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In this De-Natured segment of Nature League, Brit breaks down a recent scientific journal article about the effects of childhood trauma on adult sperm cells of mice and men.

Article citation:
Dickson, D.A., Paulus, J.K., Mensah, V., Lem, J., Saavedra-Rodriguez, L., Gentry, A., Pagidas, K., and Feig, L. A.

Reduced levels of miRNAs 449 and 34 in sperm of mice and men exposed to early life stress

Translational Psychiatry, 2018

Article link:
https://www.nature.com/articles/s41398-018-0146-2.pdf

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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.