Kelly J. Brunst, Ph.D. - US grants

? DESCRIPTION (provided by applicant): The candidate is a molecular epidemiologist with primary research interest in the programming mechanisms by which prenatal/early-life exposure to environmental and social pollutants influences the health of children, with particular interest n neurodevelopment. With research linking ambient air pollution and poor neurodevelopment, the goal of this proposal is to add to the growing research linking urban air pollutants, stress and poor neurodevelopment by identifying novel mitochondrial (mt) biomarkers through which in utero exposures may be operating to impact future neurodevelopment. Through formal coursework and expert mentorship by Drs. Rosalind Wright, Andrea Baccarelli, Robert Wright, Michelle Bosquet Enlow, Avraham Reichenberg, Luca Lambertini and Liming Lang, this award will enable me to develop the knowledge and skills necessary to become an independent transdisciplinary environmental health scientist and achieve my long-term career goals: to establish a competitive and successfully funded program to study the cumulative effects of environmental exposures (e.g., air pollution/ stress) on the programming of biological mechanisms related to chronic childhood conditions. While this award focuses on neurobehavioral outcomes, it is worth noting that the knowledge and skills obtained will be broadly applicable to a range of child health outcomes given the large number of childhood conditions with mt underpinnings (e.g., asthma, obesity, autism, and attention disorders). Specifically, the candidate will 1) undergo extensive laboratory training in Drs. Baccarelli's and Lambertini's laboratories to further enhance my molecular skills; 2) obtain training in measuring and interpreting interactions involving social stressors; and 3) receive guidance and hands-on training in selecting, administering and interpreting neurodevelopmental assessments across early childhood. The proposed study will be the first to investigate complementary mtDNA biomarkers in two target tissues (e.g., placenta and cord blood) with respect to prenatal environmental exposures (e.g., urban air pollutants and stress) and early neurobehavioral phenotypes. The intent is to use state-of-art analyses of mtDNA damage by means of a panel of complementary markers of oxidative damage, heteroplasmy, and mtDNA abundance measured at the maternal-fetal interface (e.g., placenta and cord blood). These markers have properties that make them exceptionally well suited to biomarker development, as they: 1) have been shown to be altered by the environmental exposures; and 2) can mark the presence of damaged mitochondria, a primary source of systemic oxidative stress to which the brain is particularly vulnerable. This study is also highly cost effective as we will leverage the resources of an existing well-phenotyped urban and ethnically-mixed pregnancy cohort [PRogramming of Intergenerational Stress Mechanisms (PRISM) study] with existing biospecimens and neurobehavioral & environmental data.

Project Summary Anxiety and depression are among the most debilitating disorders worldwide and increase the risk for later-life adverse health outcomes including chronic anxiety and depression, substance abuse and suicide. Anxiety and depression are also the most common psychiatric disorders among adolescents with symptoms presenting as early as 4-5 years of age. Yet, we still have a poor understanding of the etiology of anxiety and depression in youth and the mechanisms involved. Air pollutants are widely recognized for their ability to affect the central nervous system and adversely impact neurodevelopment during childhood. The epigenome is particularly sensitive to environmental stimuli and studies targeting inflammatory and oxidative stress pathways have identified DNA methylation changes resulting with exposure to air pollutants. Oxidative stress and inflammation, however, are not the only pathways involved in air pollution neurotoxicity or the pathophysiology of mental health disorders. Thus, utilizing an epigenome- wide platform may help identify novel biomarkers of exposure and effect which may otherwise be overlooked with a targeted approach. The goal of this proposal is to determine whether exposure to fine particulate matter (PM2.5) and traffic-related air pollution (TRAP) during childhood and adolescence impacts the epigenome and whether changes in DNA methylation can be used to identify children at increased risk for anxiety and depression. Using the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) and Health Outcomes and Measures of the Environment (HOME) study birth cohort, we will: 1) conduct an unbiased epigenome-wide search for DNA methylation biomarkers associated with PM2.5 and TRAP exposure prenatally through age 12 years (n=500) and 2) identify unique and pollution-related DNA methylation signatures associated with anxiety and depression. In addition, we will replicate our findings in a third, independent birth cohort, Project Viva (n=652), with similar sociodemographic characteristics and available air pollution and neurodevelopmental outcome data. The study design, based on three well-established birth cohorts with nearly two decades of follow-up, will allow for longitudinal and cross-sectional analyses of air pollution, DNA methylation, and mental health assessments all of which will increase the rigor and generalizability of our study.