On Nature League, we spend the third week of each month exploring a current trending
article from the peer-reviewed literature.
Scientific information isn't just for scientists- it's for everyone!
It just requires a bit of a break down.
[CHEERY INTRO MUSIC]
For this month's De-Natured segment, we're going to look at an article released in May
2018 in the journal Translational Psychiatry.
In this month's Lesson Plan, we talked about the different ways that organisms make more
of themselves.
We also discussed the biggest biological advantage of sexual reproduction, which is increasing
genetic diversity by combining multiple sex cells.
But it turns out that sex cells aren't the only things being passed onto the next generation.
We've long understood that certain individual traits we have come from the DNA inside of
eggs and sperm given to us from our parents.
But what about something...not so great?
What about trauma?
This paper is entitled, "Reduced levels of miRNAs 449 and 34 in /sperm of mice and
men/ exposed to early life stress" and yes, that is also the title of a play I would definitely
pay to see.
Theatre references aside, the title contains some concepts we should dig into.
Particularly, miRNA and what we know about their reduction in levels.
So here's what's already known.
Being exposed to severe stress during childhood can absolutely have negative health effects
later in life.
For example, studies have shown that adults who report having experienced more childhood
trauma are more likely to experience depression and struggle with suicidal thoughts and tendencies.
But here's the thing- the trauma doesn't stop at the adult who experienced it.
Scientists have also noticed that children of parents who experienced trauma as kids
are at a higher risk of developing psychiatric disorders.
So how does this trauma persist across generations?
Several mechanisms have come to light, but the one with the most current scientific support
has to do with small RNA in sperm.
Ribonucleic acid, or RNA, is single-stranded genetic material.
One of its most famous jobs is delivering the genetic code from inside of the cell's
nucleus to a cell's ribosome, where that same code is eventually translated into all
of the proteins we know in life on Earth.
I mean, no big deal guys, just, y'know, making the building blocks of life over here.
And as if that wasn't a big enough job, there are actually all /kinds/ of RNA that
do a ton of different things.
It turns out that sperm cells contain several types of RNA...and because it's sperm we're
talking about, these RNA have the potential to affect the development of the embryo formed
between that sperm and an egg.
Scientists have used mice to figure out ways that trauma can persist across generations,
and two separate studies have concluded that it is specifically microRNA, abbreviated as
miRNA, that might play the largest role.
But mice are mice, and although we have many similarities, the way that stress and microRNAs
are related in mice might be different than in humans.
So, in this brand new paper, scientists investigated how trauma early in life can affect the levels
of microRNA in the sperm of...you guessed it.
Mice /and/ men.
To address this phenomena in humans, the scientists took a sample of adult men and conducted an
observational study.
In this kind of research, the experimenters don't actually change anything that happens
to the subjects- they simply ask them about previous experiences and measure some kind
of response variable at the present time.
In this scenario, they measured their extent of childhood trauma by using something called
the adverse child experiences, or ACE, survey.
This questionnaire has the participating adult answer 10 yes or no questions regarding their
experiences at home until the age of 18.
Half of the questions are about the experiences of the participant themselves, and the other
half have to do with other family members.
This is an observational data set- all of the things already happened, and the scientists
didn't cause any of them to occur in a lab environment.
But, observational studies do still measure some kind of response.
For this study, the men who took the ACE survey also provided a sample of semen, and that
semen was filtered down to mature sperm that provided some data.
Demographic, behavioral, and general sperm characteristics were recorded as response
variables, and then the researchers compared these results to the ACE survey scores that
measured childhood trauma experience.
Of the 28 men included in the study, half scored between 0 and 1 on the ACE survey and
were labeled as the low ACE group.
"Low" in this case means they had experienced a low amount of childhood trauma.
7 men scored between 2 and 4, and the remaining 7 who scored more than 4 were labeled as the
high ACE group, meaning that they had experience a high amount of childhood trauma.
Since this paper is of mice and men, and our ability to ask mice survey questions isn't
/quite/ developed, the researchers exposed the study mice to early life stress by randomly
shuffling the individuals into different enclosures twice a week for 7 weeks.
Nothing life threatening or painful, but still...it definitely sucks to get a new apartment and
roommates every few days, and this level of stress was enough for the researchers to compare
experiment groups.
Since previous work had shown that microRNA could be one of the ways trauma gets passed
on to other generations, the scientists looked at the expression of microRNA in the sperm
from the low ACE group and compared it to the high ACE group.
Out of the hundreds of microRNAs detected in the human sperm samples, the team found
that microRNAs in a specific family called miR-34 and miR-449 had the most significant
differences in expression between the low childhood trauma and high childhood trauma
groups.
This was an interesting find on its own, as these specific families of microRNA have been
shown in some studies to affect things like brain development and mature sperm development,
as well as adult brain stress regulation.
Once they knew to check out the 34 and 449 families of microRNAs, they measured the expression
levels of these microRNAs in all of the study participants.
So what did they find?
For most of the demographic, behavioral, and general sperm characteristics, the team didn't
find clinically significant differences between the low, medium, and high ACE groups.
However, they did find a statistically significant inverse correlation between the levels of
microRNAs 34 and 449 and ACE scores.
Finding an inverse correlation just means that a pattern is found between two variables,
and when one goes up, the other goes down (or vice versa).
So in this situation, it means they found significantly /lower/ levels of the microRNAs
in /higher/ ACE score groups- those were the adult men who had experienced more early life
trauma.
Statistical significance aside, these differences were /really/ noticeable.
In fact, the paper reports that many of the men in the high childhood trauma group had
sperm with microRNA 34 and 449 levels /300-fold lower/ than many of the low childhood trauma
group men.
It's one thing to find a statistically significant difference between two groups, but the scientists
had to make sure that the differences were associated with early age trauma instead of
something else.
Even though data in other studies have shown that microRNA levels in sperm can be affected
by smoking and obesity, this group of researchers /didn't/ find a statistically significant
difference between these microRNA levels of smokers vs non-smokers or high vs low body
mass index scores.
They also didn't find any significant differences between microRNA expression when they looked
at variables like drug and alcohol use, sperm count, and sperm motility.
By ruling out associations with other variables, the researchers were able to conclude that
childhood trauma, as measured by ACE score, is associated with lower levels of certain
sperm microRNAs.
The researchers found the same statistically significant differences in these sperm microRNA
levels in mice when they compared the control group with the group that was exposed to the
roommate shuffling stress we talked about earlier.
Since mice can reproduce and mature much faster than humans, the researchers were able to
do some additional follow-up on the offspring of the stressed male mice.
They found that in mice, microRNA 34c and 449a levels were also reduced in the embryos
resulting from a stressed male mating with a control female.
The amazing thing, though, is what they found next.
Not only did the stressed male parent mate and produce embryos that had those lowered
levels of microRNAs, but the male embryos that grew into adult mice /also/ had sperm
with reduced levels of microRNAs.
That's right- the changes associated with trauma had actually been passed on across
generations.
This paper has received quite a bit of attention in both scientific circles and public media
outlets.
Here are some reasons why I think this study is creating such a buzz.
The world of genetics is currently undergoing major renovations.
Whereas developmental biologists used to pose the question "nature vs nurture", we're
now figuring out that the answer is a hard "nature AND nurture".
There's a wave of epigenetic research happening right now in almost all spheres of science.
Epigenetics refers to inherited changes in gene expression that don't affect the actual
genetic code, and this study is just one of the many exploring this trending topic.
And when it comes to psychiatry, epigenetics isn't a trendy topic just because it's
interesting- it also has major implications for understanding how trauma affects ourselves
and others.
We've discussed in other De-Natured episodes that being first is definitely one way to
make waves in science, and this study is no exception.
One reason the results are getting so much attention is because this is the first time
a research team has identified specific changes in human sperm microRNA levels in association
with early life trauma.
And that association means that the specific microRNA 34 and 449 molecules could eventually
be used in screening individuals for trauma.
This could be a big step forward in clinical situations if a microRNA screening was used
in addition to the ACE questionnaire.
Due to the nature of the questions on the ACE survey, it's possible that some patients
don't respond accurately, or might experience distress while sifting through painful past
experiences.
So, these microRNA markers could be used as a complement to the ACE surveys in clinical
settings, and that could be a big deal for the mental health profession moving forward.
Any observational study runs into problems when it comes to establishing causation.
All we can really accurately speak of is correlation- basically, the fact that two variables were
seen to have a relationship.
My biggest problems with this study have more to do with the sampling design than with the
fact that it's observational, and there are several that jumped out at me.
First of all, the 28 human subjects were voluntary participants, which means it's possible
that we're getting a biased sample.
For all we know, low microRNA 34 levels cause men to love being part of research trials,
so we just got a group of men with a confounding variable we didn't know about.
Additionally, the 28 men were all Caucasian, so we can't apply these results to the human
population as a whole.
And then there's the sample size.
28 semen samples.
The researchers mention that they were aiming for a sample size of 35 in order to have more
statistical power, but they halted recruitment at 28 due to low clinic volume.
When studies have a smaller than optimal sample size, there is always a possibility that the
results they observe are due to chance alone.
Throughout the discussion section, the authors do a great job of recognizing these downfalls
in methodology, and they suggest ways that the study can be expanded and improved in
the future.
Regardless of these methodological improvement points, this study is an amazing example of
a first step toward understanding the physical mechanism underlying the inheritance of trauma.
And figuring out the way our actions can affect those who aren't even born yet is definitely
worth the time and effort it takes to improve on current work.
Thanks for watching this episode of De-Natured here on Nature League.
Nature League is a Complexly production, and if you want to learn more about how trauma
can be inherited, check out this episode from our sister channel, SciShow Psych.
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