Dr. Patrick McGowan discusses how stresses early in life can potentially impact epigenetic mechanisms and disease susceptibility. This short take was shot during a break at Keystone Symposia’s meeting on Environmental Epigenomics and Disease Susceptibility held in March 2011 in Asheville, North Carolina.
Environmental Influences on Developmental Programming
Well epigenetics is really central to the kind of research that I do, which is involved at looking at environmental influences on developmental programming. So my focus is really about the effects that stress plays early in life on things like risk for mental disorders and for other kinds of health effects later in life in the progeny and particularly with the focus on maternal influences.
What I was working on was I was working on the brains of suicide victims who had been abused as children, and we have information about their life experiences going all the way back to childhood. We had police reports, and we had interviews with their immediate family members or any other family members that we could find, and we were able to really reconstruct the life history using very standardized methods. And so that’s what gave us a big advantage in terms of being able to have accurate phenotypes from the individuals that we will ultimately be able to get brains from.
And so we could compare individuals who had a history of abuse with those who had no history of abuse but still committed suicide and also controlled individuals. And so what we found is that genes that are involved in regulating stress in the brain and also genes involved in regulating neural plasticity were influenced in conditions where the individual had suffered abuse in childhood but not in conditions where an individual had suffered no abuse but had also committed suicide or in controlled conditions.
“…the overarching hypothesis is that early-life events impact on epigenetic mechanisms that confer a trajectory leading to health effects later in life.”
And so this is one of the first studies in humans that showed the impact of everyday life experiences on outcomes later in life through epigenetic mechanisms. So in my new lab, I’m continuing that work with the emphasis on early-life experiences, and I think from that perspective, we can bring to bear several ways of answering the question of how is it relevant to human health. And we use studies of humans to do that, but we also use animal work to do that as well to get at questions about biological mechanism.
Well, the overarching hypothesis is that early-life events impact on epigenetic mechanisms that confer a trajectory leading to health effects later in life. And so we’re trying to address how that occurs through several directions, one of which is to look at animal models, where we can directly manipulate stress, during the prenatal period or during the postnatal period and look at effects on health later in life with a particular focus on effects on mental health.
So these are effects in the brain and effects on behavior, and we can address this in human models as well and human models in this case would be identical twin populations where we have control over the genetic differences between individuals, and we can see how life experiences impact their epigenetic differences.
And so one of the ways that we are approaching that is that we’re looking at individual (the pairs of twins) who come from relatively harsh socioeconomic conditions versus pairs of twins who come from relatively stable families and relatively high socioeconomic conditions, and we look at the discrepancies in epigenetic profiles among the pairs of twins. And so that gives us an indication of other things aside from genetics that play a role in conferring phenotype.
And then the third way that we get at this is that we want to understand the effects of early adversity in animal models not just in the kind of austere laboratory environment, where everything is well-controlled, but we wanna see how does this translate to the real world. And so I’ve been collaborating with ecologists at the University of Toronto Scarborough to look at the effects of early stressors.
And in this case, what we’re talking about is predator stress on the maternal environment conferring epigenetic effects on the offspring, in conditions where you have very high predation or very low predation. And so we wanna see if the same genes that are impacted with respect to stress in the laboratory environment are impacted also in the real world when you have conditions of very high or very low stress.
There was a lot of optimism early on about our ability to solve the basis of a lot of diseases by knowing the genotype of the individual or the organism and being able to pinpoint genes that are involved in the phenotypic outcomes. In my case, it would be mental disorders. Even complex mental disorders like schizophrenia were thought to be solvable by knowing the differences in genotypes between individuals who are affected and individuals who are not, but that didn’t really pan out in the way that people had hoped.
And so I think that one of the things that epigenetics offers is a way to link environmental influences directly with stable effects on the phenotype through interaction with the genome, essentially altering the genome in a way that may not necessarily pass transgenerationally but may impact the individual over the course of the lifespan in a way that confers risk for mental disorders.
The talks have been really amazing and fasting, and I’m really starting to see a sense of community developing around the area in the field of environmental epigenetics that wasn’t there even a few years before. People who are older than me remember times when it was much worse than it was even a few years ago in terms of trying to convince people that epigenetic effects are relevant for understanding phenotype, but now coming to a meeting like this, there are so many people interested, so many people involved in trying to integrate an epigenetic understanding of whatever it is they’re interested in into their research program that it gives me a sense of community and makes me think that things are going to move much more rapidly along than even they have in the recent past.