The primary objectives of this study are to characterize the effects of environmental manganese (Mn) exposure on adolescent neurodevelopment. Although long known to be a critical neurodevelopmental period in pediatrics/psychology, little is known about the impact of toxic chemical exposures on neurophenotypes in adolescence. Mn is a compelling neurotoxicant to study in adolescence because: i) Mn is an essential trace metal, but it is also neurotoxic at elevated exposures; ii) the catecholaminergic system is a well-known target of Mn, and adolescence neurodevelopment involves substantial changes to the dopaminergic system, iii) Mn exposure is more ubiquitous than previously recognized, but its role in altering brain development is not well known, and iv) there are significant knowledge gaps regarding the impacts of Mn in adolescence. Preliminary results from our initial grant period show that elevated Mn exposure during pre/early adolescence is associated with deficits in attention, neuromotor, cognitive, and olfactory function in children. We will build upon these findings in a cohort of 240 adolescents to determine: 1) the role of Mn exposure timing on adolescent executive function, behavior, and self-regulation by applying novel exposure biomarkers and statistical methods to identify and define critical developmental windows of susceptibility, and 2) functional and anatomical neurophenotypes that are impacted by Mn, focusing on brain areas that subserve executive function, behavior, and self-regulation in adolescence (e.g., PFC, ventral striatum, amygdala) using functional and anatomical MRI. Our established PHIME (Public Health Impact of Manganese Exposure) cohort presents a unique opportunity to achieve these important goals. PHIME was designed to investigate long-term Mn exposure timing; it onsists of subjects (now adolescents) living in three well-characterized communities in Northern Italy that differ in the timing and intensity of environmental Mn exposure from current or historic ferromanganese alloy plant operations. Moreover, recent innovations in exposure science now allow us to retrospectively reconstruct Mn exposure across fetal life/early childhood using a novel tooth biomarker of exposure These studies will be among the first to longitudinally assess the role of environmental Mn on adolescent neurodevelopment and behavior and to objectively determine critical exposure windows that can inform the timing of future public health interventions. ExpandCollapse Abstract