New research clarifies how trauma in early life can lead to obesity in adolescence. In a study of 160 young people between the ages of 9 and 15, researcher Janitza Montalvo-Ortiz and colleagues identified seven sites in the genome where DNA methylation predicted body mass index (BMI) in adolescence. The researchers also collected information on family traumas that occurred during the participants’ childhoods and found that DNA methylation and family trauma such as child abuse interacted to predict BMI.
Epigenetics describes the ways life experiences can change how easily DNA is turned on or off. While the genes coded by DNA sequences one inherits from one’s parents never change, the structure of DNA can change. DNA methylation is one type of epigenetic change that refers to the addition of methyl groups to promoter regions of DNA in response to life events.
In this research, which was presented at the 2016 meeting of the Society of Biological Psychiatry, Montalvo-Ortiz and colleagues found that the site of DNA methylation with the strongest link to BMI in adolescence was a gene called MAP2K3. This gene had previously been linked to obesity, but this is the first time DNA methylation at this site has been linked to both obesity and childhood trauma. Other relevant gene sites where DNA methylation occurred include ANKRD2, CPXM2, NUBPL, and RFK.
In the study, published by Jesse D. Eclarinel and colleagues in The FASEB Journal, pregnant mother rats were placed in cages that each contained an exercise wheel. One group had access to a working wheel on which they could run. The other group had the same wheel, but it was locked so that they couldn’t use it for running. Daughters of the rats who ran during pregnancy ran more in adulthood (both at 60 days and 300 days after birth) than daughters of the rats who couldn’t run during pregnancy.
While it is a mystery why this occurs, it is consistent with other data about the ways that a parent’s experiences can influence the next generation, even when the offspring don’t grow up with the parents.
For example, father rats conditioned to associate a specific smell with fear of an electric shock have offspring that also fear that smell (but not other smells).
Drug use is another example. Father rats given access to cocaine have offspring that are less interested in cocaine. Interestingly, father rats exposed to marijuana have offspring that are more interested in opiates.
Experiences with drugs or stress are thought to affect the next generation via ‘epigenetic’ marks on ova or sperm. These marks change the way DNA is packaged, with long-lasting effects on behavior and chemistry. Most marks from a mother’s or father’s experiences are erased at the time of conception, but some persist and affect the next generation.
The nature versus nurture debate is getting more and more complicated. Parents can influence offspring in a number of ways: 1) genetics; 2) epigenetics in the absence of contact between parent and offspring after birth; 3) epigenetic effects of behavioral contact—that is, parents’ caring and warmth versus abuse and neglect can affect offspring’s DNA expression too. All these are in addition to any purely behavioral influence a parent may have on their offspring via discipline, teaching, being a role model, etc.
Editor’s Note: The moral of the story is, choose your parents wisely, or behave wisely if you yourself become a parent.
For decades, researchers have known that a pregnant mother’s diet, hormone levels, and psychological state can affect her offspring’s development, altering organ structure, cellular response, and gene expression. It is now becoming clear that a father’s age and lifestyle at the time of conception can also shape health outcomes for his offspring.
Older fathers have offspring with more psychiatric disorders, possibly because of increased incidence of mutations in sperm.
A 2016 article by Joanna Kitlinska and colleagues in the American Journal of Stem Cells reviewed findings from human and animal studies about the links between fathers’ behaviors and their offspring’s development.
Father’s behavior can shape gene expression through a phenomenon described as epigenetics. Epigenetics refers to environmental influences on the way genes are transcribed. While a father’s behavior is not registered in his DNA sequences, it can influence the structure of his DNA or the way in which it is packaged.
Kitlinska suggests that these types of findings should eventually be organized into recommendations for prospective parents. More research is also needed into how maternal and paternal influences interact with each other.
Some findings from the article:
- A newborn can have fetal alcohol spectrum disorder even if the mother doesn’t drink. “Up to 75% of children with [the disorder] have biological fathers who are alcoholics,” says Kitlinska.
- Father’s alcohol use is linked to low birth weight, reduced brain size, and impaired cognition.
- Dad’s obesity is linked to enlarged fat cells, diabetes, obesity, and brain cancer in offspring.
- A limited diet in a father’s early life may reduce his children and grandchildren’s risk of death from cardiovascular causes.
- Dad’s advanced age is correlated with higher rates of schizophrenia, autism, and birth defects in his children.
- Psychosocial stress on dads can affect their children’s behavioral traits.
Evidence is mounting that certain behaviors by parents can leave marks on their sperm or eggs that are passed on to their offspring in a process called epigenetics. In a recent study by researcher Mathieu Wimmer and colleagues, male rats that were exposed to cocaine for 60 days (the time it takes for sperm to develop fully) had male offspring who showed diminished short- and long-term spatial memory compared to the offspring of male rats that were not exposed to cocaine. Female offspring were not affected in this way.
The spatial tasks the offspring rats completed depended heavily on the hippocampus. Wimmer and colleagues believe that cocaine use in the fathers decreased the amount of a brain chemical called d-serine in the offspring. D-serine plays a role in memory formation and the brain’s ability to form synaptic connections. Injecting the offspring of rats who were exposed to cocaine with d-serine before the spatial memory tasks normalized the rats’ performance.
In a 2015 article in Nature Neuroscience, Stefan Bonn and André Fischer reported that when mice were prompted to use their long-term memory to recognize a specific environment, epigenetic changes occurred in their neurons and glia. Epigenetic changes refer to chemical alterations in DNA or histones (which give DNA structure) that increase or decrease the expression of certain genes. Sometimes environmental factors lead to a methyl or acetyl group joining a strand of DNA or histones, changing how easily the genes are turned on or off.
When the mice used their long-term memory, the main change that occurred was DNA methylation in their neurons. There were also changes to histones that were linked to memory acquisition but resulted in few changes in gene expression. The DNA methylation changes, on the other hand, changed neural pathways, leading to “rewiring” of the brain.
A collaboration between Norwegian and French researchers led by Bruno Etain has clarified the pathway by which childhood trauma is linked to worse outcomes among people with bipolar disorder. The researchers, who presented their work in a poster at the 2015 meeting of the Society of Biological Psychiatry, replicated earlier findings by this editor (Robert Post) that patients who experienced trauma as a child had a more adverse course of bipolar disorder. Etain and colleagues found a link between childhood trauma and an earlier age of onset of bipolar disorder, rapid cycling, suicide attempts, and cannabis misuse.
The researchers identified more than 550 patients with bipolar disorder, who answered questionnaires about their history of bipolar disorder and childhood trauma. Their DNA was also analyzed, and the researchers found that the effect of childhood trauma on age of onset was mediated by the presence of common genetic variants in proteins related to stress (the serotonin transporter) and immune function (Toll-like receptors). They also found that the traits of mood lability (or moodiness) and impulsivity mediated the effects of trauma on clinical outcomes.
The lasting epigenetic effects of child maltreatment and adversity noted in the above abstract are consistent with a large literature showing more epigenetic effects in these individuals than in controls. While genetics are important, the impact of the environment is also substantial.
Epigenetics is the process by which environmental factors affect the way a person’s genes are transcribed. These changes, which may include the addition or subtraction of methyl groups from DNA, change the DNA’s structure (how tightly it is wound around the histones that give it shape) but not its sequence. These structural changes, which affect how easily the DNA is transcribed, can then be passed on to future generations. A new study by Ulrike Stadlbauer and colleagues presented at the Society of Biological Psychiatry explored a particular pathway by which an infection in a pregnant mouse can lead to behavioral changes in three following generations of mice.
Pregnant mice were given injections that produced an infection. A first generation of offspring were interbred to create a second generation of offspring, and these were interbred to create a third generation of offspring. The first generation of offspring had epigenetic changes in methylation and hydroxymethylation to promoter regions of two enzymes that regulate synthesis of the neurotransmitter GABA, and these epigenetic changes were associated with reduced mRNA expression of these two genes.
All three generations of offspring had deficits in social interaction, short-term memory, and cued fear conditioning. Interestingly, the second and third offspring generations also exhibited depression-like behavior that had not been present in the original mothers or the first generation of offspring.
Editor’s Note: This is another fascinating demonstration of how environmental occurrences, which can include stressors, exposure to drugs, and now immune challenges, can have effects across generations, likely through epigenetic changes that persist in ova or sperm. Amazingly, it turns out that the environment can change traits in future generations, not by inducing changes to gene sequences, but through epigenetic changes to the structure of DNA or histones that persist across generations.
It is well established that certain early experiences can affect a person’s risk of developing a mental illness. Adversity in childhood, including abuse or the loss of a parent, is a risk factor not only for diagnosis of a mood disorder, but also for a more difficult course of illness. This may occur through epigenetic means. Epigenetics refers to a process by which environmental factors can change the way that DNA is transcribed, for example through the addition of methyl groups to strands of DNA. This tends to inhibit DNA from being transcribed and producing protein growth factors and other neurochemicals that are important for development.
A study by Kieran J. O’Donnell and colleagues presented at the 2015 meeting of the Society of Biological Psychiatry investigated whether epigenetics play a role in the success of a parenting intervention called the Nurse Family Partnership. Participants were 27-year-olds born to women who had received the intervention or a control intervention. Genome-wide DNA methylation was measured in the 188 participants’ blood.
Analysis of the blood revealed that the Nurse Family Partnership intervention was associated with DNA methylation at 1015 sites across 593 genes. Some of these sites were enriched for certain neurodevelopmental processes. Maltreatment in childhood was also associated with methylation at 1552 sites across 878 genes.
Editor’s Note: The take-home message of this landmark study is that maltreatment in childhood exerts lasting effects on the genome via epigenetic mechanisms, but early positive intervention also exerts lasting epigenetic effects, which likely have a normalizing impact.
Life experiences such as adversity in childhood have been linked to epigenetic changes to DNA. These changes do not affect the sequence of DNA, but can change how tightly DNA is wound, and thus how easily it is transcribed. One epigenetic change that can occur following adversity in childhood is methylation of the gene for the glucocorticoid receptor (NR3C1). A recent study by Kathryn Ridout and colleagues examined links between early adversity, methylation of this gene, and behavioral problems in childhood. Adversity was linked to methylation of the gene at exons 1D and 1F in the promoter of NR3C1. Methylation of the gene was associated with internalizing behaviors (e.g. depression, anxiety) but not externalizing behaviors (e.g. attention deficit hyperactivity disorder (ADHD) or oppositional defiant disorder) in children of preschool age. The NR3C1 methylation was a significant mediator of the internalizing behaviors in children who had experienced adversity.
Editor’s Note: Similar associations of methylation of the glucocorticoid receptor with childhood adversity have been reported in other clinical and animal studies and provide a mechanism for the long-lasting adverse effects of stressors in childhood.
Events like surgery or heart attacks that cause inflammation can lead to cognitive deficits or depression for months or years afterward, even though the direct effects of inflammation wear off within weeks. In a recent study, Natalie Tronson and colleagues subjected mice to surgical heart attack, sham surgery, or no operation, and observed how well they absorbed new learning eight weeks later.
Both male and female mice had impairments in fear learning following surgical heart attacks. Female mice that received sham surgery also showed deficits in fear learning. When the researchers dissected the mice, analyzing their blood and hippocampi after the eight-week period, inflammatory cytokine measures had normalized as expected, but the researchers found other abnormalities.
Intracellular signaling was dysregulated, and there had been epigenetic changes in cells of the hippocampus. (Epigenetic changes refer to those that change the structure of DNA, such as how tightly it is wound, rather than its sequence. For example, the addition of acetyl groups to DNA or the histones around which it is wound.) The researchers observed increased histone acetylation and phospho-acetylation following the heart attacks.
The researchers concluded that a systemic inflammatory event, such as heart attack or surgery, can cause long-term memory impairment and changes in mood through epigenetic mechanisms. They compared the findings to those of other studies in which normal aging and memory-impairing treatments such as chemotherapy had also been associated with increases in histone acetylation or decreases in histone deacetylase activity.