Christina Boeck

Inflammation in adult women with a history of child maltreatment: The involvement of mitochondrial alterations and oxidative stress.

The experience of maltreatment during childhood is associated with chronic low-grade inflammation in adulthood. However, the molecular mechanisms underlying this pro-inflammatory phenotype remain unclear. Mitochondria were recently found to principally coordinate inflammatory processes via both inflammasome activation and inflammasome-independent pathways. To this end, we hypothesized that alterations in immune cell mitochondrial functioning and oxidative stress might be at the interface between the association of maltreatment experiences during childhood and inflammation. We analyzed pro-inflammatory biomarkers (levels of C-reactive protein, cytokine secretion by peripheral blood mononuclear cells (PBMC) in vitro, PBMC composition, lysophosphatidylcholine levels), serum oxidative stress levels (arginine:citrulline ratio, l-carnitine and acetylcarnitine levels) and mitochondrial functioning (respiratory activity and density of mitochondria in PBMC) in peripheral blood samples collected from 30 women (aged 22-44years) with varying degrees of maltreatment experiences in form of abuse and neglect during childhood. Exposure to maltreatment during childhood was associated with an increased ROS production, higher levels of oxidative stress and an increased mitochondrial activity in a dose-response relationship. Moreover, the increase in mitochondrial activity and ROS production were positively associated with the release of pro-inflammatory cytokines by PBMC. Decreased serum levels of lysophosphatidylcholines suggested higher inflammasome activation with increasing severity of child maltreatment experiences. Together these findings offer preliminary evidence for the association of alterations in immune cell mitochondrial functioning, oxidative stress and the pro-inflammatory phenotype observed in individuals with a history of maltreatment during childhood. The results emphasize that the early prevention of child abuse and neglect warrants more attention, as the experience of maltreatment during childhood might have life-long consequences for physical health.

Child Maltreatment Is Associated with a Reduction of the Oxytocin Receptor in Peripheral Blood Mononuclear Cells

Background: Child maltreatment (CM) and attachment experiences are closely linked to alterations in the human oxytocin (OXT) system. However, human data about oxytocin receptor (OXTR) protein levels are lacking. Therefore, we investigated oxytocin receptor (OXTR) protein levels in circulating immune cells and related them to circulating levels of OXT in peripheral blood. We hypothesized reduced OXTR protein levels, associated with both, experiences of CM and an insecure attachment representation. Methods: OXTR protein expressions were analyzed by western blot analyses in peripheral blood mononuclear cells (PBMC) and plasma OXT levels were determined by radioimmunoassay (RIA) in 49 mothers. We used the Childhood Trauma Questionnaire (CTQ) to assess adverse childhood experiences. Attachment representations (secure vs. insecure) were classified using the Adult Attachment Projective Picture System (AAP) and levels of anxiety and depression were assessed with the German version of the Hospital Depression and Anxiety scale (HADS-D). Results: CM-affected women showed significantly lower OXTR protein expression with significantly negative correlations between the OXTR protein expression and the CTQ sum score, whereas plasma OXT levels showed no significant differences in association with CM. Lower OXTR protein expression in PBMC were particularly pronounced in the group of insecurely attached mothers compared to the securely attached group. Anxiety levels were significantly higher in CM-affected women. Conclusion: This study demonstrated a significant association between CM and an alteration of OXTR protein expression in human blood cells as a sign for chronic, long-lasting alterations in this attachment-related neurobiological system.

Intergenerational gene × environment interaction of FKBP5 and childhood maltreatment on hair steroids

BACKGROUND The inconsistency in results of cortisol alterations after childhood maltreatment (CM) might arise due to the fact that no study so far considered the effects of environmental factors such as maltreatment load and genetic factors such as the influence of FKBP5 genotype on stress hormone regulation. This study analyzed the interaction between the single nucleotide polymorphism rs1360780 within the FKBP5 gene and the severity of maternal CM experiences (maltreatment load) on hair steroid levels of mother-infant-dyads. METHODS Hair samples of N = 474 mothers and N = 331 newborns were collected < 1 week after parturition enabling a retrospective assessment of cortisol, cortisone, and dehydroepiandrosterone (DHEA) using mass spectrometry. The sum score of the Childhood Trauma Questionnaire operationalized the maternal maltreatment load. DNA from whole blood or buccal cells was used for FKBP5 genotyping. RESULTS The higher the maltreatment load, the higher maternal hair cortisol and cortisone levels in T allele carriers of FKBP5 rs1360780 were observed. Hair cortisol and DHEA levels of newborns with the T allele were reduced with an increasing maternal maltreatment load, while there was an increase of hair cortisol and DHEA in newborns homozygous for the C allele. CONCLUSIONS This study is the very first uncovering a gene (FKBP5) × environment (maltreatment load) interaction on hair steroids in mothers and their offspring, indicating an intergenerational transmission of hypothalamic-pituitary-adrenal axis alterations. These results may help to explain the inconsistency in previous findings on steroid hormone alterations after chronic and traumatic stress and should be considered in future studies.

The association between cortisol, oxytocin, and immune cell mitochondrial oxygen consumption in postpartum women with childhood maltreatment

Childhood maltreatment (CM) is associated with an increased risk for the development of psychiatric and somatic diseases in later life. Individual risk and resilience factors may, however, influence how deep psychological stress gets under the skin. We hypothesized that the stress-related hormone cortisol and the attachment-related hormone oxytocin constitute biological factors that might moderate the biological sequelae and long-term health outcomes associated with CM. As biological outcome, we thereby focused on immunocellular oxygen consumption, which we previously found to be increased with a higher severity of CM experiences. In a study cohort of N = 49 postpartum women, we investigated the interaction between CM experiences, serum cortisol and plasma oxytocin levels, and the cellular oxygen consumption of intact peripheral blood mononuclear cells (PBMC) by high-resolution respirometry. Regression analyses revealed a significant interaction between the severity of CM experiences and cortisol as well as oxytocin on cellular oxygen consumption of PBMC three months postpartum: higher cortisol levels were thereby associated with an increase in oxygen consumption related to basal mitochondrial respiration and ATP turnover, while oxygen consumption related to basal mitochondrial respiration and ATP turnover were reduced with higher oxytocin levels in individuals with higher CM severity. These associations were not seen among women with no or low CM experiences. Together, the results suggest that cortisol and oxytocin might be associated with opposite effects on CM-related alterations in the bioenergetic profile of peripheral immune cells.

Alterations of the serum N-glycan profile in female patients with Major Depressive Disorder

BACKGROUND Glycans are short chains of saccharides linked to glycoproteins that are known to be involved in a wide range of inflammatory processes. As depression has been consistently associated with chronic low-grade inflammation, we asked whether patients with Major Depressive Disorder show alterations in the N-glycosylation pattern of serum proteins that might be linked to associated changes in inflammatory processes. METHODS In a study cohort of 21 female patients with an acute depressive episode and 21 non-depressed female control subjects aged between 50 and 69 years, we analyzed the serum N-glycan profile by DNA Sequencer Adapted-Fluorophore Assisted Carbohydrate Electrophoresis (DSA-FACE) and assessed the serum levels of interleukin (IL)- 6, tumor necrosis factor (TNF)-α and C-reactive protein (CRP) by chemiluminescence immunoassays and nephelometry. RESULTS Compared to controls, MDD patients showed significant differences in the serum levels of several N-glycan structures. Alterations in the serum N-glycan profile were associated with depressive symptom severity and exploratory analyses revealed that they were most pronounced in MDD patients with a history of childhood sexual abuse. Furthermore, MDD patients showed higher levels of IL-6 and a trend for higher CRP levels, which were also associated with similar alterations in the serum N-glycan profile as those characteristic for MDD patients. LIMITATIONS The relatively small sample size and the presence of potential confounders (e.g., BMI, smoking, medication). CONCLUSION The results offer the first evidence that specific differences in the N-glycosylation pattern of serum proteins constitute a so far unrecognized level of biological alterations that might be involved in the immune changes associated with MDD.

The involvement of mitochondria in chronic low-grade inflammation associated with maltreatment experiences during childhood

Experiencing maltreatment, abuse and/or neglect during childhood (CM) is associated with adverse health outcomes later in life. A state of chronic low-grade inflammation and alterations in inflammatory processes were suggested to be involved in the high prevalence of secondary diseases observed with CM. The molecular mechanisms underlying the establishment of this pro-inflammatory phenotype remain, however, largely unknown. On a cellular level, mitochondria were recently found to be not only the main energy suppliers of human cells, but also key regulators of inflammatory processes. We therefore analyzed in a study cohort of 30 women with varying degrees of CM experiences, whether mitochondrial activity was altered in immune cells and was associated with increased levels of inflammation. With increasingly severe CM experiences, study participants displayed higher levels of endogenous, bioactive molecules linked to oxidative stress and an increased immune cell mitochondrial activity, which was associated with a higher secretion of the pro-inflammatory cytokines IL-1beta, IL-6, and TNF-alpha. Together these data support the hypothesis that alterations in immune cell mitochondrial functioning might be at the interface between the association of CM experiences and a state of chronic low-grade inflammation that persists until adulthood. The present findings further emphasize that the early prevention of child maltreatment, abuse and neglect warrants more attention, as affected individuals suffer not only from life-long consequences for mental, but also for physical health.

Abstract # 1746 Inflammation and mitochondrial dysfunction in elderly women with major depressive disorder

Inflammatory processes are supposed to play an integral role in the pathophysiology of Major Depressive Disorder (MD). Chronically elevated levels of CRP, IL-6 and TNF-alpha may contribute to the high prevalence of secondary diseases observed with MD (e.g. autoimmune diseases, cardiovascular diseases, and cancer). Besides poor health outcomes, MD patients suffer from chronic fatigue, lack of energy and difficulties concentrating. These core symptoms of depression point towards disturbances in physiological energy homeostasis. The main energy suppliers of human cells, mitochondria, are in addition to the production of adenosine triphosphate (ATP), pivotally involved in the regulation of inflammatory processes. To this end, we analyzed in a study cohort of 44 elderly women (22 MD patients and 22 healthy age-matched controls) whether mitochondrial activity was altered in immune cells of MD patients and was associated with inflammation as assessed by serum CRP, IL-6 and TNF-alpha levels. Compared to healthy controls, MD patients presented in tendency higher levels of circulating CRP, IL-6, but not TNF-alpha. Mitochondrial activity, mitochondrial maximal capacity and oxygen consumption related to ATP production were substantially reduced in immune cells of MD patients. Maximal capacity was reduced and mitochondria were operating closer to their maximal capacity with higher levels of inflammation. Together these data support the hypothesis that immune dysregulation and mitochondrial dysfunction are possibly interconnected and inherent in the pathophysiology of MD.