Maternal Childhood Adversity Associated with Low Infant Birth Weight

February 17, 2015 · Posted in Genetics · Comment 

mother and infant

In a study of the effect on infant health of a mother’s experience of adversity in childhood by researcher Deborah Kim and colleagues, both adversity in childhood (such as physical abuse or the loss of a parent) and stress during pregnancy were associated with low infant birth weight and lower gestational age at birth.

Among 146 women enrolled in the study, 58.2% percent scored a 0 on the Adverse Childhood Experience Questionnaire (ACE), 24% scored a 1, and 17.8% scored a 2. Those who scored higher on the ACE also scored higher on a scale measuring perceived stress. A score of 2 or higher on the ACE was associated with lower gestational age at birth, indicating infants born prematurely. Greater stress during pregnancy was associated with lower gestational age at birth and lower infant birth weight. When potential confounding demographic factors were removed from the analyses, ACE scores of 2 or higher were still associated with lower infant birth weight, while perceived stress was no longer associated with either low birth weight or gestational age.

Childhood adversity is associated with increases in inflammation and multiple adverse medical consequences in adults. The researchers called childhood adversity a “significant predictor of poor delivery outcomes” for women.

Editor’s Note: This research shows that a mother’s health and earlier life stressors could have an adverse effect on her child.

Childhood adversity leaves behind a residue of neuroendocrine and neuroclinical alterations that can persist into adulthood. Many are mediated by epigenetic changes, consisting of small chemical marks that attach to DNA and the histones around which it is wrapped.

In addition to these neurobiological alterations mediated by epigenetic effects, there is new evidence that some epigenetic marks can be passed on to the next generation via a mother’s egg or a father’s sperm. Thus, either directly or indirectly, parents’ adverse life experiences can influence the health of their offspring.

Transgenerational Transmission of Drug Exposure and Stress in Rodents

January 28, 2015 · Posted in Genetics · Comment 

baby rats

New data suggest that there can be transgenerational transmission of the effects of drug exposure and stress from a paternal rat to its offspring. The father mates with a female who was not exposed to drugs or stress and never has any contact with the offspring.  Consensus is now building that this transmission occurs via epigenetic alterations in sperm.

Epigenetic alterations are those that are mediated by chemical changes in the structure of DNA and of the histones around which DNA is wrapped. These changes do not alter the inherited gene sequences but only alter how easy it is for genes encoded in the DNA to be activated (transcribed) or suppressed (inhibited).

There are three common types of epigenetic modifications. One involves the attachment of a methyl or acetyl group to the N-terminals of histones. Methylation typically inhibits transcription while acetylation activates transcription. Histones can also be altered by the addition of other compounds. The second major type of epigenetic change is when the DNA itself is methylated. This usually results in inhibition of the transcription of genes in that area. The third epigenetic mechanism is when microRNA (miRNA) binds to active RNA and changes the degree to which proteins are synthesized.

At a recent scientific meeting, researchers described the various ways epigenetic changes can be passed on to future generations.

Researcher Chris Pierce reported that chronic cocaine administration increased brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex of rats. (BDNF is important for learning and memory.) The cocaine administration led to acetylation of the promoter for BDNF.

This exposure to cocaine in male rats who then fathered offspring led to two changes in the offspring, presumably conveyed by epigenetic changes to the fathers’ sperm. The first change was a decrease in cocaine reinforcement. The offspring took longer to acquire a cocaine self-administration habit. The second change was long-lasting learning deficits in the male offspring, specifically recognition of novel objects. The deficit was associated with a reduction in long-term potentiation in the offspring. Long-term potentiation is the strengthening of synapses that occurs through repeated patterns of activity. Surprisingly, the following generation also showed deficits in learning and memory, but did not show a loss of long-term potentiation.

Editor’s Note: These data indicate that alterations in sensitivity to cocaine (in this case slower acquisition of cocaine self-administration) can be transferred to a later generation, as can learning deficits in males. These data suggest that fathers’ experience of drugs can influence cocaine responsiveness and learning via epigenetic mechanisms likely mediated via epigenetic changes to the father’s sperm.

This research suggests the possibility that, in a human clinical situation, there would be three ways that a father’s drug abuse could affect his child’s DNA. First, there is the traditional genetic inheritance, where, for example, an increased risk for drug abuse is passed on to the child via the father’s genetic code. Next, drug abuse brings about epigenetic changes to the father’s sperm. (His genetic code remains the same, but acetyl groups attach to the BDNF promoter section of his DNA, changing how those proteins get produced.) Lastly, if the father’s drug abuse added stress to the family environment, this stress could have epigenetic effects on the child’s DNA.

Researcher Alison Rodgers described how epigenetic changes involving miRNA in paternal rats influence endocrine responsivity to stress in their offspring. Rodgers put rats under stress and observed a decrease in hormonal corticosterone response to stress. When a father rat was stressed, nine different miRNAs were altered in its sperm. To prove that this stress response could be passed on transgenerationally via miRNAs, the researchers took sperm from an unstressed father, loaded it with one or all nine miRNAs from the stressed animal, and artificially inseminated female rats. Rodgers found that the sperm containing all nine miRNAs, but not the sperm carrying one randomly selected miRNA, resulted in offspring with a blunted corticosterone response to stress.

Researcher Eric Nestler showed that when a rodent goes through 10 days of defeat stress (being defeated repeatedly by a larger animal), they begin to exhibit behaviors resembling those seen in depression. Social avoidance was the most robust change, and continued for the rest of the animal’s life. Animals did not have to be physically attacked by the bigger animal to show the depression-like effects of defeat stress. Just witnessing the repeated defeats of another rat was sufficient to produce the syndrome. Again, father rats that experienced defeat stress or witnessed it passed this susceptibility to defeat stress on to their offspring (with whom they never had any contact), likely by epigenetic changes to sperm. Read more

Childhood adversity, epigenetics, and hippocampal volume

September 26, 2014 · Posted in Genetics, Risk Factors · Comment 

upset boy

At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Booij reported that in humans, there is an interaction between adversity experienced during childhood, and an epigenetic variation in the short form of the serotonin transporter (5HT-T ss, or SLC6A4), which can influence hippocampal volume during depression.

Epigenetics refers to environmental influences on the way genes are transcribed. The impact of life experiences such as stress is not registered in DNA sequences, but can influence the structure of DNA or tightness of its packaging. Early life experiences, particularly psychosocial stress, can lead to the accumulation of methyl groups on DNA (a process called methylation), which generally constricts DNA’s ability to start transcription (turning on) of genes and the synthesis of the proteins the genes encode. DNA is tightly wound around proteins called histones, which can also be methylated or acetylated based on events in the environment.  When histones are acetylated, meaning that acetyl groups are attached to them, DNA is wound around them more loosely, facilitating gene transcription (i.e. the reading out of the DNA code into messenger RNA, which then arranges amino acids in order to construct proteins). Conversely, histone methylation usually tightens the winding of DNA and represses transcription.

Booij followed 33 children who had experienced some form of adversity at a young age until they were 15 or 16, examining methylation of the serotonin transporter in their T cells and monocytes compared to 36 children who had not experienced adversity during childhood. He found that in children who had experienced abuse in childhood, the degree of that abuse was correlated with methylation of the serotonin transporter and was inversely related to the volume of the hippocampus, as measured using magnetic resonance imaging (MRI). Thus, child abuse yields lasting epigenetic effects (methylation of the serotonin transporter) and has anatomical consequences in teenagers, as seen in smaller hippocampi. These data parallel converse findings by Joan Luby et al. published in the journal PNAS in 2012, in which increased maternal warmth directed toward a child aged 4-7 was associated with increased volume of the hippocampus several years later.

Digestion of Wheat and Milk Releases Peptides that Might Cause Inflammation

September 8, 2014 · Posted in Risk Factors · Comment 

bread and milk

Some people have found that gluten-free or casein-free diets have improved their intestinal, autoimmune, or neurological symptoms. (Casein is a protein found in mammals’ milk. Cow milk is high in casein while human milk proteins are 20–45% casein.) One explanation for the good effects of these diets is that peptides that are released during digestion of these foods can create epigenetic changes in gene expression, adding methyl groups to DNA strands that increase inflammation.

As infants transition from getting all of their nutrition from the placenta to using their gastrointestinal tract, their diet may lead to epigenetic modifications that affect their health later in life. Epigenetics refers to changes in genes that do not affect the inherited sequence of DNA, but affect how easily the DNA is transcribed to produce proteins. Methyl or acetyl groups can be added to DNA or the histones around which it is wound.

When a person digests casein (from either human or animal milk) or gliaden (a protein derived from wheat), peptides are released that activate opioid receptors, modulating the uptake of the amino acid cysteine in neurons and in the gastrointestinal tract. This decrease in cysteine uptake is associated with drop in the antioxidant glutathione and a methyl donor (a molecule with a reactive methyl group that can easily become part of another molecule) called S-Adenosyl methionine.

In addition to decreasing cysteine uptake, the peptides also increase DNA methylation and create epigenetic changes in genes involved in redox (changes in oxidation) and methylation homeostasis.

These processes are described in a 2014 article by Malav S.Trivedi et al. in the Journal of Nutritional Biology. Trivedi et al. conclude that milk and wheat can change antioxidant activity and gene expression. Differences in the peptides in human and cow milk may explain developmental differences between children who are breastfed and those who receive formula.

The decrease in antioxidants caused by peptides from wheat and milk can predispose people to inflammation and oxidation, explaining why wheat- or casein-free diets might be useful.

Twin Study Helps Clarify Epigenetic Component to Bipolar Disorder

May 21, 2014 · Posted in Risk Factors · Comment 


An epigenetic finding from a study of twins may shed light on why some people develop bipolar disorder and others don’t.

Epigenetics refers to changes in genes that do not affect the inherited sequence of DNA, but affect how easily the DNA is transcribed to produce proteins. Environmental events such as stress or exposure to chemicals can bring about epigenetic changes by adding or subtracting acetyl or methyl groups from strands of DNA or the histones around which it is wound. In this way twins’ DNA can differ—not in its sequence but in its physical structure and the ease with which it produces proteins.

At the 2014 meeting of the International Society for Bipolar Disorders, researcher J. Ayers Ringlera et al. presented their study of pairs of twins in which one twin had bipolar disorder and the other didn’t. The ill twins showed more methylation of SLC1A2, the gene for the excitatory amino acid transporter 2 (EAAT2), which clears the excitatory neurotransmitter glutamate from the synapse of neurons. Methylation of the gene suppresses the amount of transporter expressed, so less glutamate gets cleared.

Editor’s Note: Glutamate abnormalities play a role in bipolar disorder. This finding by Ringlera et al. may explain why the drug N-acetylcysteine (NAC) works in bipolar disorder—NAC increases the number of glial glutamate transporters and helps clear excess glutamate from the synapse.

Exercise Helps Mice with Spacial Learning

February 6, 2014 · Posted in Current Treatments, Neurochemistry · Comment 

mice exercising

Exercise increases brain-derived neurotrophic factor (BDNF), a protein that protects neurons and is important for learning and memory. In a study of mice who were trained to find objects, sedentary mice could not discriminate between familiar object locations and novel ones 24 hours after receiving weak training, while mice who had voluntarily taken part in exercise over a 3-week period could easily distinguish between these locations after the weak training.

Mice who received sodium butyrate (NaB) after training behaved similarly well to those who had exercised. Sodium butyrate is a histone deacetylase (HDAC) inhibitor, meaning it helps keep acetyl groups on histones, around which DNA is wrapped, making the DNA easier to transcribe. In this case the easy transcription of DNA enables learning under conditions in which it might not usually take place.

Both sodium butyrate and exercise promote learning through their effects on BDNF in the hippocampus. They make the DNA for BDNF easier to transcribe, suggesting that exercise can put the brain in a state of readiness to create new or more lasting memories.

HDAC Inhibitor Facilitates Extinction of Fear Memories in the Reconsolidation Window

February 5, 2014 · Posted in Potential Treatments · Comment 

mouse in its hole

Unwanted recall and re-experiencing of traumatic memories is thought to be a crucial mechanism leading to the onset of post-traumatic stress disorder (PTSD). The inability to diminish (extinguish) those memories contributes to the persistence  of PTSD. A new study suggests that the extinction of fear memories can be enhanced by a drug that acts epigenetically to alter the structure of DNA and subsequent gene expression.

DNA is wound around structures called histones, and chemical changes can affect how loosely or tightly the DNA is wound. Johannes Graff et al. reported in the journal Cell in 2014 that application of a histone deacetylase (HDAC) inhibitor, which keeps acetyl groups on histones, ensuring that DNA is wrapped more loosely and is easier to activate (or transcribe), helps rodents revise both new and old fear memories after they have been actively recalled.

When a memory is actively recalled, the trace of that memory in the brain becomes more amenable to revision over the proceeding five minutes to one hour (a period known as the reconsolidation window). New learning and extinction training (to get rid of the memory) lasts much longer when it takes place during the reconsolidation window than when the same procedures are performed 6 hours later (after the reconsolidation window has closed) or if the procedures are performed in the absence of active recall of the memory (when the reconsolidation window is never opened).

We have previously described the 2013 work of Xue et al. published in the journal Science, which showed that this specific procedure could yield long-lasting extinction of a patient’s craving for cocaine or heroin, and could reduce amygdala activation (as observed via functional magnetic resonance imaging) in response to an experiment that produces conditioned fear (Agren et al. Science, 2013).

Editor’s Note: This new work by Graff et al. adds another twist.  Older long-term memories are more stable and less amenable to new learning than more recent (but still long-term) memories.  The application of an HDAC inhibitor changes this and makes even very old memories amenable to lasting revision. The HDAC inhibitor that Graff et al. used was a specific inhibitor for HDAC type II.  However, the anticonvulsant valproate (Depakote) is a potent although nonspecific HDAC inhibitor, and presumably could have the same facilitating effect as the more selective drug.

EMDR (Eye Movement Desensitization and Reprocessing), which has been widely used for the treatment of PTSD, includes active memory recall, immediately followed by an attempt to re-interpret and construct new memories of the trauma.  These elements could open the reconsolidation window. However, EMDR works less well with older memories compared to more recent traumatic memories.

The Graff et al. data would suggest that adding an HDAC inhibitor such as valproate to EMDR-like work might make it more effective in revising more remote memories. Graff et al. encourage controlled clinical trials with a type II inhibitor to confirm that their findings in rodents would generalize to humans. While awaiting such validation through controlled clinical trials, it would not be surprising if clinicians started trying out the paradigm on their own using valproate.

Epigenetic Regulation of Social Attachment: Genes May Dictate Partner Preference

January 15, 2014 · Posted in Genetics, Neurobiology · Comment 

prairie voles

Prairie voles, which form monogamous bonds for life, are often studied as a source of information about social attachment. New findings indicate that these mating choices are regulated by epigenetics.

Epigenetics refers to changes in genes that do not affect the inherited sequence of DNA, but affect how easily the DNA is transcribed to produce proteins. Environmental events such as stress or exposure to chemicals can bring about epigenetic changes by adding or subtracting acetyl or methyl groups from strands of DNA or the histones around which it is wound.

When prairie voles mate naturally, levels of oxytocin, often thought of as the “bonding hormone,” increase in the reward area of the brain, the nucleus accumbens. When voles are given a drug that increases histone acetylation, their behavior mimics natural partner preference. The drug, known as a histone deacetylase (HDAC) inhibitor, blocks the removal of acetyl groups, and researchers Wang et al. reported in the journal Nature Neuroscience in 2013 that oxytocin levels increase in the nucleus accumbens. The voles receive the drug and mate for life, suggesting that social bonding is epigenetically regulated.

Similar epigenetic alterations may play a role in human social bonding and vulnerability to depression. Depressed mothers and their offspring have low levels of oxytocin in their blood, and maternal depression is a risk factor for depression in the offspring, as reported by Apter-Levy et al. in the American Journal of Psychiatry in 2013.

Editor’s Note: Perhaps depressed moms who show reduced physical and verbal interactions with their newborns should receive special training in holding, cuddling, cooing, and other social bonding activities that could increase their infants’ oxytocin levels and potentially also decrease their own anxiety and depression.

Types of Epigenetic Modifications

January 3, 2014 · Posted in Genetics, Theory · Comment 

DNA strandWe sometimes refer to epigenetics, a process by which the environment impacts not your inherited genes (based on the DNA nucleotides that encode amino acids to be sequenced in the production of proteins), but how easy it is to activate gene transcription or repress gene transcription.

There are various epigenetic modifications that can occur. Sometimes acetyl or methyl groups are added to DNA or the histones around which DNA is wound.

1. DNA Methylation (usually repressive)

2. Histone Methylation (usually repressive)

3. Histone Acetylation (usually activating)

4. DNA hydroxymethylation

5. Micro RNAs (si-mRNA) (repressing or activating)

6. Nucleosome remodeling by chromatin regulatory enzymes. If the histone spools around which DNA is wrapped are moved further apart, this is activating. If the histones are moved closer together, this is repressing.

Transgenerational Transmission of PTSD

January 2, 2014 · Posted in Risk Factors, Theory · Comment 

mother with newborn

At a recent scientific meeting, Rachael Yehada showed that PTSD-like traits could be passed transgenerationally. Mothers in New York City who were pregnant on September 11, 2001 and developed post-traumatic stress disorder (PTSD) produced children with low cortisol in their blood (a sign of PTSD). If the fathers had PTSD during the mother’s pregnancy, the children had high cortisol.

These gender-related findings have some parallels in studies of rodents. When a rat pup is separated from its mother for 15 minutes, the mother is overjoyed to see the pup return and licks and grooms it excessively. This maternal overprotection yields an animal with lifelong low cortisol through an epigenetic process. The glucocorticoid receptor gives a feedback message to suppress cortisol, and glucocorticoid receptors are increased in the pups’ brains because of lower methylation of the DNA promoter for glucocorticoid receptors.

If a father has PTSD, there is more methylation of the promoter for glucocorticoid receptors and less expression of them in the forebrain. There is also less feedback suppression of cortisol and the baby exhibits high cortisol.

The methylation of the glucocorticoid receptors in the offspring’s white blood cells is highly correlated (r=0.57, p<0.005, n=23) with methylation in the parent’s white blood cells.

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