From Stress to a Resilient Brain, You Got More From Dad Than Your DNA.

A guest blog post by LifeOmic software engineer and biomedical scientist Chad Jarreau

We all inherit things from our parents. Besides heirlooms and other valuable and sentimental physical possessions, we also inherit genetic material or DNA from our parents. We share eye color, skin color, height and other gene-based traits with our parents and grandparents, along with their predispositions to disease states. If your grandfather and father both had colon cancer, your physician will probably strongly recommend that you get cancer screenings starting at a relatively young age. That’s because you could have inherited genetic material such as a gene mutation, potentially present in your family for generations, that predisposes you to colon cancer.

With Father’s Day coming up this Sunday, June 16, we might be thinking about all of the things we learned, gleaned and even inherited from Dad. Maybe we got his great looks. His brown eyes and curly hair. Or maybe we even got a gene mutation from him. We probably take for granted that he passed down some of his genes to us.

But could we have been impacted by his lifestyle, whether reckless (smoking) or healthy (maybe he was a sports nut!) before we were born? Can we inherit information from our parents’ lifestyles and environments?

As it turns out, the answer is yes!

We Inherit our Parents’ Genes

Research in the field of genetic inheritance has been active since its inception by Gregor Mendel’s experiments with pea plants the 1850’s. Genetic inheritance is the process of passing genomic information from parent to offspring. Your genome is the complete set of genes or DNA present in each of your cells (or at least most of them – some cells get rid of their genetic material, like adult red blood cells!). Your genome consists of a mix of your father’s and mother’s genomes.

Our genomes are considerably stable. Adaptive change in the genome that leads to observable changes in the human body based on environmental or other evolutionary forces is a slow process that happens over a very long period of time. This is why evolutionary changes span such long timescales. It takes many generations for a genome to shift such that it responds to its environment. As a fictitious example, if you grew up on an island where generations of people had consumed a scrumptious but somewhat toxic plant as a cultural practice, you might have inherited genetic variants that helped your body neutralize the toxic substance! Why? Because these variants would have been selected for because people who had them survived longer and had more kids. But you wouldn’t inherit such a trait just because your father or grandfather happened to eat this same plant during his lifetime.

Unless…

We Inherit our Parents’ Epi-Genetic Markings

A relatively younger class of research called epigenetics deals with the study of sometimes heritable changes that do not involve fundamental alterations in the DNA sequence of our genome. Instead, epigenetics describes changes that affect gene activity and expression patterns.

Did you know that all of the DNA-containing cells in your body contain the exact same genetic information, with rare exceptions? But if a brain cell contains the same genetic information and genome as a muscle cell, how do these cells look so different and perform such different functions? Epigenetics helps explain how all of the different cells in our body use the same information in different ways. For example, neurons in our brain use or express their genetic information in immensely different ways than do skin cells, kidney cells or liver cells.

Epigenetics is a vast field of research that is ever growing. In this blog post, I would like to concentrate on one aspect of epigenetics: transgenerational epigenetic inheritance. This is the transmission of information from one generation to the next that affects the traits of offspring without altering the primary structure of their DNA. Maybe dad’s coffee drinking didn’t have an effect on our DNA sequences (all made up of four nucleotides represented by the letters A, C, G and T). But it could theoretically have added layers of chemical modifications onto our DNA that can be inherited.

When we are born, the DNA sequences that comprise our genome are a “clean slate” – almost. As we age, our cells differentiate from the initial fertilized egg to all of the specialized tissues of the body. As this happens and as we experience life, depending on how much and the types of stress we are exposed to, our exercise patterns and eating habits, our DNA gets epigenetically (epi = on top of, e.g. on top of DNA sequences) “marked” in different ways. These markings include chemical compounds such as methyl groups (hydrocarbons) that get attached to or removed from our DNA or the protein structures called histones that help coil our DNA into neat little packages in our cells. These epigenetic modifications occur to help our cells ultimately fill very specific roles in our body, whether they are neurons or skin cells. Some of these changes are meant to be essentially permanent, so that our neurons can’t randomly decide to become skin cells. Others of these epigenetic changes are more temporary. Epigenetic marks on our DNA and histones can even be triggered by byproducts of our metabolism of food, our interaction with our environments, our stress levels and more.

So what happens to these epigenetic markings when we pass down our genetic material to future generations, inside of sperm or egg cells? During embryonic development in mammals, there are two major epigenetic reprogramming events. The first reprogramming event happens shortly after fertilization. The next happens during establishment of germ cells (the cells that give rise to sperm or egg cells). Reprogramming refers the the genome-wide removal of epigenetic marks. At a later point in time, these modifications are re-added.

That’s right – those epigenetic marks that decorate our DNA during our lifetimes need to be removed at some point in the development of our offspring – and most of them are.

The point of reprogramming is to return cells to a state of totipotency. Totipotency is the power of a cell to take on any form or function found in the body. In this way, the cells in an embryo can divide and establish new epigenetic patterns to create any cell type in the body. An analogy of this concept was proposed by Conrad Waddington and is called Waddington’s epigenetic landscape. In the metaphor, a cell (type), represented by ball, is placed at the top of a hill. The top of the hill represents cell totipotency. The hill contains many grooved paths in all directions that the ball can follow. These grooves represent possible cell fates (neuron, skin cell, etc.). The ridges between the grooves maintain the cell fates once they have been established; a ball that falls down one grove can’t (easily) jump over into another grove. As a ball continues down the slope, it will follow a groove in the hill and come to rest at a low point. The low point represents a final cell state, like a skin cell or a neuron.

The concept of reprogramming carries the cell to the top of the hill, where it can trace or fall down the same or a new groove in any direction come to rest at any of the many low points (cell fates) on the hill.

Yet, despite reprogramming, some epigenetic marks are passed from parents to their offspring and even further down! How does this happen?

Imprinting

As we mentioned above, in most cases during embryonic development, the epigenetic marks located on the genome are removed during reproduction and early development. However, there are some regions of the genome where epigenetic marks are not removed. This is important to normal embryonic development and has major effects that extend into adulthood. It is called imprinting.

The most readily available examples of imprinted genes in humans are associated with disease. Imprinting plays a role in both preventing disease, for example by silencing “bad” copies of genes, and in predisposing offspring to disease states. A body of evidence also supports the role of imprinting in non-disease states. Imprinted genes could help determine regulation metabolic processes, regulation of body temperature, and behaviors ranging from infant feeding to adult social behavior.

Your Father’s Stress…

Your father’s stress levels and exposure to stress before you were born could possibly influence your own stress responses today. What is fascinating about this is that it isn’t a function of how you were raised, but rather is due to epigenetic factors (beyond DNA sequences) that your father developed in his own lifetime and passed down to you in his sperm!

Research in animal models including mice has revealed that the stress a father experiences prior to reproduction impacts the stress responses of offspring. Researchers at the University of Pennsylvania found increased expression of nine specific microRNAs (miRNAs) in fathers that were exposed to particularly stressful events prior to mating. MiRNAs are pieces of genetic material that do not code for proteins but instead silence or degrade other RNAs that do create proteins. In addition epigenetic modifications including DNA methylation and histone modification, microRNAs are often classified as epigenetic-like factors. These molecules have proven to be a key factor in paternal transmission of epigenetic changes to offspring.

Through careful experiments, researchers showed that offspring mice sired by stressed fathers had dampened stress responses compared to a control group. (A “dampening” of the stress response may sound good, but it can lead to inappropriate responses to stress and potentially mental health issues.) Furthermore, these mice had significant changes in the expression of hundreds of genes in the paraventricular nucleus of their brains, a region that directly responds to stress. This suggests that epigenetic factors including microRNAs can affect both stress responses and early brain development.

Evidence of paternal transgenerational epigenetic inheritance of stress responses in humans, based on fathers’ exposure to trauma or stress early in life, is still limited. However, some early studies suggest that paternal stress can impact brain development and emotional well-being of their children, consistent with the mouse experiments.

“Unlike the genome, the epigenome is malleable to changing environments and these changes are somewhat heritable. Germ cells (sperm and oocytes) are likely vectors that transfer environmentally affected DNA methylation profiles to future generations.” – Denham, O’Brien, Harvey & Charchar

One Health Nut to Another

We know now that fathers’ early life environmental exposures behaviors like smoking can impact their offspring’s health and disease risk in negative ways, likely due to epigenetic marks inherited through germ cells.

But we can also inherit positive health traits from Dad through his epigenetic marks! In one animal study, voluntary exercise training of male mice before reproduction resulted in offspring that had improved glucose regulation, percentage of fat mass and glucose uptake in skeletal muscles. This was due to changes in small RNAs (epigenetic factors) in the sperm cells of the exercised mice.

There’s also evidence from one human study that three months of exercise training can lead to DNA methylation (epigenetic) changes in men’s sperm cells. These changes included epigenetic marks on genes known to be paternally imprinted, or where the epigenetic marks aren’t removed when the genes are passed onto offspring. The exercise training methylated or silenced sperm cell imprinted genes associated with autism, Alzheimer’s disease, obsessive compulsive disorder, obesity, Type 2 diabetes, high blood pressure and atherosclerosis.

Another mouse study published just this year suggests that male mice exercised before breeding pass on epigenetic factors (microRNAs again!) to offspring that are highly beneficial to brain health and cognition. The offspring of exercised male mice had more growth of brain cells in adulthood and improved brain cell energy production. Exercise (and potentially intermittent fasting as well as mindfulness!) is known to directly improve brain plasticity, or the ability of the brain to learn and adapt, based on changes in gene expression that control the production of proteins like BDNF, a nerve cell growth factor.  

Did you know? Exercise also leads to all kinds of positive DNA methylation or expression changes that may protect us from various diseases including cancer! Even if your dad didn’t exercise before you were born – you should! And invite him or other family members to join you!

Whether your dad ate a poor or healthy diet before you were born may also help determine your own risk for diabetes and heart disease today.

“Nutritional status (both over- and undernutrition), insulin resistance, exercise, chemical exposure, and behavior in the parent before and during pregnancy can all affect both paternal and offspring health.” – Sales et al., 2018

It may not be so surprising that a man’s diet can impact his own germ cell and sperm quality, for example through bioactive plant chemicals, minerals and vitamins. But only recently have we realized that diet can create epigenetic changes (remember, this means on top of the genome) in sperm cells that are passed on to offspring. Poor paternal diet is a risk factor for metabolic disease in offspring. One the other hand, healthy diets rich in plants among to-be-fathers may protect offspring from metabolic disease and cancer.

Your Fate Is Still Your Own

Whether your dad ate a healthy diet, smoked, exercised regularly, was a couch potato or experienced trauma before you were born, there’s good news. Your health fate is still your own. Even if you inherited epigenetic factors from your dad that predispose you to stress, diabetes or heart disease, your own health behaviors are incredibly important factors in reducing your risk for chronic disease. Conversely, even if you inherited protective epigenetic marks from your dad, these won’t protect you forever from the consequences of a poor diet, lack of exercise, smoking or other negative health behaviors.

The game of genetics and epigenetics is a roll of the dice. Though there is a lot that we cannot control, there is a lot that we can. Just as your dad may have activated his own brain plasticity and cancer suppressing genes with exercise and a healthy diet, you can do the same.

If you think you may have inherited, or just accumulated through the course of modern hectic life, epigenetic changes that predispose you to anxiety or depression, retraining your brain through interventions like mindfulness and meditation could help. Active research in the field of mindfulness is showing that mindful practices such as breathing meditation can have positive effects on us at the epigenetic level. For example, long-term meditation can change the expression of genes associated with inflammation (more here). Meditation can also directly impact activity, growth and plasticity in areas of the brain associated with awareness, emotion regulation and memory, areas that also respond to stressful triggers in your environment.

Learn more about mindfulness-based stress reduction and even sign up for an online course here.