Kelly J. Brunst

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.

Forkhead box protein 3 (FOXP3) hypermethylation is associated with diesel exhaust exposure and risk for childhood asthma.

Kelly J. Brunst, Ph.D.1,2,†, Yuet-Kin Leung, Ph.D.2,3, Patrick H. Ryan, Ph.D.1,2,4, Gurjit K. Khurana Hershey, M.D., Ph.D.5, Linda Levin, Ph.D.1,2, Hong Ji, Ph.D.5, Grace K. LeMasters, Ph.D.1, and Shuk-Mei Ho, Ph.D.2,3,6 1Division of Epidemiology and Biostatistics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Kettering Building, Cincinnati, OH 2Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Kettering Building, Cincinnati, OH 3Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati College of Medicine, 3223 Eden Avenue, Kettering Building, Cincinnati, OH 4Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 7037, Cincinnati, OH 5Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 7037, Cincinnati, OH 6Cincinnati Veteran Affairs Medical Center, Merit Scholar, 3200 Vine Street, Cincinnati, OH

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.

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

To cite this article: Brunst KJ, Ryan PH, Lockey JE, Bernstein DI, McKay RT, Khurana Hershey GK, Villareal M, Biagini Myers JM, Levin L, Burkle J, Evans S, LeMasters GK. Unraveling the relationship between aeroallergen sensitization, gender, second‐hand smoke exposure, and impaired lung function. Pediatric Allergy Immunology 2012: 23: 479–487.

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 childrens environmental health studies is a critical priority. This review will highlight (i) the importance of exploring environmental mitochondriomics in childrens 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. Copyright

Maternal Lifetime Trauma Exposure, Prenatal Cortisol, and Infant Negative Affectivity

Little research has examined the impact of maternal lifetime trauma exposure on infant temperament. We examined associations between maternal trauma history and infant negative affectivity and modification by prenatal cortisol exposure in a sociodemographically diverse sample of mother-infant dyads. During pregnancy, mothers completed measures of lifetime trauma exposure and current stressors. Third-trimester cortisol output was assessed from maternal hair. When infants were 6 months old, mothers completed the Infant Behavior Questionnaire-Revised. In analyses that controlled for infant sex and maternal age, education, race/ethnicity, and stress during pregnancy, greater maternal trauma exposure was associated with increased infant distress to limitations and sadness. Higher and lower prenatal cortisol exposure modified the magnitude and direction of association between maternal trauma history and infant rate of recovery from arousal. The association between maternal trauma history and infant distress to limitations was somewhat stronger among infants exposed to higher levels of prenatal cortisol. The analyses suggested that maternal lifetime trauma exposure is associated with several domains of infant negative affectivity independently of maternal stress exposures during pregnancy and that some of these associations may be modified by prenatal cortisol exposure. The findings have implications for understanding the intergenerational impact of trauma exposure on child developmental outcomes.

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.

Effects of Prenatal Social Stress and Maternal Dietary Fatty Acid Ratio on Infant Temperament: Does Race Matter?

Background Infant temperament predicts a range of developmental and behavioral outcomes throughout childhood. Both maternal fatty acid intake and psychosocial stress exposures during pregnancy may influence infant temperament. Furthermore, maternal race may modify prenatal diet and stress effects. The goals of this study are to examine the joint effects of prenatal diet and stress and the modifying effects of race on infant behavior. Methods Analyses included N=255 mother-infant dyads, primarily minorities (21% Blacks; 42% Hispanics), enrolled in an urban pregnancy cohort. Maternal prenatal stress was indexed by a negative life events (NLEs) score on the Crisis in Family Systems-Revised survey. Prenatal total daily intakes of polyunsaturated fatty acids (PUFAs) (n3, n6) were estimated from a food frequency questionnaire; n3:n6 ratios were calculated. Mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), a measure of infant temperament, when the children were 6 months old. Three commonly used dimensions were derived: Orienting & Regulation, Extraversion, and Negative Affectivity. Associations among prenatal stress, maternal n3:n6 ratio, and race/ethnicity on infant temperament, controlling for maternal education and age and child sex, were examined. Results Among Blacks, prenatal stress effects on infant Orienting & Regulation scores were modified by maternal n3:n6 ratios (p=0.03): As NLEs increased, lower n3:n6 ratios predicted lower infant Orienting & Regulation scores, whereas higher n3:n6 ratios attenuated the effect of prenatal stress. There were no main or interaction effects predicting Extraversion or Negative Affectivity. Conclusions An optimal PUFA ratio may protect the fetus from stress effects on infant behavior, particularly among Blacks. These findings may have implications for later neurodevelopment and social functioning predicted by early temperamental characteristics.

Epigenome-wide cross-tissue predictive modeling and comparison of cord blood and placental methylation in a birth cohort.

AIM We compared predictive modeling approaches to estimate placental methylation using cord blood methylation. MATERIALS & METHODS We performed locus-specific methylation prediction using both linear regression and support vector machine models with 174 matched pairs of 450k arrays. RESULTS At most CpG sites, both approaches gave poor predictions in spite of a misleading improvement in array-wide correlation. CpG islands and gene promoters, but not enhancers, were the genomic contexts where the correlation between measured and predicted placental methylation levels achieved higher values. We provide a list of 714 sites where both models achieved an R2 ≥0.75. CONCLUSION The present study indicates the need for caution in interpreting cross-tissue predictions. Few methylation sites can be predicted between cord blood and placenta.

Secondhand smoke and traffic exhaust confer opposing risks for asthma in normal and overweight children

Exposure to ultrafine particles (UFP) in secondhand smoke (SHS) and traffic‐related air pollution (TRAP) may elicit chronic inflammation. It was hypothesized that the association between these exposures would be potentiated in overweight versus normal‐weight children.