Physical abuse in early childhood can impact epigenetic regulation of the stress response system, including the FKBP5 gene, even at the earliest indication of abuse, which was not found in children who had accidental injuries. The findings are important because unmitigated stress is associated with adverse health outcomes across the lifespan.
Child abuse is a leading cause of morbidity and mortality in the United States, affecting more than 650,000 children annually.
Unfortunately for many, the damage does not end at diagnosis. When compared to children who were not abused, abuse survivors have higher rates of serious physical and mental health problems later in life, such as cardiovascular disease, diabetes, cancer, anxiety, depression, PTSD, and suicide.
The biological underpinnings of these latent health vulnerabilities remain to be elucidated, and there are important gaps in our knowledge of when and how abuse confers health problems in adulthood; a better understanding of this link has clinical and prognostic relevance for these vulnerable children.
A growing body of evidence implicates the role of epigenetic alterations in linking early childhood trauma to health across the life course. The epigenome responds to physical and socioemotional stimuli in a child’s environment, influencing gene expression levels without altering the DNA sequence.
These biological responses can be adaptive or maladaptive. Recent research implicating epigenetics as a potential modulator of latent deleterious health problems has focused primarily on genes involved in the hypothalamic-pituitary-adrenal (HPA) axis.
The HPA axis is a multi-organ neuroendocrine system that regulates physiological responses to stress by modulating the release of cortisol into the bloodstream.
Several studies have found that traumatic and adverse childhood experiences are associated with epigenetic alterations in the FKBP5 gene, an important regulator of the stress response both in the brain and peripherally.
While others have not observed associations between childhood trauma and/or adversity with FKBP5 methylation in adulthood, the vast majority of these studies have been conducted in adults using retrospective ascertainment of childhood maltreatment.
This decades-long gap between exposure to maltreatment and the time of data collection introduces the possibility of bias and the potential for post-traumatic experiences to alter the epigenetic landscape in the intervening years.
Thus, questions remain as to whether early-life trauma induces DNA methylation (DNAm) changes within FKBP5 and, if so, whether such changes persist across the life course and are risk factors for health problems later in life.
A better understanding of the timing of abuse-associated epigenetic changes to the FKBP5 gene is an important addition to the knowledge base of epigenetics and child abuse.
The goal of this new study was to examine whether young children with concurrently diagnosed abusive injuries have different levels of DNAm within the FKBP5 gene compared to those diagnosed with accidental injuries.
In the study, conducted by researchers at Emory University Rollins School of Public Health and published in the journal Pediatric Research by the Nature group, they sought to identify whether children under four who were injured due to abuse had different patterns of methylation of the FKBP5 gene (a type of gene regulator) compared to children who were accidentally injured.
Methylation often acts like a “dimmer switch,” adjusting how strongly a gene is expressed and can be influenced by traumatic experiences. By studying these changes early on, the researchers hoped to better understand how abuse could lead to long-term health problems.
A representation of a DNA molecule that is methylated. The two white spheres represent methyl groups. DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can alter the activity of a segment of DNA without changing the sequence. Image: Christoph Bock, Max Planck Institute for Informatics.
In this small, cross-sectional pilot study, researchers recruited 82 children under the age of four with acute injuries from two children’s hospitals. Data on the injuries were collected along with samples from each child, specifically buccal swabs (cells from the inside of the cheek) and blood samples.
These samples were then analyzed to measure DNA methylation levels in the FKBP5 gene. A panel of experts reviewed each case and classified the injuries as resulting from abuse, accidents, or an undetermined cause.
The study found that children who were injured due to abuse had lower methylation levels in the FKBP5 gene than those with accidental injuries. This was true for both the oral and blood samples.
Importantly, this difference remained even when the researchers accounted for other factors that may influence the results, such as injury severity, socioeconomic status, and other psychological risk factors. These findings suggest that early childhood abuse can immediately alter the FKBP5 gene, affecting a child’s stress response system in ways that may have long-term consequences.
Lower methylation of FKBP5 may contribute to a delayed ability to return to a normal level of stress after a traumatic event, a factor often seen in people with anxiety-related conditions. The researchers emphasized that larger studies are needed to confirm these results and understand whether these epigenetic changes are directly related to long-term health outcomes.
This study highlights the importance of early detection and intervention for abused children to help mitigate the lifelong impact that abuse can have on their mental and physical health.
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Epigenetic differences in stress response gene FKBP5 among children with abusive vs accidental injuries.
Todd M. Everson, Kim Kaczor, Kathi Makoroff, Gabriel Meyers, Norell Rosado, Elizabeth Charleston, Gina Bertocci, Audrey Young, Janet Flores, Katie Lehnig & Mary Clyde Pierce
Nature. Pediatr Res. 94, 193–199 (2023)
Abstract:
Survivors of child abuse experience high rates of adverse physical and mental health outcomes. Epigenetic alterations in the stress response system, the FKBP5 gene specifically, have been implicated as one mechanism that may link abuse to lifelong health issues. Prior studies primarily included older individuals with a remote history of maltreatment; our objective was to test for differential methylation of FKBP5 in children with abusive vs accidental injuries at the time of diagnosis. We conducted a cross-sectional pilot study of acutely injured children <4 years old at two children’s hospitals (n = 82). Research personnel collected injury histories, buccal swabs (n = 65), and blood samples (n = 25) to measure DNA methylation. An expert panel classified the injuries as abusive, accidental, or indeterminate. Children with abusive as compared to accidental injuries had lower methylation of the FKBP5 promoter in buccal and blood cells, even after controlling for injury severity, socioeconomic status, and psychosocial risk factors. These findings suggest that epigenetic variation in FKBP5 may occur at the earliest indication of abuse and may be associated with delayed resolution of the HPA axis stress response. Additional testing for epigenetic differences in larger sample sizes is needed to further verify these findings.
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