Project Summary The Developmental Origins of Health and Disease (DOHaD) theory posits that early life environment predicts adverse health effects that may not manifest for decades. Adolescence is an understudied life stage characterized by profound brain remodeling and behavioral development, which may be influenced by the early life environment. We hypothesize that exposure to neuroactive (i.e., neurotoxic and neuroprotective) metals during the early postnatal period (0-2 years) impacts the trajectory of brain and executive function development, particularly in attention and working memory. The study of trajectories necessitates assessment of phenotypic development over time, rather than at a single time point as is most common in environmental health research. We propose studying longitudinal brain structure/function and executive function (EF) trajectories using multi-modal magnetic resonance imaging (MRI) and computerized EF tasks in an accelerated longitudinal design (ALD). An ALD is a commonly used epidemiologic tool that shortens the time needed to assess neurodevelopmental trajectories compared to a traditional longitudinal cohort design. We do so by leveraging the PHIME (Public Health Impact of Metals Exposure) study, a cohort of adolescents in Northern Italy. One third of the PHIME community lives proximal to a steel producing plant that emits neuroactive metals, supporting our ability to study the role of mixed metal exposures on health. Previously we have shown cross-sectional associations between manganese (Mn), one of the more common plant emissions, and adverse neurodevelopmental outcomes. More recently, we employed a novel, validated tooth biomarker to reconstruct prenatal and early childhood Mn exposures in naturally shed baby teeth, allowing us to show the prospective effects of early life Mn exposure on adolescent neurodevelopment measured at one time point. In this renewal, we extend our tooth biomarker to reconstruct past exposure to a mixture of common metals (Mn, Pb, Zn, Cu and Cr) and link specific exposure life stages [i.e., fetal life [(14 weeks gestation through birth), early postnatal life (0-2 years) and childhood (2-6 years)] to trajectories of structural/functional brain development and neurobehavior throughout adolescence. To complement the tooth biomarker, we will enroll new cohort members to assess phenotype trajectories from age 7-25 years (i.e. the onset through conclusion of adolescence). This renewal builds prior cross-sectional and prospective findings by creating a life course study of adolescent developmental trajectories of brain structure/function and EF. All told, our life course study covers 25 years in a single grant cycle and will be a model for future studies of early life environment and adolescent health, an understudied life stage representing the transition into adulthood. In sum, this renewal within PHIME will determine the critical exposure windows for early life metal exposure on adolescent developmental trajectories, a key research need so that interventions may be applied at the appropriate age to promote optimal development and improved health.

Project Narrative Adolescence is an understudied life stage during which profound brain remodeling and behavioral development can be influenced by early life environmental factors such as metals. We propose that exposure to a mixture of neuroactive metals in early life (age 0-2 years) impacts brain development manifesting as maladaptive trajectories of executive function, specifically involving attention and working memory.