Anthony Kang ’18 and Katty Wu ’18

It’s 1:50pm. You have an assignment to submit in 10 minutes. You are meeting your team project members in about an hour. You need to call your parents about your health insurance. You have a paper due tomorrow. And you still have not eaten lunch.

Do you feel anxious? These feelings of anxiety are a normal reaction to stressful feelings of tensions and thoughts. And though these feelings may be uncomfortable and seemingly uncontrollable, these feelings keep us alert and inform us about how to behave.

Though feelings of anxiety are common, depending on the person, there are various degrees of how we experience anxiety. But why is this the case? It probably would not be surprising if I told you that your susceptibility to anxious behaviors are a result of the environment you are in. Now, what if I told you that your susceptibility can be affected by the lifestyle of your parents, or even your grandparents? Would you be surprised?

We wanted to explore this topic of how the lifestyle of past generations may affect our susceptibility to feelings of anxiety. In this essay, we focus on dad’s lifestyle and how his environment may alter his sperm and be passed onto future generations. These alterations then affect his offsprings’ susceptibility to feelings of anxiety.

The inheritance of our behaviors is a topic of ongoing research. During reproduction, mom and dad pass down their genetic information to their offspring through an egg and a sperm cell, respectively. If you are an old school techie, you are certainly familiar with a CD. Like how data is stored in a CD, genetic information is stored within DNA (Figure 1). So when mom and dad pass on their DNA to their child, this is similar to how we may give a CD to a friend. In both cases, the recipient acquires the information that is given to them. This is the concept of genetic inheritance. For example, this is why people say we look like mom and dad. It is because we inherit our physical features as a result of the genetic information passed down from our parents.

Figure 1: Summary of CD Analogy

However, the inheritance of behaviors, such as anxiety, is not this simple. For example, research found that paternal heroin exposure can lead to higher levels of anxiety in multiple generations of offspring1. Male mice who were directly given heroin showed an increase in anxiety and aggressive behaviors compared to male mice who were not given any narcotics. The mice who were born from this father also showed increased anxiety levels and aggressive behaviors. What this suggests is that the effects of heroin were passed down from the father to his offspring, even if the offspring were never directly introduced to the narcotic. However, the authors suggest that the inheritance of susceptibility to these anxious behaviors is not just the result of genetic information being passed down. Rather, it may be the result of the ability to utilize this genetic information.

Our cells don’t utilize all of the genetic information at a single time, instead our genetic information is divided into many small sections of information, called genes, that carry out different functions. Sometimes these genes cannot be utilized properly and our cells will turn off genes based on environmental signals and what the cell needs. This is similar to how data on a CD is sorted into different files (Figure 1). If the individual files on a CD are like the individual genes that make up our DNA, then we are able to open certain files for our purposes just like how cells can utilize specific genes for their purposes.

These alterations to how we are able to utilize our genetic information without changing it are known as epigenetic changes. In other words, the files on the CD do not change, but instead our ability to open these files is altered. The ability of these alterations to be passed down is known as epigenetic inheritance, which involves different mechanisms.

One mechanism of epigenetic inheritance involves the cell putting a chemical tag on a gene to turn it off. This process is known as methylation. In our analogy of a CD, this is similar to placing a parental lock on certain files, so that they cannot be opened. Note that methylation of certain genes is not necessarily bad. Instead, it is just a marker to tell our cells to not utilize that gene.

In fact, research found that paternal exercise can change the methylation of certain genes and can decrease the susceptibility to certain conditions, such as those that are anxiety-related. Joshua Denham et al. showed that the effects of paternal exercise could be passed down from generation to generation2. They found that a father who exercises influences the methylation patterns of the DNA in the sperm2. They also suggested that this change in methylation patterns affects the offspring’s susceptibility to many different conditions, including anxiety-related behaviors2. In addition, Silvia Cimino et al. explored that in humans, a father’s methylation pattern is related to his offspring’s methylation pattern on the DAT gene3. The DAT gene is related to how much we feel the effect of a signal called dopamine. Dopamine acts to make us feel satisfaction. Therefore, by methylating the DAT gene, the cell will change how often the DAT gene is utilized and influence how we feel the effects of dopamine. This results in a change in our overall emotion and behavior. The researchers believe that the methylation pattern of the DAT gene in the father can influence not only the father’s susceptibility to anxiety, but also be passed down to affect the offspring’s susceptibility to feelings of anxiety.

This passing down of these methylation patterns from generation to generation is a form of epigenetic inheritance (Figure 2). This occurs when an egg and a sperm cell come together and the zygote (the product of the two) undergoes epigenetic reprogramming. This includes global DNA demethylation, which is the removal of any methylation on the DNA4. This removal of all epigenetic changes is because the zygote will eventually develop into all the other cells in the body, such as the skin cells, the muscle cells, or the brain cells. Therefore the cell attempts to remove all methylation marks and start with a clean slate so that all the genes are available to be utilized to develop into the proper cells.

Figure 2: Epigenetic Inheritance through Sperm. Image modified from Yeshurun et al. 2018.

Think about how this relates to a CD. Let’s say you are passing on your CD to a friend. You will have to remove all of the parental locks on the files so that your friend can utilize all of the data on the CD. This is similar to global demethylation. In our DNA, this leaves a blank methylation pattern that can be modified over the course of development of the zygote. However, research has shown that there have been specific areas in DNA that escape DNA demethylation and these methylation marks are left behind on the parents’ DNA and get passed down to the offspring4. In other words, some of the files on your CD still have their parental locks and your friend cannot utilize these files. This would explain how the methylation patterns in the father can cause the same methylation patterns in the offspring and lead to anxiety-related behaviors.

There is another mechanism through which epigenetic inheritance can occur. Even if there is no methylation and the cell can utilize the gene, structures called micro-RNAs (miRNAs) can still disrupt the gene from being utilized properly. So in our analogy, even if there is no parental lock and we have the ability to open up a file, sometimes it will not open up because the file may be corrupted from other reasons. In addition, from generation to generation, miRNAs can be maintained in the sperm to be passed on to regulate the development of the organism and its behavior, such as anxiety5. Let’s say on our CD, a file is corrupted when it is given to your friend. If the factors that caused the corruption remain on the CD, the file your friend receives will still be corrupted. For example, researcher A.K. Short found that when male mice exercise, it can alter the miRNA of their sperm6. This miRNA is maintained and passed down. This can lead to a positive effect on their offspring. The offspring of fathers who did exercise were less susceptible to feeling anxiety compared to the offspring of fathers who did not exercise6.

The research behind the epigenetic susceptibility of anxiety is ongoing. It has informed us of the potential long-term effects of environmental abuse or environmental stress. Through methylation patterns, as well as differences in miRNA, the lifestyle of dad is able to be passed down to affect his offspring’s susceptibility to anxiety. This can potentially carry on for multiple generations, but more research needs to be done.

It is also important that we recognize that there are caveats to mouse studies. In mouse studies, the researchers measure anxiety behaviors by tests such as the Open-Field test, which measures whether or not the mouse was anxious being in a field of bright light. Another test includes the Elevated-Plus Maze test which measures whether or not the mouse was anxious being on an open ledge at a tall height. Though these tests are common to measure anxiety in mouse models, we must remember that the fear, escape, and avoidance behaviors are animal states that are present throughout the animal kingdom. Therefore, it may be possible that a mouse who avoids entering a field of bright light may not be representative of a human who is anxious (Morris-Rosendahl, 2002). However, despite the fact that these studies are difficult and imperfect, it does not diminish the fact that these studies have provided us with continued growth and knowledge in understanding the biological mechanisms that are inherited.

The idea that our susceptibility to feelings of anxiety can be inherited from our parents and grandparents is exciting. However, with this excitement, we have to keep in mind that science produces information that does not exist as a pure form of research and knowledge. There will be social implications that come hand-in-hand with research. Science has been used to support and disprove public thought and opinion. And it has been used to drive change, whether it be the production of new pharmacological treatments or social change in our daily habits.

With these studies, we can come to some disheartening conclusions of how our behaviors are prophecy-like — determined from the lifestyles of our parents and grandparents. However, we want to recognize that feelings of anxiety are not the result of solely genetic or epigenetic mechanisms. The leftover specific methylation of DNA and the miRNA content that you receive from your father in his sperm may make you more vulnerable to feelings of anxiety. However, other social factors involved, such as your education, financial resources, social status, environment, will also play a large role in determining how your epigenetic predisposition will play out. Having anxiety is not an epigenetic prophecy to be fulfilled.

On a brighter note, our research suggests that our susceptibility to feelings of anxiety can be inherited from previous generations. This suggestion can reduce the stigma behind feelings of anxiety and how people understand what it means to be anxious. It may help others feel less alone in their battle with anxiety and know that there are innate and uncontrollable reasons for for why they feel anxious and uncomfortable in certain situations. It can bring a more “tangible” side to anxiety.

Understanding the mechanisms of epigenetic inheritance of behaviors will help us understand the different degrees of feelings of anxiety and give us a more holistic understanding of how to deal with these feelings. Additionally, understanding the relationship between our environment and how its effects are passed onto future generations helps us to tackle the infamous, classical debate of nature vs. nurture. In our opinion, this debate is outdated and archaic because it views nature and nurture as two separate, mutually exclusive entities. However, our research suggests that the effects of nurture of the environment which Dad is in (as well as Mom is in), will be passed on to their offspring via methods of nature, such as germ cell epigenetic modifications and gene regulation in humans.

References

  1. Naquiah, M. Z., James, R. J., Suratman, S., Lee, L. S., Hafidz, M. I., Salleh, M. Z., & Teh, L. K. (2016). Transgenerational effects of paternal heroin addiction on anxiety and aggression behavior in male offspring. Behavioral and Brain Functions,12(1). doi:10.1186/s12993-016-0107-y
  2. Denham, J., Obrien, B. J., Harvey, J. T., & Charchar, F. J. (2015). Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans. Epigenomics,7(5), 717-731. doi:10.2217/epi.15.29
  3. Cimino, S., Cerniglia, L., Ballarotto, G., Marzilli, E., Pascale, E., D’Addario, C., Tambelli, R. (2018). DNA Methylation at the DAT Promoter and Risk for Psychopathology: Intergenerational Transmission between School-Age Youths and Their Parents in a Community Sample. Frontiers in Psychiatry,8. doi:10.3389/fpsyt.2017.00303
  4. Hackett, J. A., Sengupta, R., Zylicz, J. J., Murakami, K., Lee, C., Down, T. A., & Surani, M. A. (2012). Germline DNA Demethylation Dynamics and Imprint Erasure Through 5-Hydroxymethylcytosine. Science,339(6118), 448-452. doi:10.1126/science.1229277
  5. Pang, T. Y., Short, A. K., Bredy, T. W., & Hannan, A. J. (2017). Transgenerational paternal transmission of acquired traits: Stress-induced modification of the sperm regulatory transcriptome and offspring phenotypes. Current Opinion in Behavioral Sciences,14, 140-147. doi:10.1016/j.cobeha.2017.02.007
  6. Short, A. K., Yeshurun, S., Powell, R., Perreau, V. M., Fox, A., Kim, J. H., . . . Hannan, A. J. (2017). Exercise alters mouse sperm small noncoding RNAs and induces a transgenerational modification of male offspring conditioned fear and anxiety. Translational Psychiatry,7(5). doi:10.1038/tp.2017.82

Image Sources

Figure 1 Gene Vector (Modified) – https://ghr.nlm.nih.gov/primer/basics/gene

Figure 2 Epigenetic Inheritance through Sperm (Modified) from Figure 1 in Yeshurun, S., & Hannan, A. J. (2018). Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders. Molecular Psychiatry. doi:10.1038/s41380-018-0039-z

Audio Sources

Intro/Outro Music – https://www.youtube.com/watch?v=Dw20ZkMwI10&list=PLoRsiQFY-9jIm0LWWeIVPNnAj2FlmQoXj&index=2

Transition Music – https://www.youtube.com/watch?v=sGsC98vR4Q4&list=PLoRsiQFY-9jIm0LWWeIVPNnAj2FlmQoXj&index=1

Fighting Sound Effect – https://www.youtube.com/watch?v=4oVcuhT1cgc

Ding Sound Effect – https://www.youtube.com/watch?v=NovyGK3L9hY

Bloop Sound Effect – https://www.youtube.com/watch?v=0brnh65myJU

Clean Slate Sound Effect – https://www.youtube.com/watch?v=CANUZ6ncygY

Lock Sound Effect – https://www.youtube.com/watch?v=4gnHTyyDDHY

Phone Call Sound Effect – https://www.youtube.com/watch?v=HRtC2sDiKqM

Chomp Sound Effect – https://www.youtube.com/watch?v=BGmezpWWico

Featured Image Source

Yeshurun, S., & Hannan, A. J. (2018). Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders. Molecular Psychiatry. doi:10.1038/s41380-018-0039-z