Increasing Temporal Sensitivity of Omics Association Studies with Epigenome-Wide Distributed Lag Models.

Current methods for identifying temporal windows of effect for time-varying exposures in omics settings can control false discovery rates at the biomarker-level but cannot efficiently screen for timing-specific effects in high dimensions. Current approaches leverage separate models for site screening and identification of susceptible time windows, which miss associations that vary over time. We introduce the epigenome-wide distributed lag model (EWDLM), a novel approach that combines traditional false discovery rate methods with the distributed lag model (DLM) to screen for timing-specific effects in high dimensional settings. This is accomplished by marginalizing DLM effect estimates over time and correcting for multiple comparisons. In a simulation investigating timing-specific effects of ambient air pollution during pregnancy on DNA methylation across the epigenome at age 12 years, EWDLM achieved an increased sensitivity for associations limited to specific periods of time compared to traditional two-stage approaches. In a real-world EWDLM analysis, 353 CpG sites at which DNAm measured at age 12 was significantly associated with PM2.5 exposure during pregnancy were identified. EWDLM is a novel method that provides an efficient and sensitive way to screen epigenomic datasets for associations with exposures localized to specific time periods.

Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.

Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation.

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.

Fluoride exposure during early adolescence and its association with internalizing symptoms.

BACKGROUND: Early, chronic, low-level fluoride exposure has been linked to attention-deficit hyperactivity disorder (ADHD) and learning deficits in children. Rodent studies suggest a link between fluoride exposure and internalizing behaviors. No human studies have examined the impact of fluoride on internalizing behaviors during adolescence. OBJECTIVE: Evaluate the relationship between urinary fluoride and early adolescent internalizing symptoms in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS). METHODS: Participants in CCAAPS provided non-fasting spot urine samples at age 12 years (n = 286). Urine samples were analyzed using a microdiffusion method to determine childhood urinary fluoride (CUF) concentrations and were log-transformed for analyses. Caregivers of CCAAPS participants completed the Behavior Assessment System for Children-2 (BASC-2) at the age 12 study visit to assess internalizing symptoms (e.g., anxiety, depression, somatization), and a composite score of the three domains; T-scores ≥ 60 were used to identify adolescents in a clinically "at-risk" range. Race, age of the adolescent, household income, maternal age at birth, caregiver depression, caregiver-child relationships, and age 12-year serum cotinine concentrations were considered covariates in regression models. Sex-specific effects of fluoride exposures were investigated through the inclusion of interaction terms. RESULTS: Higher CUF concentrations were significantly associated with increased somatization (ß = 3.64, 95% CI 0.49, 6.81) and internalizing composite T-scores in a clinically "at-risk" range (OR = 2.9, 95% CI 1.24, 6.9). Compared to females, males with higher CUF concentrations had more internalizing (pinteraction = 0.04) and somatization symptoms (pinteraction = 0.02) and were nearly seven times more likely to exhibit "at-risk" internalizing symptomology. CUF concentrations were not significantly associated with depression or anxiety symptoms. CONCLUSIONS: This is the first study to link fluoride exposure and internalizing symptoms, specifically somatization. Somatization represents an interface of physical and psychological health. Continued follow-up will help shed light on the sex-specific relationship between fluoride and mental health and the role of somatization.

Myo-inositol mediates the effects of traffic-related air pollution on generalized anxiety symptoms at age 12 years.

BACKGROUND: Exposure to traffic-related air pollution (TRAP) has been linked to childhood anxiety symptoms. Neuroimaging in patients with anxiety disorders indicate altered neurochemistry. OBJECTIVES: Evaluate the impact of TRAP on brain metabolism and its relation to childhood anxiety symptoms in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS). METHODS: Adolescents (n = 145) underwent magnetic resonance spectroscopy. Brain metabolites, including myo-inositol, N-acetylaspartate, creatine, choline, glutamate, glutamate plus glutamine, and glutathione were measured in the anterior cingulate cortex. Anxiety symptoms were assessed using the Spence Children's Anxiety Scale. TRAP exposure in early-life, averaged over childhood, and during the 12 months prior to imaging was estimated using a validated land use regression model. Associations between TRAP exposure, brain metabolism, and anxiety symptoms were estimated using linear regression and a bootstrapping approach for testing mediation by brain metabolite levels. RESULTS: Recent exposure to high levels of TRAP was associated with significant increases in myo-inositol (ß = 0.26; 95%CI 0.01, 0.51) compared to low TRAP exposure. Recent elevated TRAP exposure (ß = 4.71; 95% CI 0.95, 8.45) and increased myo-inositol levels (ß = 2.98; 95% CI 0.43, 5.52) were also significantly associated with increased generalized anxiety symptoms with 12% of the total effect between TRAP and generalized anxiety symptoms being mediated by myo-inositol levels. CONCLUSIONS: This is the first study of children to utilize neuroimaging to link TRAP exposure, metabolite dysregulation in the brain, and generalized anxiety symptoms among otherwise healthy children. TRAP may elicit atypical excitatory neurotransmission and glial inflammatory responses leading to increased metabolite levels and subsequent anxiety symptoms.

Maternal Lifetime Trauma and Birthweight: Effect Modification by In Utero Cortisol and Child Sex.

OBJECTIVES: To evaluate associations between maternal lifetime traumatic stress and offspring birthweight and examine modifying effects of third trimester cortisol and fetal sex. STUDY DESIGN: Analyses included 314 mother-infant dyads from an ethnically mixed pregnancy cohort. Maternal lifetime trauma was reported via the Life Stressor Checklist-Revised. Fenton birthweight for gestational age z-scores (BWGA-z) were calculated. A 3-cm scalp-nearest maternal hair segment collected at birth was assayed to reflect cumulative third trimester cortisol secretion. Multivariable regression was used to investigate associations between maternal lifetime trauma and BWGA-z and examine 2- and 3-way interactions with cortisol and fetal sex. Because subjects with low or high cortisol levels could represent susceptible populations, varying coefficient models that relax the linearity assumption on cortisol level were used to assess the modification of maternal lifetime trauma associations with BWGA-z as a function of cortisol. RESULTS: Women were primarily minorities (41% Hispanic, 26% black) with ≤12 years education (63%); 63% reported ≥1 traumatic event. Prenatal cortisol modified the association between maternal lifetime trauma and birthweight. Women with higher lifetime trauma and increased cortisol had significantly lower birthweight infants in males; among males exposed to the 90th percentile of cortisol, a 1-unit increase in trauma score was associated with a 0.19-unit decrease in BWGA-z (95% CI, -0.34 to -0.04). Associations among females were nonsignificant, regardless of cortisol level. CONCLUSIONS: These findings underscore the need to consider complex interactions among maternal trauma, disrupted in utero cortisol production, and fetal sex to fully elucidate intergenerational effects of maternal lifetime trauma.

Prenatal fine particulate exposure associated with reduced childhood lung function and nasal epithelia GSTP1 hypermethylation: Sex-specific effects.

BACKGROUND: In utero exposure to particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) has been linked to child lung function. Overlapping evidence suggests that child sex and exposure timing may modify effects and associations may be mediated through glutathione S-transferase P1 (GSTP1) methylation. METHODS: We prospectively examined associations among prenatal PM2.5 exposure and child lung function and GSTP1 methylation in an urban pregnancy cohort study. We employed a validated satellite-based spatiotemporally resolved prediction model to estimate daily prenatal PM2.5 exposure over gestation. We used Baysian distributed lag interaction models (BDLIMs) to identify sensitive windows for prenatal PM2.5 exposure on child lung function and nasal epithelia GSTP1 methylation at age 7 years, and to examine effect modification by child sex. RESULTS: BDLIMs identified a sensitive window for prenatal PM2.5 exposure at 35-40 weeks gestation [cumulative effect estimate (CEE) = - 0.10, 95%CI = - 0.19 to - 0.01, per µg/m3 increase in PM2.5] and at 36-40 weeks (CEE = - 0.12, 95%CI = - 0.20 to - 0.01) on FEV1 and FVC, respectively, in boys. BDLIMs also identified a sensitive window of exposure at 37-40 weeks gestation between higher prenatal PM2.5 exposure and increased GSTP1 percent methylation. The association between higher GSTP1 percent methylation and decreased FEV1 was borderline significant in the sample as a whole (ß = - 0.37, SE = 0.20, p = 0.06) and in boys in stratified analyses (ß = - 0.56, SE = 0.29, p = 0.05). CONCLUSIONS: Prenatal PM2.5 exposure in late pregnancy was associated with impaired early childhood lung function and hypermethylation of GSTPI in DNA isolated from nasal epithelial cells. There was a trend towards higher GSTP1 percent methylation being associated with reduced FEV1. All findings were most evident among boys.

Maternal Lifetime Stress and Prenatal Psychological Functioning and Decreased Placental Mitochondrial DNA Copy Number in the PRISM Study.

Psychosocial stress contributes to placental oxidative stress. Mitochondria are vulnerable to oxidative stress, which can lead to changes in mitochondrial DNA copy number (mtDNAcn). We examined associations of maternal lifetime stress, current negative life events, and depressive and posttraumatic-stress-disorder symptom scores with placental mtDNAcn in a racially/ethnically diverse sample (n = 147) from the Programming of Intergenerational Stress Mechanisms (PRISM) study (Massachusetts, March 2011 to August 2012). In linear regression analyses adjusted for maternal age, race/ethnicity, education, prenatal fine particulate matter exposure, prenatal smoking exposure, and the sex of the child, all measures of stress were associated with decreased placental mtDNAcn (all P values < 0.05). Weighted-quantile-sum (WQS) regression showed that higher lifetime stress and depressive symptoms accounted for most of the effect on mtDNAcn (WQS weights: 0.25 and 0.39, respectively). However, among white individuals, increased lifetime stress and posttraumatic stress disorder symptoms explained the majority of the effect (WQS weights: 0.20 and 0.62, respectively) while among nonwhite individuals, lifetime stress and depressive symptoms accounted for most of the effect (WQS weights: 0.27 and 0.55, respectively). These analyses are first to link increased maternal psychosocial stress with reduced placental mtDNAcn and add to literature documenting racial/ethnic differences in the psychological sequelae of chronic stress that may contribute to maternal-fetal health.

Impact of Maternal Lifetime Interpersonal Trauma on Children's Asthma: Mediation Through Maternal Active Asthma During Pregnancy.

OBJECTIVE: Traumatic stressors, including child abuse and/or interpersonal violence over a woman's lifecourse, can affect the health of her children. This study examines the associations between maternal lifetime interpersonal trauma (IPT) and children's asthma by age 6 years (n = 857). METHODS: Pregnant women completed the Revised Conflict Tactics Scale; IPT exposure was categorized as unexposed (55%), early (childhood and/or teen years only, 25%), late (adulthood and/or index pregnancy, 7%), and chronic (early and late, 13%). Clinician-diagnosed asthma in children was reported by mothers at each follow-up visit until the child reached age 6 years. We examined the effects of maternal IPT categories and child's asthma using logistic regression. Using structural equation models, we also examined indirect relationships between maternal chronic IPT and child asthma operating through active asthma in pregnancy, prepregnancy BMI, prenatal smoking, and/or increased exposure to other adverse life events or environmental toxins prenatally. Effect modification by the child's sex was examined. RESULTS: Mothers were primarily Hispanic (55%) or black (30%) with less than high school education (62%). In logistic regression models, chronic maternal IPT (compared with unexposed) was associated with asthma in boys (odds ratio = 2.87, 95% confidence interval = 1.48-5.57) but not girls (odds ratio = 0.69, 95% confidence interval = 0.23-2.12; pinteraction = .042). In structural equation models, chronic IPT was associated with maternal active asthma in pregnancy (ß = 0.59, p < .001), maternal active asthma was associated with children's asthma (ß = 0.20, p = .009), and the total indirect effect for this path was significant (ß = 0.12, p = .031). Associations were most evident among boys. CONCLUSIONS: Mothers' history of chronic IPT was associated with asthma in boys. This association was mediated through active maternal asthma in pregnancy.

Timing and Duration of Traffic-related Air Pollution Exposure and the Risk for Childhood Wheeze and Asthma.

RATIONALE: The timing and duration of traffic-related air pollution (TRAP) exposure may be important for childhood wheezing and asthma development. OBJECTIVES: We examined the relationship between TRAP exposure and longitudinal wheezing phenotypes and asthma at age 7 years. METHODS: Children completed clinical examinations annually from age 1 year through age 4 years and age 7 years. Parental-reported wheezing was assessed at each age, and longitudinal wheezing phenotypes (early-transient, late-onset, persistent) and asthma were defined at age 7 years. Participants' time-weighted exposure to TRAP, from birth through age 7 years, was estimated using a land-use regression model. The relationship between TRAP exposure and wheezing phenotypes and asthma was examined. MEASUREMENTS AND MAIN RESULTS: High TRAP exposure at birth was significantly associated with both transient and persistent wheezing phenotypes (adjusted odds ratio [aOR] = 1.64; 95% confidence interval [CI], 1.04-2.57 and aOR = 2.31; 95% CI, 1.28-4.15, respectively); exposure from birth to age 1 year and age 1 to 2 years was also associated with persistent wheeze. Only children with high average TRAP exposure from birth through age 7 years were at significantly increased risk for asthma (aOR = 1.71; 95% CI, 1.01-2.88). CONCLUSIONS: Early-life exposure to TRAP is associated with increased risk for persistent wheezing, but only long-term exposure to high levels of TRAP throughout childhood was associated with asthma development.

Validation of a Food Frequency Questionnaire for Estimating Micronutrient Intakes in an Urban US Sample of Multi-Ethnic Pregnant Women.

OBJECTIVE(S): To validate the Block98 food frequency questionnaire (FFQ) for estimating antioxidant, methyl-nutrient and polyunsaturated fatty acids (PUFA) intakes in a pregnant sample of ethnic/racial minority women in the United States (US). METHODS: Participants (n = 42) were from the Programming of Intergenerational Stress Mechanisms study. Total micronutrient intakes from food and supplements was ascertained using the modified Block98 FFQ and two 24-h dietary recalls collected at random on nonconsecutive days subsequent to completion of the FFQ in mid-pregnancy. Correlation coefficients (r) corrected for attenuation from within-person variation in the recalls were calculated for antioxidants (n = 7), methyl-nutrients (n = 8), and PUFAs (n = 2). RESULT(S): The sample was largely ethnic minorities (38 % Black, 33 % Hispanic) with 21 % being foreign born and 41 % having less than or equal to a high school degree. Significant and adequate deattenuated correlations (r ≥ 0.40) for total dietary intakes of antioxidants were observed for vitamin C, vitamin E, magnesium, and zinc. Reasonable deattenuated correlations were also observed for methyl-nutrient intakes of vitamin B6, betaine, iron, and n:6 PUFAs; however, they did not reach significance. Most women were classified into the same or adjacent quartiles (≥70 %) for total (dietary + supplements) estimates of antioxidants (5 out of 7) and methyl-nutrients (4 out of 5). CONCLUSIONS: The Block98 FFQ is an appropriate dietary method for evaluating antioxidants in pregnant ethnic/minorities in the US; it may be less efficient in measuring methyl-nutrient and PUFA intakes.

Integrating mitochondriomics in children's environmental health.

The amount of scientific research linking environmental exposures and childhood health outcomes continues to grow; yet few studies have teased out the mechanisms involved in environmentally-induced diseases. Cells can respond to environmental stressors in many ways: inducing oxidative stress/inflammation, changes in energy production and epigenetic alterations. Mitochondria, tiny organelles that each retains their own DNA, are exquisitely sensitive to environmental insults and are thought to be central players in these pathways. While it is intuitive that mitochondria play an important role in disease processes, given that every cell of our body is dependent on energy metabolism, it is less clear how environmental exposures impact mitochondrial mechanisms that may lead to enhanced risk of disease. Many of the effects of the environment are initiated in utero and integrating mitochondriomics into children's environmental health studies is a critical priority. This review will highlight (i) the importance of exploring environmental mitochondriomics in children's environmental health, (ii) why environmental mitochondriomics is well suited to biomarker development in this context, and (iii) how molecular and epigenetic changes in mitochondria and mitochondrial DNA (mtDNA) may reflect exposures linked to childhood health outcomes.

Racial/ethnic and sociodemographic factors associated with micronutrient intakes and inadequacies among pregnant women in an urban US population.

OBJECTIVE: To assess sociodemographic correlates of micronutrient intakes from food and dietary supplements in an urban, ethnically diverse sample of pregnant women in the USA. DESIGN: Cross-sectional analyses of data collected using a validated semi-quantitative FFQ. Associations between racial, ethnic and sociodemographic factors and micronutrient intakes were examined using logistic regression controlling for pre-pregnancy BMI, maternal age and smoking status. SETTING: Prenatal clinics, Boston, MA, USA. SUBJECTS: Analyses included pregnant women (n 274) in the PRogramming of Intergenerational Stress Mechanisms (PRISM) study, an urban longitudinal cohort designed to examine how stress influences respiratory health in children when controlling for other environmental exposures (chemical stressors, nutrition). RESULTS: High frequencies of vitamin E (52 %), Mg (38 %), Fe (57 %) and vitamin D (77 %) inadequacies as well as suboptimal intakes of choline (95 %) and K (99 %) were observed. Factors associated with multiple antioxidant inadequacies included being Hispanic or African American, lower education and self-reported economic-related food insecurity. Hispanics had a higher prevalence of multiple methyl-nutrient inadequacies compared with African Americans; both had suboptimal betaine intakes and higher odds for vitamin B6 and Fe inadequacies compared with Caucasians. Nearly all women (98 %) reported Na intakes above the tolerable upper limit; excessive intakes of Mg (35 %), folate (37 %) and niacin (38 %) were also observed. Women reporting excessive intakes of these nutrients were more likely Caucasian or Hispanic, more highly educated, US-born and did not report food insecurity. CONCLUSIONS: Racial/ethnic and other sociodemographic factors should be considered when tailoring periconceptional dietary interventions for urban ethnic women in the USA.

Epigenome-wide association study of fluoride exposure during early adolescence and DNA methylation among U.S. children.

Exposure to fluoride in early childhood has been associated with altered cognition, intelligence, attention, and neurobehavior. Fluoride-related neurodevelopment effects have been shown to vary by sex and very little is known about the mechanistic processes involved. There is limited research on how fluoride exposure impacts the epigenome, potentially leading to changes in DNA methylation of specific genes regulating key developmental processes. In the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS), urine samples were analyzed using a microdiffusion method to determine childhood urinary fluoride adjusted for specific gravity (CUFsg) concentrations. Whole blood DNA methylation was assessed using the Infinium MethylationEPIC BeadChip 850 k Array. In a cross-sectional analysis, we interrogated epigenome-wide DNA methylation at 775,141 CpG loci across the methylome in relation to CUFsg concentrations in 272 early adolescents at age 12 years. Among all participants, higher concentrations of CUF were associated with differential methylation of one CpG (p < 6 × 10-8) located in the gene body of GBF1 (cg25435255). Among females, higher concentrations of CUFsg were associated with differential methylation of 7 CpGs; only three CpGs were differentially methylated among males with no overlap of significant CpGs observed among females. Secondary analyses revealed several differentially methylated regions (DMRs) and CpG loci mapping to genes with key roles in psychiatric outcomes, social interaction, and cognition, as well as immunologic and metabolic phenotypes. While fluoride exposure may impact the epigenome during early adolescence, the functional consequences of these changes are unclear warranting further investigation.

Child and Adolescent Manganese Biomarkers and Adolescent Postural Balance in Marietta CARES Cohort Participants.

BACKGROUND: Manganese (Mn) plays a significant role in both human health and global industries. Epidemiological studies of exposed populations demonstrate a dose-dependent association between Mn and neuromotor effects ranging from subclinical effects to a clinically defined syndrome. However, little is known about the relationship between early life Mn biomarkers and adolescent postural balance. OBJECTIVES: This study investigated the associations between childhood and adolescent Mn biomarkers and adolescent postural balance in participants from the longitudinal Marietta Communities Actively Researching Exposures Study (CARES) cohort. METHODS: Participants were recruited into CARES when they were 7-9 y old, and reenrolled at 13-18 years of age. At both time points, participants provided samples of blood, hair, and toenails that were analyzed for blood Mn and lead (Pb), serum cotinine, hair Mn, and toenail Mn. In adolescence, participants completed a postural balance assessment. Greater sway indicates postural instability (harmful effect), whereas lesser sway indicates postural stability (beneficial effect). Multivariable linear regression models were conducted to investigate the associations between childhood and adolescent Mn biomarkers and adolescent postural balance adjusted for age, sex, height-weight ratio, parent/caregiver intelligence quotient, socioeconomic status, blood Pb, and serum cotinine. RESULTS: CARES participants who completed the adolescent postural balance assessment (n=123) were 98% White and 54% female and had a mean age of 16 y (range: 13-18 y). In both childhood and adolescence, higher Mn biomarker concentrations were significantly associated with greater adolescent sway measures. Supplemental analyses revealed sex-specific associations; higher childhood Mn biomarker concentrations were significantly associated with greater sway in females compared with males. DISCUSSION: This study found childhood and adolescent Mn biomarkers were associated with subclinical neuromotor effects in adolescence. This study demonstrates postural balance as a sensitive measure to assess the association between Mn biomarkers and neuromotor function. https://doi.org/10.1289/EHP13381.

Programming of respiratory health in childhood: influence of outdoor air pollution.

PURPOSE OF REVIEW: This overview highlights recent experimental and epidemiological evidence for the programming effects of outdoor air pollution exposures during early development on lung function and chronic respiratory disorders, such as asthma and related allergic disorders. RECENT FINDINGS: Air pollutants may impact anatomy and/or physiological functioning of the lung and interrelated systems. Programming effects may result from pollutant-induced shifts in a number of molecular, cellular, and physiological states and their interacting systems. Specific key regulatory systems susceptible to programming may influence lung development and vulnerability to respiratory diseases, including both central and peripheral components of neuroendocrine pathways and autonomic nervous system (ANS) functioning which, in turn, influence the immune system. Starting in utero, environmental factors, including air pollutants, may permanently organize these systems toward trajectories of enhanced pediatric (e.g., asthma, allergy) as well as adult disease risk (e.g., chronic obstructive pulmonary disease). Evidence supports a central role of oxidative stress in the toxic effects of air pollution. Additional research suggests xenobiotic metabolism and subcellular components, such as mitochondria are targets of ambient air pollution and play a role in asthma and allergy programming. Mechanisms operating at the level of the placenta are being elucidated. Epigenetic mechanisms may be at the roots of adaptive developmental programming. SUMMARY: Optimal coordinated functioning of many complex processes and their networks of interaction are necessary for normal lung development and the maintenance of respiratory health. Outdoor air pollution may play an important role in early programming of respiratory health and is potentially amenable to intervention.

Migraine and its association with pubertal maturation and behavioral traits among adolescent girls.

OBJECTIVE: To determine if the ages at pubertal milestones are associated with the prevalence of adolescent migraine. BACKGROUND: Migraine headaches are a common disease in adolescent girls. Past studies have evaluated the relationship between age of onset of menarche and migraine headache, but none have studied earlier pubertal milestones such as thelarche and pubarche. METHODS: In this cross-sectional study, a previously validated questionnaire was administered to girls (15-18 years) in Breast Cancer and the Environment Research Program puberty cohort to ascertain if they met criteria for migraine over the past year. Ages of pubertal development were ascertained by serial examinations beginning at 6-8 years of age and ending in late puberty. Logistic regression analyses determined if age of onset of each pubertal milestone (thelarche, pubarche, menarche separately) was associated with adolescent migraine after adjusting for other risk factors. RESULTS: Of 761girls, 222 (29.2%) met the criteria for migraine. Later thelarche was associated with a lower odds of adolescent migraine (OR 0.83; 95% CI 0.72-0.97, p = 0.019). In models further adjusted for BASC-2 internalizing problems (n = 490), both later thelarche (OR 0.78; 95% CI 0.64-0.96, p = 0.016) and later menarche (OR 0.81; 95%CI 0.67-0.98, p = 0.026) were associated with a lower migraine prevalence. Internalizing problems (OR 1.05; 95% CI 1.03-1.07) externalizing problems (OR 1.05; 95% CI 1.02-1.07) and behavioral symptoms (OR 1.05; 95% CI 1.03-1.08) were associated with increased prevalence of migraine in separate models. CONCLUSIONS: Age of onset of thelarche and menarche, and internalizing, externalizing, and behavioral symptoms were all associated with adolescent migraine.

Unraveling the relationship between aeroallergen sensitization, gender, second-hand smoke exposure, and impaired lung function.

BACKGROUND: Contradictory findings on the differential effects of second-hand smoke (SHS) on lung function in girls and boys may result from masked relationships between host and environmental factors. Allergic sensitization may augment the relationship between SHS and decreased lung function, although its role in relation to the inconsistent gender differences in children has not been elucidated. HYPOTHESIS: We hypothesize that there will be differences between boys and girls related to early-life allergic sensitization and exposure to SHS on pulmonary function later in childhood. METHODS: Participants in this study (n = 486) were drawn from the Cincinnati Childhood Allergy and Air Pollution (CCAAPS) birth cohort study consisting of 46% girls. Allergic sensitization was assessed by skin prick test (SPT) to 15 aeroallergens at ages 2, 4, and 7, while pulmonary function and asthma diagnosis occurred at age 7. SHS exposure was measured by hair cotinine at ages 2 and/or 4. Gender differences of SHS exposure on pulmonary function among children with positive SPTs at ages 2, 4, and 7 as well as first- and higher-order interactions were examined by multiple linear regression. Interactions significant in the multivariate models were also examined via stratification. Comparisons within and between stratified groups were assessed by examining the slope of the parameter estimates/beta coefficients and associated p-values and confidence intervals. RESULTS: Increased cotinine levels were significantly associated with decreases in FEV(1) (-0.03 l, p < 0.05), peak expiratory flow (-0.07 l/s, p < 0.05), and FEF (25-75%) (-0.06 l/s, p < 0.01). The interaction between cotinine and sensitization at age 2 was borderline significant (p = 0.10) in the FEF(25-75%) model and showed an exposure response effect according to the number of positive SPTs at age 2; zero (-0.06 l/s, p < 0.01), one (-0.09 l/s, p < 0.05), or two or more positive SPTs (-0.30 l/s, p < 0.01). Despite increased polysensitization among boys, the association between cotinine and FEF(25-75%) among girls, with two or more positive SPTs at age 2, showed the greatest deficits in FEF(25-75%) (-0.34 l/s vs. -0.05 l/s and -0.06 l/s for non-sensitized girls and boys, respectively. Girls with two or more positive SPTs showed a twofold greater decrease in FEF(25-5%) (-0.34 l/s; 95% CI: -0.55, -0.13) compared to boys with the same degree of allergic sensitization (-0.18 l/s; 95% CI: -0.41, 0.06), although this difference was not statistically significant. CONCLUSIONS: Reductions in lung function were observed among children exposed to SHS, and the number of aeroallergen-positive SPTs at age 2 modifies this relationship. Girls experiencing early childhood allergic sensitization and high SHS exposure are at greater risk of decreased lung function later in childhood compared to non-sensitized girls and boys and demonstrate greater deficits compared to boys with similar degrees of sensitization.

Mental and Physical Stress Responses to Personal Ultrafine Particle Exposure in Adolescents.

Incidence rates of mental health disorders among adolescents is increasing, indicating a strong need for effective prevention efforts at a population level. The etiology of mental health disorders includes genetic, social, and environmental factors. Ultrafine particles (UFPs; particles less than 0.1 µm in diameter) have been shown to exert neurotoxic effects on the brain; however, epidemiologic evidence on the relationship between UFPs and childhood mental health outcomes is unclear. The objective of this study was to determine if exposure to UFPs was associated with symptoms of mental health in adolescents. Adolescents completed personal UFP monitoring for one week as well as a series of validated Patient-Reported Outcomes Measurement Information System (PROMIS) assessments to measure five domains of mental and physical stress symptoms. Multivariable linear regression models were used to estimate the association between PROMIS domain T-scores and median weekly personal UFP exposure with the inclusion of interactions to explore sex differences. We observed that median weekly UFP exposure was significantly associated with physical stress symptoms (ß: 5.92 per 10-fold increase in UFPs, 95% CI [0.72, 11.13]) but no other measured domains. Further, we did not find effect modification by sex on any of the PROMIS outcomes. The results of this study indicate UFPs are associated with physical symptoms of stress response among adolescents, potentially contributing to mental health disorders in this population.

Prenatal particulate matter exposure and mitochondrial mutational load at the maternal-fetal interface: Effect modification by genetic ancestry.

Prenatal ambient particulate matter (PM2.5) exposure impacts infant development and alters placental mitochondrial DNA abundance. We investigated whether the timing of PM2.5 exposure predicts placental mitochondrial mutational load using NextGen sequencing in 283 multi-ethnic mother-infant dyads. We observed increased PM2.5exposure, particularly during mid- to late-pregnancy and among genes coding for NADH dehydrogenase and subunits of ATP synthase, was associated with a greater amount of nonsynonymous mutations. The strongest associations were observed for participants of African ancestry. Further work is needed to tease out the role of mitochondrial genetics and its impact on offspring development and emerging disease disparities.