Jenna L. Riis

The Science of Early Life Toxic Stress for Pediatric Practice and Advocacy

Young children who experience toxic stress are at high risk for a number of health outcomes in adulthood, including cardiovascular disease, cancers, asthma, and depression. The American Academy of Pediatrics has recently called on pediatricians, informed by research from molecular biology, genomics, immunology, and neuroscience, to become leaders in science-based strategies to build strong foundations for children’s life-long health. In this report, we provide an overview of the science of toxic stress. We summarize the development of the neuroendocrine-immune network, how its function is altered by early life adversity, and how these alterations then increase vulnerability to disease. The fact that early environments shape and calibrate the functioning of biological systems very early in life is both a cautionary tale about overlooking critical periods in development and reason for optimism about the promise of intervention. Even in the most extreme cases of adversity, well-timed changes to children’s environments can improve outcomes. Pediatricians are in a unique position to contribute to the public discourse on health and social welfare by explaining how factors that seem distal to child health may be the key to some of the most intractable public health problems of our generation. We consider the challenges and opportunities for preventing toxic stress in the context of contemporary pediatric practice.

State of the art review: poverty and the developing brain

In the United States, >40% of children are either poor or near-poor. As a group, children in poverty are more likely to experience worse health and more developmental delay, lower achievement, and more behavioral and emotional problems than their more advantaged peers; however, there is broad variability in outcomes among children exposed to similar conditions. Building on a robust literature from animal models showing that environmental deprivation or enrichment shapes the brain, there has been increasing interest in understanding how the experience of poverty may shape the brain in humans. In this review, we summarize research on the relationship between socioeconomic status and brain development, focusing on studies published in the last 5 years. Drawing on a conceptual framework informed by animal models, we highlight neural plasticity, epigenetics, material deprivation (eg, cognitive stimulation, nutrient deficiencies), stress (eg, negative parenting behaviors), and environmental toxins as factors that may shape the developing brain. We then summarize the existing evidence for the relationship between child poverty and brain structure and function, focusing on brain areas that support memory, emotion regulation, and higher-order cognitive functioning (ie, hippocampus, amygdala, prefrontal cortex) and regions that support language and literacy (ie, cortical areas of the left hemisphere). We then consider some limitations of the current literature and discuss the implications of neuroscience concepts and methods for interventions in the pediatric medical home.

State school policies and youth obesity.

The objective of this study was to examine relations between state-level school policies and childhood obesity for youth ages 10–17 years. Secondary analysis of the 2003–2006 School Nutrition Environment State Policy Classification System, 2003–2007 Physical Education Related State Policy Classification System, and 2003 and 2007 National Surveys of Children’s Health was performed. Eleven nutrition and 5 physical education (PE) domains were examined for elementary (ES), middle (MS), and high school (HS) children. Logistic regression models examined the association of policies on obesity prevalence in 2007 as well as change scores for the policy assessments. Scores for 5 of 11 nutrition domains and 4 of 5 PE domains increased between 2003 and 2006–2007. Controlling for individual, family and neighborhood factors, nutrition policies were positively associated with the odds of 2007 obesity in 3 ES and 2 MS domains and negatively associated with 1 HS domain. Adjusted positive associations also were observed between 2 ES and 1 MS PE policy domains and 2007 obesity. Controlling for covariates, nutrition policy change scores showed positive associations between increases in 1 ES and 1MS domain, and negative associations with 1 ES and 1 HS domain and 2007 obesity. PE policy change scores showed positive adjusted associations between increases in 2 ES, 2 MS and 1 HS domains and 2007 obesity. The findings indicate that state-level school health policies are associated with childhood obesity after adjusting for related factors, suggesting that states with higher obesity levels have responded with greater institution of policies.

Salivary Cytokines in Healthy Adolescent Girls: Intercorrelations, Stability, and Associations with Serum Cytokines, Age and Pubertal Stage

Theoretically, the measurement of cytokines in saliva may have utility for studies of brain, behavior, and immunity in youth. Cytokines in saliva and serum were analyzed across three annual assessments in healthy adolescent girls (N = 114, 11-17 years at enrollment). Samples were assayed for GM-CSF, IFNγ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, TNFα, adiponectin, and cotinine. Results revealed: (1) cytokine levels, except IFNγ and IL-10, were detectable in saliva, and salivary levels, except IL-8 and IL-1β, were lower than serum levels; (2) salivary cytokine levels were lower in older girls and positively associated with adiponectin; (3) compared to serum levels, the correlations between salivary cytokines were higher, but salivary cytokines were less stable across years; and (4) except for IL-1β, there were no significant serum-saliva associations. Variation in basal salivary cytokine levels in healthy adolescent girls reflect compartmentalized activity of the oral mucosal immune system, rather than systemic cytokine activity.

Salivary cytokines as a minimally-invasive measure of immune functioning in young children: Correlates of individual differences and sensitivity to laboratory stress

There is growing interest in minimally-invasive measures of environmentally-responsive biological systems in developmental science. Contributing to that endeavor, this study explores the intercorrelations, correlates, and task-sensitivity of proinflammatory salivary cytokines in childhood. Saliva was sampled from 125 healthy five-year old children (49% male) across a series of cognitive and emotional challenge laboratory tasks. Samples were assayed for cytokines (IL-1β, IL-6, IL-8, TNFα), and markers of hypothalamic-pituitary-adrenal (HPA) and autonomic nervous system (ANS) activation (salivary cortisol and alpha-amylase [sAA]). Cytokines were positively intercorrelated and task-sensitivity varied. Except IL-8, cytokines were elevated in children with oral health issues and tobacco smoke exposure. Among boys, cytokines were positively related to sAA and negatively related to cortisol. The findings suggest that in healthy children, salivary cytokine levels reflect compartmentalized oral immune activity. Associations between ANS and HPA activity and cytokines in saliva may present opportunities for minimally-invasive methods to explore neuroendocrine-immune interactions during development.

Maternal distress and child neuroendocrine and immune regulation

RATIONALE Neuroendocrine-immune regulation is essential for maintaining health. Early-life adversity may cause dysregulation in the neuroendocrine-immune network through repeated activation of the stress response, thereby increasing disease risk. OBJECTIVE This paper examined the extent to which maternal psychological well-being moderates neuroendocrine-immune relations in children. METHODS We used data from a laboratory-based study of mothers and their five-year old children (n = 125 mother-child pairs) conducted from 2011 to 2013 in Baltimore, Maryland. Child saliva was assayed for markers of immune function (i.e., cytokines: interleukin [IL]-1β, IL-6, IL-8, tumor necrosis factor alpha [TNF-α]) and hypothalamic-pituitary-adrenal activity (i.e., cortisol). A composite score for depressive symptoms, anxiety, and parenting stress characterized maternal psychological distress. Multilevel mixed models examined the relationship between maternal psychological well-being and child neuroendocrine-immune relations. RESULTS Significant cytokine × maternal distress interactions indicated that as maternal distress increased, expected inverse cytokine-cortisol relations within children became weaker for IL-1β, IL-6, and TNF-α. Sex-stratified models revealed that these interactions were only significant among girls. Among boys, there were inverse cytokine-cortisol relations for all cytokines, and, while in the same direction as observed among girls, the cytokine × maternal distress interactions were non-significant. CONCLUSION The findings suggest that maternal distress is associated with child neuroendocrine-immune relations in saliva and may alter the sensitivity of inflammatory immune processes to cortisols inhibitory effects. This desensitization may place the child at risk for inflammatory diseases. The findings support efforts for the early detection and treatment of at-risk mothers to protect maternal and child health and well-being.

Adiponectin: Serum-saliva associations and relations with oral and systemic markers of inflammation

&NA; This study addresses gaps in our understanding about the validity and utility of using salivary adiponectin to index serum adiponectin levels. Matched blood and saliva samples were collected on a single occasion from healthy adults (n = 99; age 18–36 years, 53% male). Serum and saliva was assayed for adiponectin and inflammatory cytokines (IL‐1&bgr;, IL‐6, IL‐8, TNF&agr;), and saliva was also assayed for markers of blood contamination (transferrin), total protein (salivary flow rate) and matrix metalloproteinase‐8 (MMP‐8). We examined the extent to which salivary adiponectin was associated with serum adiponectin, and the influence of potential confounders on the serum‐saliva correlation, including age, sex, body mass index, and markers of inflammation, oral health, salivary blood contamination, and flow rate. Findings revealed a modest serum‐saliva association for adiponectin, and strong positive associations between salivary adiponectin and salivary levels of inflammatory cytokines, MMP‐8, transferrin, and total protein. By contrast, salivary adiponectin was not related to serum levels of inflammatory activity. The magnitude of the serum‐saliva association was strengthened when controlling for total protein in saliva, blood leakage into oral fluid, salivary inflammatory cytokines, and MMP‐8. The pattern of findings extends our understanding of salivary adiponectin and its potential use as an index of circulating adiponectin levels. HighlightsSalivary adiponectin was positively correlated with salivary inflammatory activity.Salivary and serum adiponectin were not related to serum inflammatory activity.Serum and salivary adiponectin were moderately positively correlated.Adjusting for oral inflammation improved the adiponectin serum‐saliva correlation.

Income, Family Context, and Self-Regulation in 5-Year-Old Children

Objective: Self-regulation (SR) is a core aspect of child development with enduring effects on health and wellbeing across the lifespan. Early childhood poverty may shape SR development. This study examined the cross-sectional relationship among family income, family context, and SR in 5-year-old children. Methods: A total of 140 five-year-old children and their mothers participated in the study. Children completed a battery of SR tasks; mothers completed questionnaires. Cognitive and emotional SR composite scores were generated based on a principal component analysis of the SR tasks. The SR scores were first regressed on family income (in 10 levels ranging from <5000 to 150,000+) adjusting for age, sex, and race of the child; family context variables were subsequently added to the models. Results: Controlling for age, sex, and race, each level increase in family income was associated with 0.04 SD increase in emotional SR (p = .32) and 0.08 SD increase in cognitive SR (p = .01). In fully adjusted models, exposure to household instability and experiencing 10 or more negative life events was associated with worse emotional SR; exposure to mothers depressive symptoms was associated with worse cognitive SR. Higher income buffered childrens SR from some contextual risk factors. Family contextual variables explained 62% of the correlation between higher income and better cognitive SR scores. Conclusion: Income-based cognitive SR disparities were associated with family contextual factors. Screening for family adversity in pediatric care and linking families to needed resources may protect childrens developing SR capacities, with benefits to health and well-being.

Salivary Uric Acid: Associations with Resting and Reactive Blood Pressure Response To Social Evaluative Stress in Healthy African Americans

High levels of uric acid are associated with greater risk of stress-related cardiovascular illnesses that occur disproportionately among African Americans. Whether hyperuricemia affects biological response to acute stress remains largely unknown, suggesting a need to clarify this potential connection. The current study examined how salivary uric acid (sUA) is associated with resting and reactive blood pressure - two robust predictors of hypertension and related cardiovascular disease and disparity. Healthy African Americans (N = 107; 32% male; M age = 31.74 years), completed the Trier Social Stress Test to induce social-evaluative stress. Systolic and diastolic blood pressure readings were recorded before, during, and after the task to assess resting and reactive change in blood pressure. Participants also provided a saliva sample at baseline that was assayed for sUA. At rest, and controlling for age, sUA was modestly associated with higher systolic (r = .201, p =  .044), but not diastolic (r = .100, p =  .319) blood pressure. In response to the stressor task, and once again controlling for age, sUA was also associated with higher total activation of both systolic (r = .219, p =  .025) and diastolic blood pressure (r = .198, p <  .044). A subsequent moderation analysis showed that associations between sUA and BP measures were significant for females, but not for males. Findings suggest that uric acid may be implicated in hypertension and cardiovascular health disparities through associations with elevated blood pressure responses to acute social stress, and that low levels of uric acid might be protective, particularly for females.