Article summary with Using Principles of Behavioral Epigenetics to Advance Research on Early-Life Stress by Conradt - 2017

What is this article about?

It is known that in the United States, at least 16 million children under the age of 6 experience stress early in their lives. This stress ranges from abuse to neighbourhood violence. Especially children living in poverty experience a lot of stress. This stress starts in utero, when their mothers experience a lot of stress. They often have lower birth weight, and they experience more neighbourhood and family violence. Also, they are less likely to be cared for by a nurturing adult, and their caregivers often have psychopathological disorders.

Being exposed to such adversities in childhood predicts one third of adult-onset psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD). However, knowing this does not tell us anything about how this happens. Also, why do some children that experience the same stressors seem unaffected by it?

Early childhood is a sensitive period for the effects of stress on development. So, stress experienced in early lifehood can have a big impact on later development. However, the effect of this stress differs between children. Some children are affected to a great extent, while others do not seem to have any problems. The answer as to how this is possible may stem from epigenetics.

Epigenetics has not been used often in research in developmental science. However, it may yield interesting insights. For example, epigenetic processes may be one way in which early life stress leads to biological changes, which alters how children respond physiologically and behaviorally to stress. Also, epigenetics may also help to identify which children are vulnerable to early life stress.

What is epigenetics?

The DNA of an organism does normally not change without an unusual environmental event (such as radiation). Twins have the same DNA, but why do they look and often behave differently? This may be due to epigenetics. Epigenetics are modifications to DNA, that do not alter the sequence of DNA itself. Thus, the DNA is the same, but there are small differences. Epigenetic processes can be the result of histone modifications, genomic imprinting, and DNA methylation. DNA methylation is the best well-studied form of epigenetics. To explain, DNA exists of four nucleotides: cytosine, guanine, adenine, and thymine. The expression of genes occur in a region of the gene called the ‘promotor’,  in which there are many cytosine and guanine nucleotides. They are often clustered in the promotor region, and these clusters are called CpG islands. When a methyl molecule is added to a cytosine molecule, DNA methylation occurs. This blocks transcription, and thus activity of the gene is turned off.

DNA methylation does not directly lead to changes in behavior. Often, it has no result at all. It only results in behavioral changes when the methylation occurs close to a transcription factor binding site. This transcription factor induces gene expression.

For developmental researchers, this is important information, because this suggests that there should be specific CpG sites selected which are close to transcription factors.

Van Ijzendoorn and colleagues defined child development as “experiences being sculpted in the organism’s DNA through methylation.” Thus, when children grow up in stressful conditions, because of DNA methylation, they may suffer from psychological and physical diseases.

How can epigenetics explain how early-life stress becomes biologically embedded?

Researchers state that when an association is found between a stressor and a physiological marker, this indicates that an experience has been biologically embedded.

For example, one study with rodents showed that maternal licking, grooming, and arched-back nursing led to lower levels of DNA methylation in Exon 17 of the promotor region of glucocorticoid receptor gene NR3C1. In turn, this leads to greater expression of glucocorticoid receptors, and more efficiency of the hypothalamic-pituitary-adrenal (HPA) axis. This HPA axis regulates the amount of cortisol in our bloodstream, the stress hormone. Compared to rodents who did not receive this maternal care, the group who did get the maternal care appeared less stressed and anxious, explored more, and showed lower levels of cortisol. Researchers tried to translate these findings to humans, but this showed to be difficult, because it’s easier to examine the brains of rats. In humans, one can mostly use peripheral tissues.

However, Oberlander succeeded in showing a similar finding in humans. He found that three-months-old of mothers who had depression showed greater cord blood methylation of Exon 1F in the promotor region NR3C1. Also they showed greater cortisol reactivity. Another study showed that DNA methylation in other sites of Exon 1F also leads to more cortisol reactivity in response to a social stressor for infants of 5 months old. In turn, this leads to less optimal self-regulation in behavior.

When children experience abuse early in life, this also leads to DNA methylation. For example, in 11 to 14 year olds, greater methylation was found as a result of physical abuse.

Gunnar and Loman stated that maternal sensitivity is the analogue of the licking and grooming in rats. This can help to regulate and buffer children’s responses to stress. The authors of this article tested this hypothesis. They examined whether maternal sensitivity, maternal depression, or both are related to DNA methylation of Exon 1F of the NR3C1 promotor. They found that maternal sensitivity and maternal depression predict DNA methylation. Also, infants of mothers who were depressive and less sensitive showed greater methylation. This is different compared to mothers who had depression, but who were sensitive to their infants.

How can epigenetic processes be used to identify who is most susceptible to the effects of early-life stress?

There have been four studies conducted that have looked into epigenetic processes as moderators of early-life stress on behavioral outcomes. The results showed that prenatal depression was related to less self-regulation, more lethargy, and more hypotonia (low tone), but only if the infants had high levels of methylation of a specific CpG site of NR3C1. Another study showed that a variant of the serotonin transporter gene predicted more unresolved loss or trauma in adulthood, but only for those individuals who had lower levels of DNA methylation in their serotonin transporter. Thus, it could be the case that prenatal exposure to maternal depression has an impact on their infant’s behavior, through epigenetic processes.

What are some challenges in the field of epigenetics and what are potential solutions?

The field of epigenetics is not an old field. Thus, there are several challenges, namely:

• There is an overreliance on candidate genes. Most often, the NR3C1 gene is examined. However, more genes should be examined.
• There is a need for studies of normative developmental trajectories. There is not much known about how DNA methylation develops normatively. Researchers should try to identify this.
• Tissue type. All the studies that have been published in epigenetics have used peripheral tissue. However, this is problematic, because it may not be the same as neural tissue.
• Independent replication. Independent replication is important, because some epigenetic studies have reported false positives (Type I errors), and some have reported false negatives (Type II errors).
• Measuring phenotype. There is a need for finding associated epigenetic processes with a phenotype of interest (such as temperament, stress reactivity). If this is not found, it is difficult to measure the associations between epigenetic processes and these traits.
• Assumptions of causality. Causality can not be determined without intervention research. Therefore, there should be intervention work conducted.

What are the conclusions?

Exposure to early life stress leads to a lot of negative consequences, ranging from diabetes to depression. Therefore, it is important to know how to decrease these consequences. One such way can come from epigenetics.