Psychoneuroendocrinology

In response to acute stress, prior studies have found an increase in circulating cell-free mitochondrial DNA (cf-mtDNA) and pro-inflammatory cytokines, highlighting two potential inter-related mechanisms by which stressors can get under the skin. However, prior studies lacked a resting control condition to isolate the effect of psychological stress from other aspects related to laboratory procedures. Here, we conducted a crossover experimental trial examining responses to a socio-evaluative stressor under laboratory conditions. 72 volunteers (age 20-50, 48% women) were tested on two occasions, counterbalanced, separated by at least a month. On one occasion, they were exposed to a 5-min socio-evaluative stressor (speech task), and on the other occasion, rested for the same period. Blood samples were obtained at 10 timepoints from pre- to 2 hours post-exposure to assess neuroendocrine (cortisol, catecholamines), pro-inflammatory cytokine (IL-6, IL-10, TNF-[a]), and both plasma and serum cf-mtDNA responses. Compared to the control visit, the stressor significantly increased anxiety, heart rate, blood pressure, cortisol, and norepinephrine (ps<0.05-0.0001), confirming the psychobiological impact of the stressor. Unexpectedly, IL-6 and plasma cf-mtDNA increased (time effect p<0.0001) in both the stress and control conditions. While no significant effect of time was found for serum cf-mtDNA, plasma cf-mtDNA showed a bi-phasic response with an initial 22-24% increase at 5-10 min (g=0.07, stress-control visits), followed by a decrease and another 70-81% increase from 45 to 75 min (g=0.59 (stress visit), g=0.41 (control visit)). There were no significant associations between the pro-inflammatory and cf-mtDNA responses, pointing to their independent regulation. While mood, cardiovascular, and neuroendocrine reactivity were selectively induced by socio-evaluative stress, IL-6 and blood cf-mtDNA increased across both the stress and control conditions, suggesting that these biomarkers may reflect non-specific responses to the laboratory protocols (e.g., blood draw) rather than to socio-evaluative stress itself.

Mastering emotion regulation is crucial for social skills and mental health. Hormonal fluctuations, particularly in oestradiol levels (E2) across the menstrual cycle, significantly impact emotion processing. E2 is known to influence emotion regulation, mental health, and the plasticity of limbic and striatal regions, which are involved in emotion processing and are rich in E2 receptors. Although, research indicate that E2 levels may impact grey matter volume (GMV) of limbic and striatal areas, sufficient causal evidence is missing so far. Further, because of the additional fluctuations of progesterone across the menstrual cycle, the sole impact of E2 on brain volume has been difficult to disentangle. To isolate the effects of E2 from other fluctuating sex hormones, we employed a randomised placebo-controlled, double-blind, cross-over design and administered oral E2 to 27 naturally cycling females during their early follicular phase (low endogenous sex hormones levels). We analysed emotion regulation strategies and E2 levels to assess their impact on regional grey matter volume (GMV). Our data showed that a rapid increase of E2 is negatively associated with bilateral striatal GMV. Moreover, greater use of reappraisal is associated with reduced GMV of the striatum. Rapidly increased E2 did not influence GMV of other limbic regions. These results highlight that rapid increases in E2 and individual differences in emotion regulation dynamically modulate limbic GMV. This offers important implications for female mental and brain health during associated with hormonal fluctuations. Considering female endocrine profiles improves to a hormone-informed health care and therefore supports individualized medicine.

1.Sex steroid hormones influence hypothalamic micro- and macrostructure in humans and animal models. Neuroimaging studies have suggested that estrogen and anti-androgen treatment decreases volumes of multiple cortical and subcortical brain areas in transgender individuals, including total hypothalamus volume. Here, we aim to further explore potential effects of gender-affirming hormone treatment (GHT) in transgender individuals on hypothalamic volume by providing additional information on hypothalamic subfields. 38 transgender men (TM) and 15 transgender women (TW), with gender dysphoria (DSM-5), as well as 32 cisgender women (CW) and 21 cisgender men (CM) underwent two magnetic resonance imaging (MRI) measurements with an interval of at least four months (median interval TM= 134.5 days (interquartile range (IQR): 126-152.25); TW= 149 days (IQR: 126-178.5); CW= 147 days (IQR: 139.75-170.5); CM= 146 days (IQR: 132-247)) between both sessions. In transgender individuals GHT, consisting of estrogen and anti-androgen treatment in TW and testosterone treatment in TM, was initiated directly after the first measurement. To assess how GHT interacts with hypothalamic structures, the hypothalamus and its subunits were segmented using FreeSurfer. Subject group x time interaction effects were evaluated using repeated measures ANCOVA models. The Bonferroni method was used to correct for multiple comparisons. Significant decreases of total hypothalamic volume and associated subunits were detected in TW after estrogen and anti-androgen treatment compared to cisgender groups. Effects were found in the total hypothalamus volume (pcorr= 0.001), the left and right hypothalamus (pcorr= 0.002), the inferior tubular subunit bilaterally (right: pcorr= 0.001; left: pcorr= 0.001), the left superior tubular subunit (pcorr= 0.003) the right anterior inferior subunit (pcorr= 0.002), as well as the right anterior superior subunit (pcorr= 0.0002) of the hypothalamus. Here, we observed significant volumetric effects on the adult human hypothalamus after an interval of at least four months of estrogen and anti-androgen treatment in TW and added knowledge on associated subfields. Further studies investigating influences of sex steroid hormones on brain structure and functional connections are still needed.

Traumatic experiences during childhood can persistently alter mental and physical health in humans and have been implicated in transmission of symptoms to the progeny in animal models. Molecular evidence from these models implicates epigenetic/non-genetic factors, such as microRNAs (miRNAs), in the expression of trauma-induced symptoms and their transmission to the offspring. To confirm these findings in humans, we assembled three cohorts of subjects exposed to childhood trauma and examined selected miRNAs linked to psychological and pathophysiological manifestations of childhood trauma. Children aged 7-12 years (n = 72, control n = 30) exposed to paternal loss and maternal separation (PLMS) exhibited increase in two miRNAs, miR-16 and miR-375 in serum and reduced level of high-density lipoproteins (HDL) compared to control children. Comparable miRNA changes were observed in serum of adult men aged 18-25 years (n = 13, control n = 17) who had been exposed to PLMS at a young age. Finally, the same miRNAs were altered in sperm of adult men aged 21-50 years (n = 23, control n = 35) exposed to two or more significant traumatic events in childhood, assessed retrospectively using the standardized childhood trauma questionnaire (CTQ). In vitro experiments show that regulation of these miRNA involves the HDL receptor SRB-1, suggesting a link between trauma-associated miRNAs and metabolic alterations.

ObjectiveThe neurotrophic protein brain-derived neurotrophic factor (BDNF) plays a pivotal role in brain function and is affected by acute and chronic stress. We here investigate the patterns of BDNF and cortisol stress reactivity and recovery under the standardized stress protocol of the TSST and the effect of perceived chronic stress on the basal BDNF levels in healthy young men. MethodsTwenty-nine lean young men underwent the Trier Social Stress Test (TSST) and a resting condition. Serum BDNF and cortisol were measured before and repeatedly after both conditions. The perception of chronic stress was assessed by the Trier Inventory for Chronic Stress (TICS). ResultsAfter the TSST, there was a significant increase over time for BDNF and cortisol. Stronger increase in cortisol in response to stress was linked to an accelerated BDNF decline after stress. Basal resting levels of BDNF was significantly predicted by chronic stress perception. ConclusionsThe increased BDNF level following psychosocial stress suggest a stress-induced neuroprotective mechanism. The presumed interplay between BDNF and the HPA-axis indicates an antagonistic relationship of cortisol on BDNF recovery post-stress. Chronically elevated high cortisol levels, as present in chronic stress, could thereby contribute to reduced neurogenesis, and an increased risk of neurodegenerative conditions in persons suffering from chronic stress. HighlightsO_LIAcute psychosocial stress increases serum BDNF and cortisol C_LIO_LIStress-induced cortisol secretion may accelerate the decline of BDNF after stress. C_LIO_LIChronic stress is linked to lower basal serum BDNF levels C_LI

Cell-free mitochondrial DNA (cf-mtDNA) has emerged as a dynamic molecular signal responsive to psychological stress and a potential biomarker of stress-related physiological adaptations. While previous work has established the acute stress reactivity of cf-mtDNA in saliva, little is known about its diurnal regulation. In this intensive-sampling study, we characterized the diurnal dynamics of saliva cf-mtDNA across one weekday and one weekend day in healthy adults (N = 25, 52% female, 826 samples). Saliva was collected at awakening, during the first hour post-awakening, and at hourly intervals throughout the day. Using a quantitative PCR-based assay, we observed a robust cf-mtDNA awakening response, with concentrations peaking approximately 45 minutes after waking (2.5-fold change, Cohens d = 0.90), followed by a second peak at 180 minutes post-awakening (5.7-fold change, d = 1.70) and relatively stable levels thereafter. Saliva cf-mtDNA closely tracked cell-free nuclear DNA (cf-nDNA) across time points (rS = .85), suggesting shared release mechanisms. Diurnal cf-mtDNA showed limited correspondence with cortisol and other hormones in saliva. Psychosocial stress indicators--including daily hassles, lack of social support, negative emotional affect, trait anxiety, fatigue, and depressive symptoms--were associated with higher awakening cf-mtDNA levels, a diminished awakening response, and lower diurnal variability. These findings suggest that saliva cf-mtDNA exhibits a diurnal rhythm and is sensitive to psychosocial stress exposure. By establishing its diurnal patterns and individual-level variability, this study advances saliva cf-mtDNA as a promising non-invasive biomarker to dynamically capture stress-related mitochondrial signaling.

Sex differences in sleep architecture are well-documented, with females experiencing longer total sleep time (TST), more slow wave sleep (SWS) and shorter Rapid Eye Movement (REM) sleep duration than males. Although studies imply that sex hormones could affect sleep, effects of exogenous sex hormones on sleep architecture remain unclear. This study examined sleep architecture changes in transgender individuals after 3 months of gender-affirming hormone therapy (GAHT). We assessed sleep architecture in 73 transgender individuals: 38 transmasculine participants who started using testosterone and 35 transfeminine participants who started using estrogens and anti-androgens. Sleep architecture was measured before GAHT and after 3 months of GAHT for 7 nights using an ambulatory single-electrode sleep EEG device. Changes in sleep architecture were analyzed using linear mixed models, and non-normally distributed outcomes were log-transformed and reported as percentages. In transmasculine participants, SWS decreased by 7 minutes (95% CI: -12; -3) and 1.7% (95% CI: -3%; - 0.5%), REM sleep latency decreased by 39% (95% CI: -52%; -22%) and REM sleep duration increased by 17 minutes (95% CI: 7; 26) after 3 months of GAHT. In transfeminine participants, sleep architecture showed no significant changes after 3 months of GAHT. Sleep architecture changes after three months of masculinizing GAHT in line with sleep in cisgender males, while it shows no changes after feminizing GAHT. The sex-specific nature of these changes raises new questions on sex hormones and sleep. Future research should focus on studying possible underlying neural mechanisms and clinical consequences of these changes. Statement of significanceSleep architecture shows differences between men and women, with women showing longer sleep, longer slow wave sleep and shorter REM sleep than men. Rodent research indicates that sex hormones can alter sleep architecture, but research on sex hormones and sleep architecture in humans is still lacking. This study examined effects of three months of gender-affirming hormone use in transgender individuals. Results show that testosterone use in persons assigned female at birth resulted in sleep architecture changes similar to cisgender males, whereas estradiol- and anti-androgen use by persons assigned male at birth did not change sleep architecture. These novel findings indicate that sex hormones could change sleep architecture in a sex-specific manner, warranting further studies into causal mechanisms underlying these changes.

Growing evidence suggests that social relationship quality can influence age-related health outcomes, although how the quality of ones relationships directly relates to the underlying aging process is less clear. We hypothesized that lower social support and higher relationship strain would be associated with an accelerated epigenetic aging profile among older adults in the Health and Retirement Study. Adults (N = 3,647) aged 50-96 years completed ratings of support and strain in relationships with their spouse, children, other family, and friends. They also provided a blood sample and DNA methylation profiling derived epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging methylation (PoAm). Generalized linear models adjusting for age, sex, and race/ethnicity revealed that lower support from ones spouse, children, other family, and friends and higher strain with ones spouse, children, and friends was associated with an accelerated epigenetic aging profile. In secondary analyses that further adjusted for socioeconomic and lifestyle factors and following false discovery rate correction, support from other family members and friends was associated with epigenetic aging. Findings suggest that lower support within close relationships relates to epigenetic aging acceleration, offering one mechanism through which relationship quality might influence risk for age-related disease.

BackgroundShift work is a well-established disruptor of sleep, yet the biological mechanisms driving sleep disturbances remain poorly understood. Salivary cortisol (HPA axis), -amylase (sympathetic- adrenomedullary output), and DHEA-S (adrenal androgen with anti-glucocorticoid/resilience properties) are candidate indicators of stress-related sleep disruption. We therefore examined whether changes in these biomarkers were associated with 6-month sleep trajectories in health professionals. MethodsIn a prospective 6-month repeated-measures design, 52 healthcare professionals (daytime vs. rotating shifts; mean age 31.4 {+/-} 9.4 years; 57% female) completed validated sleep assessments, PROMIS Sleep Disturbance, PROMIS Sleep Impairment, the Sleep-Wake Disorder Index (SWDI), and the NIH 7-day Sleep Diary, at baseline and six-month follow-up. Salivary cortisol, DHEA-S, and alpha-amylase were collected on the morning of Day 7 of each diary period. Change scores ({Delta} = follow-up - baseline) were computed. Repeated-measures ANOVA, Pearson correlations, and multivariable regressions assessed group differences and biomarker-sleep associations. ResultsCompared with daytime workers, rotating shift workers reported significantly greater increases in sleep disturbance, impairment, and reduced sleep efficiency over time (all p < 0.05). Reductions in cortisol and alpha-amylase were significantly associated with worsening PROMIS Sleep Disturbance and SWDI scores (r = -0.65 and -0.53, respectively; p < 0.05). Multivariable regression showed that decreased cortisol ({beta} = -41.845, p = 0.0064) and increased DHEA-S ({beta} = 0.001, p = 0.0405) associated with worsening PROMIS Sleep Impairment. A combined model including reduced cortisol, and increased DHEA-S associated with greater PROMIS Sleep Disturbance (adjusted R{superscript 2} = 0.698). ConclusionIn this pilot, changes in salivary cortisol and DHEA-S were associated with longitudinal changes in sleep. These results suggest potential utility for biomarker-informed risk stratification, warranting confirmation in larger, controlled studies. Plain Language SummaryPeople working rotating shifts often experience disrupted sleep and chronic stress due to irregular work hours. This study followed a group of rotating shift workers over six months to explore how stress levels, measured through saliva samples, and sleep quality changed over time. Researchers collected data on key stress hormones, including cortisol, alpha-amylase, and DHEA-S, and compared them with both subjective sleep surveys and daily sleep diaries. The results showed that as stress biomarkers declined, participants reported worse sleep quality and greater impairment in daily functioning. This suggests that when the bodys stress response system becomes weakened, what scientists call "lower cortisol levels" it may be a sign of long-term health strain. These physiological changes mirrored growing sleep disturbances over time. The findings highlight the importance of monitoring both sleep and biological stress markers in shift workers. Interventions that target better sleep hygiene and stress management may help protect the health of these essential workers. Future studies with larger, more diverse groups are needed to confirm these results and develop personalized strategies to reduce the negative effects of shift work. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/25336161v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@75a0c6org.highwire.dtl.DTLVardef@8e4a47org.highwire.dtl.DTLVardef@1ae7eadorg.highwire.dtl.DTLVardef@fec508_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundAge at menopause varies widely across women, yet little is known about how this relates to long-term behavioral and brain-structural changes. Previous research has focused primarily on the menopausal transition itself, and studies investigating cognitive outcomes suggest reduced age-related cognitive performance with earlier menopause. ObjectivesThis study aims to investigate whether earlier age at menopause is associated with reduced cognitive performance and brain structure in later-life in a population-based cohort. To our knowledge, this is one of the only studies examining both cognition and neuroimaging in the same cohort of post-menopausal women, and the first study to formally test whether gray matter volume mediates the relationship between menopause timing and cognitive performance within the same population-based sample. MethodsWe analyzed data from the Cambridge Centre of Neuroscience and Aging, which included 747 postmenopausal women who underwent cognitive testing (Addenbrookes Cognitive Examine Revised, ACE-R). A subset (n=190) was additionally tested with a fluid intelligence test and underwent structural brain scans to measure gray and white matter volume (GMV and WMV). Multiple linear regression models were used to evaluate the association between menopause age and cognitive performance, as well as gray matter volume, controlling for chronological age. ResultsEarlier menopause was associated with lower cognitive performance, as measured by the ACE-R, with similar associations for fluid intelligence. Structural brain analyses revealed that earlier age at menopause was associated with decreased total gray matter volume (TIV-corrected). No significant interactions were observed between age at menopause and chronological age for any of the outcomes. GMV was a partial mediator between age at menopause and cognitive performance, while controlling for chronological age. ConclusionIn a population-based sample, women with earlier age at menopause show both reduced cognitive performance and lower GMV, suggesting that GMV reduction may be one mechanism linking earlier menopause to cognitive decline. However, the cross-sectional nature of this study prevents causal conclusions, and longitudinal research is needed to establish causal links and to explore potential targeted interventions.

BackgroundPsychosocial adversity (PSA) contributes to long-term health disparities and increased risk for non-communicable diseases. The effects of PSA arise through complex interactions between genes and the environment, which involve immune, endocrine, and epigenetic dysregulation. MethodsTo examine how adversity affects mental and physical health via epigenetic alterations in a more controlled way, we examined the relationship between PSA and epigenetic aging in 28 monozygotic (MZ) twin pairs discordant for negative life experiences. Whole-blood DNA methylation (DNAm) profiling was performed using the Illumina Infinium EPIC v2 BeadChip array. Epigenetic age acceleration (EAA) was calculated using a panel of first to third-generation clocks, namely, Horvath, Hannum, PhenoAge (Levine), GrimAge (v2.0), Elastic Net and DunedinPACE. ResultsThough we did not observe any significant group-level differences in epigenetic age acceleration between PSA and control at large, sex-stratified analyses revealed that PSA exposed males exhibited significant reductions in EAA compared to their co-twins when assessed using the Hannum, PhenoAge, and DunedinPACE clocks. In females, regression analyses showed significant positive associations between EAA and both negative life events and shame perception. Application of the dimensional model of adversity further revealed that psychosocial threat was strongly associated with increased EAA in females, whereas deprivation showed a weaker but significant association with EAA in males. These findings suggest a sex-specific and context-dependent biological response to PSA, potentially reflecting either adaptive or maladaptive epigenetic remodelling. ConclusionThe observed epigenetic age deceleration in PSA-exposed males, together with the associations between EAA and threat, shame perception, and life events in females, highlight the importance of context and perception in shaping sex-specific responses to adversity. Our results underscore the utility of MZ twin study designs in isolating psychosocial stress driven epigenetic effects and support DNAm clocks as biomarkers of stress-related biological aging. Overall, this study advances our understanding of the molecular underpinnings of social health inequalities and may inform future interventions aimed at promoting resilience and stress adaptation.

Adolescence is a vulnerable period for the emergence of mental health problems. Adrenarche, an early stage of pubertal development marked by rising adrenal androgens, particularly dehydroepiandrosterone (DHEA), may influence emotional and behavioral development. However, longitudinal evidence linking preadolescent endocrine influences to adolescent psychopathology remains limited. Using data from the Adolescent Brain Cognitive Development (ABCD) Study (Nmax=10,562), we analyzed whether salivary DHEA during preadolescence predicted later externalizing and internalizing symptoms during adolescence. To create a more robust estimate for hormonal levels in preadolescence, hormone concentrations were averaged across baseline and 1-year follow-up (age range=8.9-12.4 years). Outcomes were measured via the Child Behavior Checklist (CBCL) at the 2-, 3-, and 4-year follow-ups (age range=10.6-15.8 years). Sex-stratified linear mixed models were employed, adjusting for age, race/ethnicity, BMI and physical activity. In males, higher DHEA levels were linked to fewer externalizing symptoms across all follow-ups (e.g., {beta}=-0.07 SD change of CBCL per SD-change of log-transformed DHEA levels (95% CI [-0.10, -0.04] at 3-year) and to fewer internalizing symptoms at 3-year and 4-year follow-ups. The effect of preadolescent DHEA in males translated into a reduced probability of externalizing symptoms crossing borderline or clinical thresholds at each follow-up (e.g., adjusted Risk Ratio=0.76 to reach clinical threshold for CBCL externalizing per SD increase in log-transformed DHEA; 95% CI [0.62, 0.98] at 3-year). In females, no hormone-symptom associations emerged. Interestingly, sex-by-DHEA interaction effects increased with age for both symptom domains. These findings suggest that preadolescent adrenal endocrine influences may play a role in thedevelopment of sex-specific vulnerability during adolescence. Future studies should consider adrenarche as a sensitive period for hormonal effects on mental health.

BackgroundExperiencing early life adversity (ELA) and chronic stress activation early in childhood increases the risk for altered developmental trajectories that lead to lifelong impacts on physical and mental health. This results in a toxic stress response - the dysregulation of neuroendocrine, immune and metabolic functions that causes allostatic load and a higher risk for poor health. A major challenge in current pediatric screening practices for identifying toxic stress is the typically use of parent retrospective or child prospective Adverse Childhood Experience (ACEs) questionnaires, which are no better than chance in predicting poor health outcomes. We have proposed that the adaptative processes to ELA converge on mitochondrial function and is measurable in several ways, including the gold standard marker of oxidative stress, F2-Isoprostanes (F2 - IsoPs). The aim of this study was to evaluate the relation between F2-IsoPs measures and child neurodevelopment and how those relations change over critical developmental periods. MethodsIn our ongoing "Family First" longitudinal study, F2-IsoPs were measured from child urine samples collected at 6-,12-, and 24 months. Maternal adversity was assessed using the ACES questionnaire at 6- and 12-months. The Bayley 4 was administered to assess neurodevelopment at all study time points. ResultsMaternal ACEs scores were significantly correlated to higher F2-IsoPs levels at 12 months. Elevated infant F2-IsoPs at 6 months were correlated significantly with lower language and motor scores Bayley scores. Assessment of the relation between maternal ACEs on changes in F2-IsoPs levels over the first year of life demonstrated there were significantly different F2-IsoPs trajectories for infants whose mothers endorsed 0, 1-2, or 3+ ACEs. ConclusionsThe data indicate that there are specific physiologic contributions of mitochondrial generated oxidative stress to a toxic stress response in young children. A broader approach to pediatric screening for toxic stress predictability may be the incorporation of F2 -IsoPs measures in the first two years postnatal.

Suffering the stress of others (termed empathic stress or stress contagion) may affect an individuals health and well-being. To understand the underlying hormonal processes of empathic stress, N = 108 opposite-sex dyads were tested, with one dyad partner passively observing the other undergo a standardized psychosocial laboratory stressor. A positive link between oxytocin release and empathic stress responding was hypothesized, while a negative relationship was expected for testosterone release. Associations of observer oxytocin and testosterone levels with two components of empathic stress were examined: stress resonance (i.e., synchronized observer - target responses) and vicarious stress (observer responses independent of target stress). During the passive observation of a stressed target, saliva oxytocin and testosterone levels increased by 16.64% and 23.00%, respectively, followed by a drop back to baseline levels. Supporting our hypotheses, increased observer oxytocin reactivity was linked to greater stress resonance in HF-HRV reactivity, while in low oxytocin responders, this association was reversed. Also, testosterone reactivity was negatively linked to stress resonance in heart rate activity. However, testosterone also showed a positive association with vicarious cortisol activity, which resembles the response pattern seen in first-hand stress exposure. We conclude that stress resonance may be the more empathy-dependent component of the empathic stress construct, aligning with previous work on the implication of oxytocin and testosterone in empathy. To draw further conclusions about the role of oxytocin and testosterone in empathic stress responding, future studies including a control group and stimulation of hormones are called for.

BackgroundThe present study examines the link between DNA methylation at the nerve growth factor-induced protein A (NGFI-A) binding domain of the NR3C1 1F promoter and later cognitive functions in children from families living in disadvantaged psychosocial conditions. MethodsParticipants were 132 children who took part in a Swiss Parents as Teachers (PAT) randomized controlled trial (72 in the intervention group, 60 in the control group). DNA methylation was quantified from saliva samples collected at age three using sodium bisulfite next-generation sequencing (NGS). Cognitive functions were assessed at age five using the SON-R 2.5-7 Intelligence Test. Results(a) DNA methylation at age three predicted lower IQ at age five through increased concentration problems; (b) participation in the three-year PAT program predicted lower methylation levels at the end of the intervention; and (c) early life stressors predicted lower IQ through increased methylation and concentration problems with descriptively stronger effects in the control group. ConclusionsThese findings demonstrate a link between early DNA methylation at the NGFI-A binding site of the NR3C1 1F promoter and later cognitive functions in children and highlight the role of early life stressors and the PAT intervention in shaping these associations.

ImportanceEconomic and racial inequality is linked to disparities in childrens mental health. Biomarkers that reflect these social disparities are lacking. ObjectiveWe examined the hypothesis that salivary DNA-methylation patterns of higher inflammation and faster pace of biological aging are economically, racially and ethnically stratified and are associated with child mental health. DesignThe Texas Twin Project is an on-going, observational, longitudinal study that began in May 2012. Analyses were preregistered on May 7, 2021, and completed on August 23, 2021. SettingThe population-based study identified and recruited participants from public school rosters in the greater Austin area. ParticipantsParticipants in the analytic data set included all participants that agreed to contribute DNA samples and whose samples were assayed by January 2021. ExposuresFamily- and neighborhood-level socioeconomic inequality, racial and ethnic identities (White, Latinx, Black, Asian). Main Measure(s)Environmental exposures were analyzed in relation to salivary DNA- methylation profiles of higher inflammation (DNAm-CRP) and faster pace of biological aging (DunedinPoAm). Child internalizing problems, attention problems, aggression, rule-breaking, ADHD, oppositional defiant disorder, and conduct disorder were measured using parent-reports and self-reports on abbreviated versions of the Achenbach Child Behavior Checklist and Conners 3.The hypotheses being tested were formulated after data collection of the present data freeze and were pre-registered prior to analyses being conducted. ResultsIn a sample of N=1,183 8-to-19-year-olds (609 female, age M=13.38y), childrens salivary DNA-methylation profiles and psychiatric symptoms differed by socioeconomic conditions, race and ethnicity. Children with more parent-reported internalizing symptoms had higher DNAm-CRP (r=0.15, 95% CI=0.05 to 0.25, P=0.004) and DunedinPoAm (r=0.15, CI=0.05 to 0.25, P=0.002), and children with more parent-reported aggression problems had higher DNAm-CRP (r=0.17, CI=0.04 to 0.31, P=0.013). DNAm-CRP partially mediated advantage of higher family socioeconomic status (16% of total effect) and White racial identity (12% of total effect) on reduced internalizing symptoms. DunedinPoAm also partially mediated advantage of White racial identity on internalizing (19% of total effect). Conclusions and RelevanceSocioeconomic and racial inequality are visible in childrens epigenetic profiles of inflammation and the rate of biological aging in a manner that is tied to social disparities in mental health. Key PointsO_ST_ABSQuestionC_ST_ABSWe examined whether salivary DNA-methylation profiles are socially stratified and associated with child mental health. FindingsIn this preregistered, cross-sectional observational study of 1,183 children and adolescents, socioeconomic, racial, and ethnic disparities in mental health were associated with salivary DNA-methylation profiles of inflammation and the pace of biological aging. MeaningDNA-methylation biomarkers hold promise as tools to quantify the biological impact of socioeconomic inequality and being racially minoritized in a manner that is tied to social disparities in mental health.

This study aims to improve our understanding of how previous life experiences (psychosocial adversity, PSA) affect mental health through biological mechanisms. We examine how PSA affects DNA methylation (DNAm) patterns, and its implications for mental health. Using a sample of monozygotic (MZ) twins, this study controls for confounding genetic factors, focusing exclusively on PSA experienced postnatally. Data on PSA is collected using questionnaires, while psychological symptoms are assessed with a structured clinical interview. DNAm data is derived from whole blood. We will first assess whether variations in DNAm mediate the link between PSA and within-pair differences in psychological symptoms and their severity. We will then evaluate hypo- and hypermethylation in selected genomic regions and explore potential associations with psychological symptoms. Finally, we hypothesize that genes exhibiting differential methylation in regulatory regions influence mental health outcomes.

BackgroundResidential segregation is associated with differential exposure to air pollution. Hippocampus structure and function are highly susceptible to pollutants and associated with posttraumatic stress disorder (PTSD) development. Therefore, we investigated associations between residential segregation, air pollutants, hippocampal neurobiology, and PTSD in recent trauma survivors. MethodsParticipants (N = 278; 34% non-Hispanic white, 46% Non-Hispanic Black, 16% Hispanic) completed multimodal neuroimaging two weeks after trauma. Yearly averages of air pollutants (PM2.5 and NO2) and racial/economic segregation (Index of Concentration at the Extremes) were derived from each participants address. Linear models assessed if air pollutants mediated associations between segregation and hippocampal volume, threat reactivity, or parahippocampal cingulum fractional anisotropy (FA) after covarying for age, sex, income, and 2-week PTSD symptoms. Further models evaluated if pollutants or segregation prospectively predicted PTSD symptoms six months post-trauma. ResultsNon-Hispanic Black participants lived in neighborhoods with significantly greater segregation and air pollution compared to Hispanic and non-Hispanic white participants (ps<.001). There was a significant indirect effect of NO2 between segregation and FA values ({beta} = 0.08, 95% CI[0.01, 0.15]), and an indirect effect of PM2.5 between segregation and threat reactivity ({beta} = -0.08, 95% CI[-0.14, -0.01]). There was no direct effect of segregation on hippocampal features. Pollutants and segregation were not associated with PTSD symptoms. ConclusionResidential segregation is associated with greater air pollution exposure, which is in turn associated with variability in hippocampal features among recent trauma survivors. Further research is needed to assess relationships between other environmental factors and trauma and stress-related disorders.

People with posttraumatic stress disorder (PTSD) are at increased risk for poor health, which could be explained by faster rates of biological aging. However, associations between PTSD and aging have most often been investigated using cross-sectional designs, with few longitudinal studies using more recently developed epigenetic measures of aging. To test whether changes in PTSD status were associated with changes in biological aging over roughly 12 years, we used data from 400 veterans assessed at two visits in the Post-Deployment Mental Health Study. Biological aging was assessed by DunedinPACE, with additional results shown for PC-GrimAge and PC-PhenoAge. Between two occasions spanning an average of 11.9 years, veterans who developed new onset PTSD showed significant increases in DunedinPACE ({beta} = 0.24, 95% CI [0.07, 0.41], p = .006), whereas remission in PTSD between occasions was not associated with significant decreases in the rate of aging ({beta} = -0.13, 95% CI [-0.33, 0.08], p = .207). When assessing PTSD symptoms, increases in PTSD symptoms between baseline and follow-up were associated with increases in DunedinPACE over the same period ({beta} = 0.07, 95% CI [0.01, 0.14], p = .032), and vice versa. Estimates for PC-GrimAge largely replicated those for DunedinPACE, whereas PC-PhenoAge replicated some associations. ConclusionsThese results suggest that changes in PTSD are associated with longitudinal changes in biological aging. Efforts to prevent the onset of PTSD and reduce PTSD symptoms could slow aging and reduce risk for poor health.

Cisgender women report higher stress than cisgender men, potentially due to psychosocial and biological factors, including sex hormone levels. Gender-affirming hormone therapy (GAHT) alters hormone levels, but its impact on perceived stress remains unclear. This study examined changes in perceived stress after 3 and 12 months of GAHT and potential differences between feminizing (FHT) and masculinizing hormone therapy (MHT). Data were drawn from two prospective cohort studies (ENIGI and RESTED) in the Netherlands, Belgium, and Israel. A total of 442 individuals (median age 23 years, IQR 20.5 to 28.0) completed the 10-item Perceived Stress Scale (PSS) before starting GAHT and after 3 and 12 months. Linear mixed models assessed changes after starting GAHT and differences between FHT and MHT groups. Baseline perceived stress levels did not significantly differ between groups (0.15, p = 0.84). No significant changes in perceived stress were observed after 3 or 12 months, nor were there significant differences in changes between FHT and MHT (-1.0, p = 0.21; 0.25, p = 0.76). Improvements in well-being during GAHT may not reduce perceived stress, potentially due to ongoing gender minority stressors. Future research should explore stressors and coping mechanisms to identify strategies for reducing perceived stress during GAHT.