Neurotransmitters Can Also Function As Epigenetic Marks

June 2, 2020 · Posted in Genetics, Peer-Reviewed Published Data · Comment 
lab rat

The most common epigenetic marks involve methylation of DNA (which usually inhibits gene transcription) and the acetylation and methylation of histones. Acetylation opens or loosens the winding of DNA around the histones and facilitates transcription, while methylation of histones leaves the DNA tightly wound and inhibits transcriptional activation.

Researcher Ashley E. Lepack and colleagues have identified a surprising type of epigenetic mechanism involving neurotransmitters. They report in a 2020 article in the journal Science that neurotransmitters such as serotonin and dopamine can act as epigenetic marks. Dopamine can bind to histone H3, a process called called dopaminylation (H3Q5dop). In rats undergoing withdrawal from cocaine, Lepack and colleagues found increased levels of H3Q5dop in dopamine neurons in a part of the midbrain called the ventral tegmental area (VTA), a part of the brain’s reward system. When the investigators reduced H3Q5dop, this decreased dopamine release in the reward area of the brain (the nucleus accumbens) and reduced cocaine seeking. Thus, dopamine can be both an important transmitter conveying messages between neurons and a chemical mark on histones that alters DNA binding and transcriptional regulation.

Researcher Jean-Antoine Girault provided commentary on the article by Lepack and colleagues, writing that “[t]he use of the same monoamine molecule as a neurotransmitter and a histone modification in the same cells illustrates that evolution proceeds by molecular tinkering, using available odds and ends to make innovations.”

Editor’s Note: Epigenetic marks may remain stable and influence behavior over long periods of time. They are involved in the increased reactivity or sensitization to repeated doses of cocaine through DNA methylation. Such sensitization can last over a period of months or longer. If the methylation inhibitor zebularine is given, animals fail to show sensitization. Now a newly identified epigenetic process, dopaminylation, is found to alter histones and is associated with long-term changes in cocaine-seeking.

The clinical message for a potential cocaine user is ominous. Cocaine not only creates a short-term “high,” but its repeated use rewires the brain not only at the level of changes in neurotransmitter release and receptor sensitivity, but also at the genetic and epigenetic level, changes that could persist indefinitely.

The sensitization to motor hyperactivity and euphoria that occur with cocaine use can progress to paranoia and panic attacks and eventually even seizures (through a process known as kindling).

The dopaminylation of histones in the VTA could lead to persistent increases in drug craving and addiction that may not be easily overcome. Thus, the appealing short-term effects of cocaine can spiral into increasingly adverse behaviors and drug-seeking can become all consuming. While these adversities do not emerge for everyone, the best way to ensure that they do not is to avoid cocaine from the start.

Manic episodes that include a feeling of invincibility, increased social contacts, and what the DSM-5 describes as “excessive involvement in pleasurable activities that have a high potential for painful consequences” are a time that many are at risk for acquiring a substance problem. For the adolescent who has had a manic episode, ongoing counseling about avoiding developing this type of additional long-term, difficult-to-treatment psychiatric illness could be lifesaving. Describing the epigenetic consequences of substance use may or may not be helpful, but may be worth a try.

Environment Can Leave “Molecular Scars” Via Epigenetic Processes

May 29, 2020 · Posted in Genetics, Peer-Reviewed Published Data · Comment 
DNA

A 2020 review article by researchers Julia Richetto and Urs Meyer in the journal Biological Psychiatry provides a good overview of the role epigenetic modifications play in schizophrenia and related disorders.

The article provides a powerful understanding of how the environment can induce long-lasting changes in the structure of DNA (not only in schizophrenia, but also in bipolar disorder). This process, known as epigenetics, can have life-long influences on brain chemistry and behavior, and remarkably, some of these epigenetic changes can even be transmitted to the next generation.

While the sequence of DNA that one inherits from one’s parents does not change over the course of one’s life, what can change is how loosely or tightly the DNA is wound around proteins called histones, making it easier or harder to transcribe the genetic material held there. The addition of a methyl group to DNA usually inhibits transcription, while the addition of an acetyl group to histones usually facilitates transcription. These alterations in the shape of the DNA that result from environmental exposures or behavior can be passed on through generations.

Richetto and Meyer describe these chemical changes to DNA as “molecular scars,” which are left when environmental stress occurs during sensitive developmental periods. For example, patients with schizophrenia who experienced stressors in early life have higher levels of the enzyme histone deacetylase than patients who had stress or trauma later in life. Histone deacetylase would remove the acetyl groups on histones, which would inhibit gene transcription.

Other factors that have been implicated in epigenetic modifications in schizophrenia, such as DNA methylation of key developmental pathways, include pre- or post-natal stress, a challenge to a mother’s immune system during pregnancy, pre- and post-natal nutrition, exposure to drugs or toxic substances, and cannabis use in adolescence.

Richetto and Meyer suggest that epigenetics may explain why schizophrenia (and we would add bipolar disorder) can differ so much across individuals, and may help researchers and clinicians determine how best to treat different individuals.

Editor’s Note: This editor has written about how epigenetic changes can mediate sensitization to the recurrence of life stressors, episodes of mood disorder, and bouts of substance abuse, each of which can drive illness exacerbation and progression in bipolar disorder (see the 2016 article by Robert M. Post in the journal Bipolar Disorders, “Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention”).

The chemical changes to our DNA, histones, and microRNA emphasize how important it is to begin long-term preventative treatment starting after a first episode of mania. This not only helps limit episode recurrence and the accumulation of stressors and bouts of substance use that can cause illness deterioration, but also limit the placement of these “molecular scars” on our DNA. The key to treating bipolar disorder is: prevent episodes, protect the person and the brain.

Civil War Data Shows Father’s Trauma Can Affect Son’s Lifespan

November 27, 2018 · Posted in Risk Factors · Comment 

Civil War soldiers

An economist at the University of California Los Angeles (UCLA) has used Civil War data to determine that trauma experienced by a father can affect the lifespan of his son, but that a mother’s healthy diet during pregnancy can neutralize this risk.

Researcher Dora Costa used records from the National Archive to identify Union soldiers who were held as prisoners of war (POWs) by the Confederacy. She compared records of their children’s lifespans to the children of Union soldiers who were never held as POWs, finding that the sons of POWs were more likely to have died at any given age. (The study included only children who lived to be at least 45 years old.) Detailed records were kept because families of soldiers and POWs were eligible for generous pensions.

When looking at the data, Costa expected to find that socioeconomic status was the factor that explained discrepancies in lifespans among children of Civil War veterans. However, she noticed that the difference in lifespan only appeared in sons, and only to sons born after the war.

This pointed to an epigenetic explanation. Epigenetics is the idea that some aspects of a parent’s experiences (such as deprivation, drug use, etc.) can be passed on to their children during the gene transcription process. While a parent’s inherited genetic sequence doesn’t change, the structure of their DNA can be wound tightly or loosely depending on life experiences, and this affects how easily their genes are transcribed when passed on to their children.

The sons of POWs in the worst camp environments (typically during the later years of the war when prisoner exchanges were less frequent and overcrowding and malnutrition were common in camps) had even shorter lifespans than the sons of POWs who were imprisoned in less dire circumstances.

The research also looked at birth months to determine whether mothers would have had access to good nutrition while pregnant. Sons born to POW fathers in the later months of the year (whose mothers were likely to have had access to good nutrition) had lifespans comparable to the sons of non-POWs, while sons of POWs born earlier in the year fared worse.

The research was published in the journal Proceedings of National Academy of Sciences in 2018.

Editor’s Note: This is another example in humans of findings that have been clear-cut in animal studies. A father’s experiences, such as stressors or substance abuse, can influence the next generation even if the parent has no contact with the offspring. Epigenetic marks on DNA, histones (the structures around which DNA is wound), or microRNA of the sperm appear to carry these unexpected transgenerational effects.

Phthalates in Plastics and Creams Cause Epigenetic Changes to Sperm

March 16, 2018 · Posted in Genetics, Risk Factors · Comment 

sperm

A recent study suggests that chemicals called phthalates that are used to make plastic flexible and to improve the texture of lotions, creams, and powders have effects on human sperm. Phthalates have become common in our environment since the invention of plastics, and most people have detectable levels of phthalate metabolites in their bodies.

The study, published by Haotian Wu and colleagues in the journal Human Reproduction in 2017, measured DNA methylation in a group of men’s sperm and compared this to levels of phthalate metabolites in the men’s urine.

DNA methylation changes the structure of a DNA strand. Extra methyl groups are attached to the strand, affecting the way it is transcribed, even though the inherited genetic sequence on the DNA strand remains the same. Changes like these to the structure of DNA and histones, which give DNA its helix shape, are known as epigenetic changes.

Wu and colleagues found 131 regions of DNA methylation in the men’s sperm that they could link to at least one of the phthalate metabolites found in the men’s urine.

Sperm takes 72 days to mature. Wu and colleagues suggest that exposure to phthalates in plastics or personal care products during this period may cause alterations to sperm, which could potentially affect the ease of conception or the development of potential offspring. The changes the researchers observed affected genes related to growth, development, and cellular function and maintenance.

In addition to chemical exposure, stressors and drug use can also bring about epigenetic changes to sperm. A father’s offspring may then have altered risk of drug use or other behaviors as a result of these epigenetic changes.

Phthalates, which can disrupt the endocrine system, have previously been found to alter men’s hormone levels and to hurt sperm quality. This is the first study to find that in people, phthalate concentrations measured before conception are associated with DNA methylation in sperm. This was a fairly small study in 48 men, and it remains to be studied whether the changes to sperm affect the offspring’s prenatal and early childhood development.
In addition to their presence in flexible plastics, phthalates may also be found in products such as shaving cream, shampoo, soaps, and detergents.

Child Abuse Linked to Adolescent Obesity

December 7, 2016 · Posted in Risk Factors · Comment 

child abuse linked to adolescent obesityNew 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 Rats, Mother’s Exercise Habits Affect Those of Offspring

October 10, 2016 · Posted in Genetics · Comment 

mothers who exercise more have offspring who exercise moreA recent study suggests that when a mother rat exercises during pregnancy, her offspring will exercise more too.

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.

Father’s Age, Behavior Linked to Birth Defects

September 28, 2016 · Posted in Risk Factors · Comment 

dad's behavior can affect baby's health

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.

In Rats, Dad’s Cocaine Use Affects Son’s Spatial Memory

July 14, 2016 · Posted in Genetics, Neurobiology · Comment 

cocaine use affects offspring's spatial memory

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.

Memory Activates Epigenetic Changes in Mice Brain Cells

April 4, 2016 · Posted in Genetics, Neurobiology · Comment 

epigenetic changes to mouse brain cells

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.

Link Between Childhood Trauma and Difficult Course of Bipolar Disorder Clarified

November 9, 2015 · Posted in Genetics, Risk Factors · Comment 

Trauma in childhood linked to course of bipolar disorder

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.

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