Associations between Social Adversity and Biomarkers of Inflammation, Stress, and Aging in Children.

BACKGROUND: Prior work has found relationships between childhood social adversity and biomarkers of stress, but knowledge gaps remain. To help address these gaps, we explored associations between social adversity and biomarkers of inflammation (interleukin-1ß [IL-1ß], IL-6, IL-8, tumor necrosis factor-alpha [TNF-α], and salivary cytokine hierarchical "clusters" based on the three interleukins), neuroendocrine function (cortisol, cortisone, dehydroepiandrosterone, testosterone, and progesterone), neuromodulation (N-arachidonoylethanolamine, stearoylethanolamine, oleoylethanolamide, and palmitoylethanolamide), and epigenetic aging (Pediatric-Buccal-Epigenetic clock). METHODS: We collected biomarker samples of children ages 0-17 recruited from an acute care pediatrics clinic and examined their associations with caregiver-endorsed education, income, social risk factors, and cumulative adversity. We calculated regression-adjusted means for each biomarker and compared associations with social factors using Wald tests. We used logistic regression to predict being in the highest cytokine cluster based on social predictors. RESULTS: Our final sample included 537 children but varied based on each biomarker. Cumulative social adversity was significantly associated with having higher levels of all inflammatory markers and with cortisol, displaying a U-shaped distribution. There were no significant relationships between cumulative social adversity and cortisone, neuromodulation biomarkers or epigenetic aging. CONCLUSION: Our findings support prior work suggesting that social stress exposures contribute to increased inflammation in children. IMPACT: Our study is one of the largest studies examining associations between childhood social adversity and biomarkers of inflammation, neuroendocrine function, neuromodulation, and epigenetic aging. It is one of the largest studies to link childhood social adversity to biomarkers of inflammation, and the first of which we are aware to link cumulative social adversity to cytokine clusters. It is also one of the largest studies to examine associations between steroids and epigenetic aging among children, and one of the only studies of which we are aware to examine associations between social adversity and endocannabinoids among children. CLINICAL TRIAL REGISTRATION: NCT02746393.

Salivary cytokine cluster moderates the association between caregivers perceived stress and emotional functioning in youth.

Some individuals exposed to early life stress show evidence of enhanced systemic inflammation and are at greater risk for psychopathology. In the current study, caregivers and their offspring (0-17 years) were recruited at a pediatric clinic visit at the University of California, San Francisco (UCSF). Mothers and seven-year-old children from the Growing Up inSingaporeTowards healthy Outcomes (GUSTO) prospective birth cohort were used as a replication cohort. Caregivers perceived stress was measured to determine potential intergenerational effects on the children's functioning and inflammation levels. Children's emotional functioning in the UCSF cohort was evaluated using the Pediatric Quality of Life (PedsQL) inventory. Child emotional and behavioral functioning was measured using the Child Behavior Checklist (CBCL) in GUSTO. Saliva was collected from the children and salivary levels of IL-6, IL-1ß, IL-8 and TNF-α were measured using an electrochemiluminescent cytokine multiplex panel. Child IL-6, IL-1ß, IL-8 cytokine levels were clustered into low, average, and high cytokine cluster groups using hierarchical cluster analysis. We did not find that salivary cytokine clusters were significantly associated with children's emotional or behavioral function. However, cytokine clusters did significantly moderate the association between increased caregiver perceived stress and reduced child emotional functioning (UCSF cohort) and increased Attention-Deficit-Hyperactivity (ADH) problems (GUSTO cohort, uncorrected Cohen's F2 = 0.02). Using a cytokine clustering technique may be useful in identifying those children exposed to increased caregiver perceived stress that are at risk of emotional and attention deficit hyperactivity problems.

Family Socioeconomic Status, Cortisol, and Physical Health in Early Childhood: The Role of Advantageous Neighborhood Characteristics.

OBJECTIVE: Children from families with lower socioeconomic status (SES) evidence greater physiological dysregulation and poorer health. Despite recognition of environmental contributors, little is known about the influence of neighborhood characteristics. The present study examined the moderating role of community-level risks and resources on the relation of family SES to children's daily cortisol output and physical health during the kindergarten year. METHODS: In fall and spring of kindergarten, children's (N = 338) daily total cortisol was measured and parents and teachers rated children's global physical health. Parents reported family SES. Neighborhood characteristics were assessed using the Child Opportunity Index, a population-level tool that evaluates the quality of multiple domains of neighborhood attributes. RESULTS: In fall, children reared in lower SES family environments had higher cortisol when residing in lower quality (lower opportunity) neighborhoods (b = -.097, p < .001), but there was no relation between family SES and children's cortisol in more advantaged (higher opportunity) neighborhoods (b = -.023, p = .36). Lower family SES was prospectively associated with poorer physical health in spring (controlling for fall health) only among children living in lower opportunity neighborhoods (b = -.250, p = .018) and was unrelated to physical health among children residing in higher opportunity neighborhoods (b = .042, p = .70). CONCLUSIONS: Higher opportunity neighborhoods may protect against the negative consequences of low family SES on children's stress physiology and physical health. Public health interventions that bolster neighborhood opportunities may benefit young children reared in socioeconomically disadvantaged family environments.

Physical activity moderates effects of stressor-induced rumination on cortisol reactivity.

OBJECTIVE: Physically active individuals have lower rates of morbidity and mortality, and recent evidence indicates that physical activity may be particularly beneficial to those experiencing chronic stress. The tendency to ruminate increases and prolongs physiological stress responses, including hypothalamic-pituitary-adrenal (HPA) axis responses as indexed by cortisol reactivity to stressful experiences. We examined the association between ruminating in response to a laboratory stressor task and HPA axis reactivity and recovery and examined whether a physically active life-style moderates the associations between rumination and cortisol output trajectories. METHODS: Forty-six postmenopausal women underwent the Trier Social Stress Test, whereas salivary cortisol was repeatedly measured. Twenty-five minutes after the end of the stressor, participants reported level of rumination in response to the stress. RESULTS: Findings indicate that physical activity moderated the initial rate (B = -0.10, standard error = 0.04, p < .05) and curvature (B = -0.03, standard error = 0.01, p = .06) of the relationship between rumination and log-transformed cortisol trajectory. Among sedentary participants, those who responded to the stressor with higher levels of rumination had a more rapid initial increase in cortisol level (0.26 versus 0.21, p < .001), a later peak in cortisol reactivity (56 versus 39 minutes), and a delayed recovery from stress (curvature: -0.07 versus -0.08, p < .001) compared with those with lower levels of rumination. In active participants, cortisol trajectories were equivalent, regardless of the level of rumination. CONCLUSIONS: In sum, individuals who maintain a physically active life-style may be protected against the effects of rumination on HPA axis reactivity to and recovery from acute stress.

Measures of social position and cortisol secretion in an aging population: findings from the Whitehall II study.

OBJECTIVE: To examine whether dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis associated with disadvantaged social position in working populations also occurs in older age groups. METHODS: This study examines the association of several indicators of social position with two measures of cortisol secretion, a product of the HPA axis. We examined the cortisol awakening response (CAR), and slope of the decline in cortisol secretion across the day. We examine whether the association is mediated by behavioral, psychosocial, and biological factors in 3992 participants of phase 7 (2002-2004) of the Whitehall II study, who provided six salivary cortisol samples across the day. RESULTS: In this older cohort (mean age = 61 years; range = 50-74 years), lowest social position (assessed by current or previous occupational grade and wealth) was associated with a flatter slope in the decline in cortisol secretion. For example, over the course of the day, men in the lowest employment grades had a reduction in their cortisol by 0.125 (nmol/L/h), which was a shallower slope than those in the high grades (-0.129 nmol/L/h). The difference in slopes by employment grade among men, but not women, was statistically significant (p = .003). The difference in slopes was explained primarily by poor health and sleep behaviors, although financial insecurity also played a role. No effects were apparent with the CAR or other measures of social position. CONCLUSIONS: In men, poorer health and sleep behaviors (primarily smoking and short sleep duration), and financial insecurity mediate the impact of occupational status and wealth on cortisol secretion.

Biological sensitivity to context: the interactive effects of stress reactivity and family adversity on socioemotional behavior and school readiness.

This study examined the direct and interactive effects of stress reactivity and family adversity on socioemotional and cognitive development in three hundred and thirty-eight 5- to 6-year-old children. Neurobiological stress reactivity was measured as respiratory sinus arrhythmia and salivary cortisol responses to social, cognitive, sensory, and emotional challenges. Adaptation was assessed using child, parent, and teacher reports of externalizing symptoms, prosocial behaviors, school engagement, and academic competence. Results revealed significant interactions between reactivity and adversity. High stress reactivity was associated with more maladaptive outcomes in the context of high adversity but with better adaption in the context of low adversity. The findings corroborate a reconceptualization of stress reactivity as biological sensitivity to context by showing that high reactivity can both hinder and promote adaptive functioning.

Depressive symptoms are associated with blunted cortisol stress responses in very low-income women.

OBJECTIVE: The purpose of this study was to examine the association between depressive symptoms and salivary cortisol responses to stress in a high-risk population of very poor Mexican women. METHODS: Adult women (N = 1109) between the ages of 18 and 44 years (mean age, 29) were identified in a house-to-house survey in low-income areas (income <20th percentile nationally) of urban Mexico. An interview containing the Spanish version of the Center for Epidemiologic Studies--Depression Scale (CES-D) was administered to all women. The naturalistic stressor was defined as the unexpected arrival of a team of researchers at the participants' homes followed by an in-depth interview and physical assessment, with saliva samples taken at time of arrival (baseline), 25 minutes, and 50 minutes after arrival. RESULTS: The mean CES-D score was 19.42 (range, 0-53). Results of hierarchical linear modeling analyses revealed no effect of depressive symptoms on baseline salivary cortisol levels. However, a significant depressive symptom by time interaction revealed that women with elevations in depressive symptoms (CES-D scores = 35) failed to exhibit a cortisol response to the stressor. In contrast, in women with lower CES-D scores, cortisol levels significantly increased in response to the stressor. CONCLUSION: Consistent with research on individuals with major depressive disorder, results of this study demonstrate that women with very high levels of depressive symptoms exhibit blunted cortisol responses to a naturalistic psychological stressor. Results also contribute to previous research by generalizing findings to a high risk, underserved population of women.

Social inequalities in childhood dental caries: the convergent roles of stress, bacteria and disadvantage.

The studies reported here examines stress-related psychobiological processes that might account for the high, disproportionate rates of dental caries, the most common chronic disease of childhood, among children growing up in low socioeconomic status (SES) families. In two 2004-2006 studies of kindergarten children from varying socioeconomic backgrounds in the San Francisco Bay Area of California (Ns = 94 and 38), we performed detailed dental examinations to count decayed, missing or filled dental surfaces and microtomography to assess the thickness and density of microanatomic dental compartments in exfoliated, deciduous teeth (i.e., the shed, primary dentition). Cross-sectional, multivariate associations were examined between these measures and SES-related risk factors, including household education, financial stressors, basal and reactive salivary cortisol secretion, and the number of oral cariogenic bacteria. We hypothesized that family stressors and stress-related changes in oral biology might explain, fully or in part, the known socioeconomic disparities in dental health. We found that nearly half of the five-year-old children studied had dental caries. Low SES, higher basal salivary cortisol secretion, and larger numbers of cariogenic bacteria were each significantly and independently associated with caries, and higher salivary cortisol reactivity was associated with thinner, softer enamel surfaces in exfoliated teeth. The highest rates of dental pathology were found among children with the combination of elevated salivary cortisol expression and high counts of cariogenic bacteria. The socioeconomic partitioning of childhood dental caries may thus involve social and psychobiological pathways through which lower SES is associated with higher numbers of cariogenic bacteria and higher levels of stress-associated salivary cortisol. This convergence of psychosocial, infectious and stress-related biological processes appears to be implicated in the production of greater cariogenic bacterial growth and in the conferral of an increased physical vulnerability of the developing dentition.