Exposure to fluoride is ubiquitous in many developed countries including the United States and Mexico due to fluoridation of water and salt, respectively. Several studies from Canada and Mexico suggest that exposure to fluoride (as measured in urine) prenatally or early in childhood could result in impaired neurodevelopment. This notion is supported by our preliminary data suggesting increases in fluoride are associated with internalizing symptoms at age 12 years. To date, there have been no studies capable of assessing critical windows of fluoride exposure starting in utero and continuing through early childhood. We hypothesize that exposure to fluoride during critical windows occurring prenatally and in early childhood impacts cognition, neurobehavior, and brain structure in adolescence. We will leverage existing resources from two well- characterized ongoing longitudinal birth cohorts: the Cincinnati Combined Childhood Cohorts (C4) study (Discovery Cohort) and the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort (Replication Cohort). We will utilize weekly temporal tooth fluoride exposure and neurobehavioral data to examine associations between the timing and intensity of fluoride exposure with IQ, externalizing (i.e., hyperactivity, aggression) and internalizing behaviors (i.e., anxiety, depression) assessed in childhood (7-8 years) and adolescence (12 years). Given that very little is known about the mechanistic processes by which fluoride impacts neurobehavior and cognition, we also propose to leverage structural magnetic resonance imaging (MRI) data collected at 12 years to assess whole brain, cortical and subcortical structural volumes. This will allow us to identify developmental periods during which fluoride exposure is associated with total and regional changes in white and gray matter brain volumes. The study design, based on two well-established birth cohorts with over 12 years of follow-up, will allow for the first-time longitudinal investigations of the impact of fluoride on neurodevelopment and brain structure. The scientific knowledge to be gained has the potential to establish new paradigms in fluoride neurotoxicity and improve public health by providing evidence-based research to inform regulatory and preventative interventions targeted to reduce fluoride exposure if warranted.