different
effects right so the anxiety the stress
of not having the alcohol or what not so
I think we can eliminate the fact that
the mother is having withdrawal symptoms
or anxiety or stress coming from the
alcohol that she's passing on to her
offspring because she is on the alcohol
the whole time and is feeling good okay
so so then it is definitely exciting
stuff because it's showing us that you
know even Grandma and Grandpa could have
contributed to some of the stuff that
we're seeing in the offspring so then I
I want to ask what can be done are there
ways to kind of help these individuals
kind of interventions things that could
be done to maybe make early diagnosis
ways to block the methylation or alter
the methylation status or even
behavioral things that need to be done
early on to help with the kids that are
born well I'm very excited you asked
that because we just had our paper
accepted to neuropharmacology at the
Journal neuropharmacology brand-new we
just got it accepted a couple of weeks
ago I think it's been published now and
this is on our choline model so choline
is a supplement not too far off from
something like folate or folic acid
which we know is important in
development particularly for closure of
the neural tube and development choline
is something that does alter that one
carbon metabolism and seems to have
Amelia two effects on those phenotypes
that we see in mice exposed or it all
there's a couple different rodent models
before us that would show some
behavioral release or a relief from
behavioural effects of alcohol that was
exposed during the prenatal period we
did a very extensive study we had some
good idea again because we know that
that methylation could be altered and
improve
by high doses of choline that would be
administered along with the ethanol okay
so and we found really really fantastic
effects that it pretty much rescued in
some cases completely when we see the
the changes in methylation we see a
complete rescue of ethanol dangers right
or debt bad effects by giving the
choline along with the ethanol we see
that rescue in terms of the aberrant
connection and the patterning it's a
partial rescue so we see that when we
look at controls versus ethanol versus
ethanol with choline ethanol with
choline don't have a complete rescue but
it's about 50% improved or so in terms
of those altered connections and we also
see these rescuing of phenotypic effects
but most importantly I think rather than
just thinking about how the brain is
improved is the behavior right and we do
see pretty much across the board we see
this this improvement in behavior these
long-term behavioral outcomes from the
ethanol when the choline was Co
administered with the ethanol in
pregnancy and this was particularly
point actually for females because we
did you know in our studies were being
very careful in separating out because
there are some differential effects in
males versus females so this was very
exciting for us because it does provide
a kind of I we like to call it a
preventative cure we have it tested
whether or not the animal you know who's
just been exposed to ethanol whether we
can give choline once they're born to
try to repair some of the damage than
that we've administered it along with it
so if you think about if this is very
important for someone who maybe isn't
alcoholic can't stop even though maybe
she knows she should but she can't stop
she could take cooling supplements
during the pregnancy to help support
some of those negative effects of
alcohol so I could imagine this being as
one of the you know like supplements
that you take one with the vitamins that
most
take if they want to get pregnant to
kind of you know just like folic acid
for example and so you could throw this
and has a cocktail of one of those
vitamins just in case you happens to
have a drink so do you think like adding
choline as one of the supplements be
great you know occasionally you will see
on some prenatal vitamins you will
occasionally see some small dosing of
choline in there but it's not as
pervasive or it's not considered as
important as something like folic acid
where you know doctors will go out of
their way to say you know make sure that
you're taking your prenatal vitamins
because of the folic acid because we
have this very very strong link between
little folic acid levels and you know
spina bifida in babies for example you
know it's interesting because you know
in in our diet most most people have a
good amount of folic acid in their diet
so it's probably not as important but
certainly in in developing countries it
absolutely is and even in parts of Asia
they actually the government will
fortify the flour with folate and I
think in it you know we really do need
to make the medical public aware
particularly OBGYNs that you know having
if you do really you really need to talk
to the moms about their drinking advise
them but you know be sensitive as a
physician to understand you know are
they getting nervous when you're having
this conversation
are they being combative are they trying
to look for reasons why they can drink
and if so maybe encouraging them to take
the the choline but I want to make clear
that choline is I mean it's not a
hundred percent preventative we do see
rescue but it's not a hundred percent
rescue on all of our of our biological
effects I don't want to add on to the
whole choline of course colon is great
but if you do have a child with you know
you did drink and your child does have
symptoms of FAS there are studies that
show that environmental enrichment you
know if they have fine motor skill
deficit
or sensory motor integration balancing
or whatnot if you give them the tools
whether it's Montessori toys or dance
classes or you know cognitive
development learning stuff there is huge
evidence out there that that says that
children can catch up and can actually
improve their deficits based on their
environmental enrichment and the tools
they're giving so that's that's that's
exciting as well that if you catch them
early there are interventions that could
be done and of course but there is no
diagnostic test right so it's centrally
facial features and behavioral stuff so
Olga what are some of the different
diseases or behavioral stuff that FAS
can be confused with and whether it
really does matter to diagnose somebody
with one versus the other in terms of
those interventions that talked about or
you don't think there are any yeah
that's a great question because it's
like I said the mother doesn't admit to
drinking alcohol while pregnant it's
hard to diagnose that unless they have
the real severe facial features but
autism is one autism is also a spectrum
FAS is also a spectrum so the cognitive
deficits that are associated with autism
may be children diagnosed with
Asperger's and versus children with
common deficits with FAS that have been
exposed to alcohol when you know they
were in utero I'm a lot of these effects
overlap so a lot of children with FAS I
think could be misdiagnosed with having
autism or Asperger's or being on that
kind of spectrum because the mother
didn't admit to drinking the alcohol so
I think it's important like Kelly said
to have these mothers to educate them
and and you know it's okay to tell your
doctor yes I did drink you know the
consensus is that zero alcohol no amount
of alcohol is safe but in order for your
child to get diagnosed properly I think
it's important for transparency to be
there so yeah you know there's huge
overlap in autism or or ADHD you know a
lot of FAS children display
hyperactivity
and you know can't sit still as
five-year-old in the classroom can't pay
attention so they often get diagnosed
with ADHD as the mother didn't admit to
drinking alcohol so it's important for
transparency to be there for appropriate
diagnosis purposes right and for
treatments because that's important with
you know we have very clear treatments
for ADHD right we have psychomotor
stimulants for example Ritalin Adderall
these things are not gonna work
they're not gonna work on a child who is
showing that sort of hyperactivity from
alcohol exposure you know the idea the
smart money is really on that it's a
different mechanism that leads to kind
of similar looking behaviors in the end
and that it but so it when it's a
different mechanism that means there are
different causes for the behavior then
the same treatments are not gonna work
the same and something like that work
you know you could say oh you know I
don't know why you know ritalin Sun
improving my child well it could be that
what they they don't really have they're
not on the the hyperactivity spectrum
they're on the fetal alcohol right so in
regards to that I was just thinking in
my head so you found these methylation
differences that you say is
transgenerational so could that be used
as some sort of a biomarker to not maybe
even diagnose at they asked if the
methylation pattern is prominent in
there for example the blood cells or
skin cells that could be used to to look
for this methylation pattern and then
say well this is different than autism
or another mira cognitive deficit
disorder and be able to really hone in
on okay this is where FASB well our
methylation changes that we find are
specifically in brain tissues so
obviously that makes it not possible as
sort of using it for diagnostic purposes
I don't you know especially because
we're looking at it with using something
called methylation specific PCR which is
to relook at how for given genes which
are involved in patterning at the green
within brain tissue
how those methylation profiles are
different so I don't know how that I
actually don't know how that would
readout and changes in other kinds of
body tissues such as what our skin that
could be readily used for testing I
really don't know the answer because all
of our work is done specifically in the
brain tissues and even region-specific
right we'll take samples from the front
of the brain versus the back to look at
the sort of regional differences in
methylation change I personally think so
this is all great great but remember
Kelly when we did another interview with
HuffPost and we were talking to these
bloggers moms and they're like well when
I drink alcohol
I feel good so my baby feels good
there's this kind of misconception going
around where it's like if I'm relaxed my
baby's relaxed so if I'm feeling good
it's good for my baby I think us as
scientists as clinicians what do we do
to change people's perspective on this
stuff you know we can educate them but
because I often come across people who
you know are drinking in my presence and
I will tell them you know you probably
shouldn't have that drink but it's like
this there's a defense mechanism the
other go on the defensive well why not I
you know I'm creating it you know it's a
pregnancy craving that's why I'm
drinking so what do we do as you know
kind of pioneers in the field to stop
this kind of thinking process yeah
that's a good question interesting in
that and you know there's worldwide
there are a fairly good-sized group of
scientists who are studying this
particularly people from Australia
Canada also where the FASD rates are
quite high and what's interesting is
there's actually a movement in the field
not to shame and is when you were first
talking I was thinking well really the
only way to really motivate them is
through fear like say if you do this
then you will be punished with a baby
and you're hurting your baby it really
kind of shaming them into not doing it
but in the in the field there's really a
movement to stop shaming women for this
behavior so it
it's an interesting conundrum that we
find ourselves in because if we don't we
don't want to shave them because we want
them to come forward it could help Ben
or for them to say I can't stop drinking
so can you help me and we can suggest
you know other sorts of diets or
supplements or whatever to help them or
even to get the diagnosis accurate so
that the children can get that
enrichment that they need so we don't
want to shame them but you know fear is
also a powerful motivator right you know
when I was pregnant I absolutely did not
why I didn't drink but something like
taking Advil you know I know that Advil
can cause increased bleeding and you
know and all these other effects so I
absolutely did not take Advil and and
you know a lot of women they won't take
Advil and in many cases they won't smoke
cannabis aside because that's another
new issue that we now have with people
thinking that cannabis is okay to do
during pregnancy but yeah it's a good
question and I think we can we can try
to educate and it's very important that
we educate the doctors alright aren't
there because if they are telling people
and I have you know I'm I'm many many of
my friends of course have children and
they were told you know you can drink a
little here and there in the third
trimester in particular which is maybe
not the time where those key parts of
the brain are developing that are
responsible for your breathing or your
heartbeat or major sort of body
functions but the part that cortex is
strongly developing at that time so if
you're taking an alcohol at the in the
third trimester when the cortex is
developing remember that's the part of
the brain that is responsible for our
sophisticated behaviors in our our
complex cognition what allows us to be
engineers and mathematicians you know
that part of the brain is important too
maybe not for clear survival but for the
big ability to have sort of normal and
optimal development I think we could say
yeah and I also would say like would you
give would you give your baby some
whiskey and a baby bottle of course they
wouldn't right so
it's really it's really not different
and I think people need to understand
that and I think part of it is really
education and getting it out there
because you know there's there's
obviously everybody knows getting drunk
and driving is a bad thing and there's a
full huge movement about you know
preventing drunk drivers and I think
there should be some kind of a movement
like that about mothers against mothers
drinking alcohol for example you know
during pregnancy something that lets
people know educate them and I think
there is not a lot and most people don't
understand it because there's not a
constant exposure about the dangers of
this in their mind in terms of
advertisements and presentations or even
pamphlets that should be made to be
handed out during pregnancy and if you
google I'm pregnant is it safe to drink
actually several of the first few sites
that will come up will say it is changed
and I looked at the numbers it's it's
quite fascinating that FAS and FASB are
are much higher prevalence compared to
autism and some of the other
neurocognitive deficits that we see it's
that's almost like tenfold higher and
yet there's not as much you know
attention brought to it and not much is
being done in terms of public awareness
about the consequences of drinking while
pregnant and then the father's - I mean
if you're considering having a child
then maybe you should abstain from very
high levels of alcohol either before or
right before pray like you know you're
considering having a child yeah it's
always safe to detox a couple of months
before conception right but that's not a
very popular thing right with the guys
right that's and you know when we were
first embarking in this field I remember
when we found our first phenotypes I
thought oh my god you know this is gonna
be so great it's gonna be in the news
and it was it
the news but it wasn't in the news as
much as you know a Denmark study that
showed you know from their metrics that
it was safe to drink in pregnancy and I
think especially in America you know the
land of free choice people people don't
like to be told what you can't do people
like to be told
do whatever you want to do it's make
yourself happy right that's kind of our
culture now unfortunately and
unfortunately in some cases so well are
very good at focusing on evidence that
supports their view that allows them to
do what they want to do and you know we
also see hide the highest cancer rates
of all time right so a lot of this has
to do with people
really it's a hedonistic lifestyle and
not willing to make sacrifice and like I
said I think for children
I just I guess now you're a strong
alcoholic it's very difficult to stop
drinking for nine months for sure
no doubt but for a lot of times it's not
alcoholics it's women who you know drink
socially or that's the theme right like
to add on to that that's the thing with
alcohol is such a complex topic it's
because that's how we socialize as
adults right it's socially accepted to
drink it's not really socially accepted
to go out and smoke cannabis or you know
to do other sorts of drugs or whatever
that will hurt your child about finally
but because alcohol is socially accepted
it's kind of like an easier drug to have
access to and is socially acceptable to
consume while pregnant so I think we
will get there with cannabis and
unfortunately I think I mean I remember
not that long ago seeing on a mom blog
kind of Facebook page where it was as
cannabis safe just to do in pregnancy
and I was blown away out of the you know
six hundred comments how at least 75% of
them were saying absolutely as you know
maybe not if you smoke it but if you eat
it if you you know do some drops as the
oil or whatever have a have a brown
that it helps calm you down and it's you
know it's it's natural it's from the
earth it's it's very wet but I mean I
just I just feel like there needs to be
more out spoken scientist and physician
when it comes to this and and really I
think part of it has to do with making a
hard line and you know if you say you
could have a drink here and there no
it's zero alcohol during pregnancy and
that should be the policy of every OB
guy or every physician and and clearly
you guys have excellent and fascinating
data to show that and now just you but
the whole field is kind of going towards
that way and just also it's not about
just your child but your grandkid and
their kid you know so it's a it's
multiple generations that you're
affecting during that nine month period
where you you know you could be doing
the right stuff so you know it's and
it's the importance to of listening to
the science I think that's what's really
really important because culturally we
see I think a move against science in
this country I think we see people you
know relying more on anecdotal you know
information oh well my cousin she drank
a lot and her kids fine you know and
remember we can't go back and do the
experiment to see maybe that child would
have been the next Einstein and now he's
not right so we have to understand that
science is not motivated it shouldn't be
and at least in academics it's not
motivated by greed or any of these other
things but finding out the truth so you
know we we have to relearn as a society
to trust the science and not the Google
I think and not just what someone you
know says in a tweet or a Facebook post
and I think also part of the confusion
is we physicians and scientists that we
don't do and
they'll see a news blurb that alcohol
drinking is good for blah blah blah and
then another study would come out show
that there is no effect and then another
study would show the opposite effect and
people are hearing these different
things and of course the way the mind
works they're always going to gravitate
towards the study that show them what
they wanted to hear and they don't see
these other stuff so we should be
careful I think that scientists are and
physicians when you publish clinical
data or any kind of data that shows a
positive correlation and then another
study that shows a negative correlation
we should be summarizing these and
saying hey the answer is not known or
look these clinical trial data are
showing one thing but you know these are
the caveats so we don't do a good job of
explaining to the public about the
results and sometimes they're not really
100% truths it's just the facts that
might not be the case in our larger
study and that's the thing about
explaining results I feel like us as
scientists yes we do the research yes we
publish papers but a regular person and
chances are they're not going to go on
PubMed comm and download our publication
and read what's happening so I think us
as scientists we need to do more blog
posts but put our information out there
any more readily understandable ways so
that a regular person it would have
interest reading it and be understand
what they're reading really without all
the jargon that we throw in there this
is why we're doing this yeah this is one
of the reasons I started this to bring
in people like you guys who have done
incredible work with the sciences but
explain that to the people that don't
understand it and it's put it in a way
that we guys have been doing really
wonderfully so that the general public
understands and can relate to it and
start thinking about it themselves and
be more critical and of course on an
important topic like this it's really
important that the public understands
the data yeah and what's really
interesting about it is that you know
millions of dollars of grant funding are
going towards studying this to try to
understand the development of fetal
alcohol spectrum disorders when in fact
there is a cure
a preventative care sitting right in
front of us which is to abstain and
that's the interesting thing about it is
that I'm you know I'm dedicating my
life's work to something that if people
just chose to not drink it wouldn't even
be an issue I think there's hope though
because if we look at cancer rates lung
cancer rates among the teens sorry
smoking rates and the cancer rates of
lung cancer it's been declining so it
looks like the education of the the
teenager is about abstaining from
smoking is really having an impact on
their smoking rates and the resulting
decrease in lung cancer so hopefully
with more education the abstaining from
alcohol during pregnancy will also go in
that direction but I think it'll take a
long time and we still need ways to help
those kids that are born with it so it's
I think the research you guys have done
with choline and again by no means that
should promote people from for drinking
but at least there is some intervention
that could be done and also the
behavioral stuff that Olga was talking
about in terms of intervention are also
excellent ways that we can hopefully try
to rescue some of these defects in these
children as they're going into adulthood
now I do have one last quick question do
do these kids that or at least it also
in the mice when they're born from FAS
with FAS sorry are they more prone to
having tendencies to drink alcohol later
on are they sort of more addicted to it
or in humans are they more likely to
become addicts of some kind our studies
don't address that directly but
certainly there's human data to show
that children of alcoholics are more
prone to drink alcohol in their lives
however it's kind of it's compounded by
experience right so a child who's
growing up around alcohol is going to
and watching you know their parents do
it too whatever they're going to be more
prone like in terms of just the learning
environment not necessarily something
that is transgenerational immediated or
even just from the direct effect
themselves but you know maybe Olga
you're more familiar with literature on
the addiction literature later on with
experience yeah there's definitely a
genetic predisposition to having an
affinity towards alcohol when you're
genetically exposed to it and we do see
that in animal models so there's a
higher risk of becoming an alcoholic if
you're you come from ancestry alcoholics
but that doesn't mean you are going to
become an alcoholic but you have the
predisposition so depending you know
when you're a teenager and you start
kind of experimenting with your friends
if you do have a predisposition there's
a higher chance of you kind of getting
hooked on the alcohol just like any
other drug but yeah that's that's
generally the consensus so this has been
an awesome discussion I've enjoyed it
very much I think I've learned a lot
myself and hopefully it's going to be
educational for the public listening to
this so if you guys have any last
remarks before we come to the end just
that I would say you know in terms of
that hard line it took it took the CDC
Centers for Disease Control it took them
a very very long time to draw hard and
they finally did it a couple of years
ago and you know I think I think that
should be followed you know and I
understand that it you know it really
did take them a very long time to come
to it and there was so much data backing
that statement up that finally they had
no choice but to really truly say that
there is no safe amount of alcohol in
pregnancy and I I hope that women can
get help if they need it right and do
their best to really really obscene for
the health of the baby all right it's
just nine months you know you can do
anything
and you know it's not just about you
it's about your baby's future so don't
succumb to temptation and yeah look at
the evidence because this is all
evidence-based it's not anecdotal and
that's where we need to make the shift
going from my aunt drink you know my
sister drank my niece is okay everyone
Europe that famous one everyone in
Europe drinks or everyone in China or
JAC Japan eat some sushi right so their
kids are okay we can have tuna or raw
fish or whatever well I want to thank
you both for taking your time and then
doing this and hopefully in the future
we'll have another such interview where
there is more positive outcome in terms
of the work you guys are doing in terms
of educating the public and declining
rates of FAS and I'm really interested
in the transgenerational stuff so maybe
in the future we'll also have a specific
discussion on that topic itself so with
that I want to thank you both and once
again I appreciate you guys coming on
and giving us your expertise yes thank
you for inviting us thank you so much
guys have a wonderful day and I'll see
you hopefully on another show
you
