Longitudinal Impact of Fluoride on Neurodevelopment and Neuroimaging Outcomes During Childhood and Adolescence in the United States and Mexico

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.

Grant Number: 1R56ES036268-01
NIH Institute/Center: NIH
Principal Investigator: Kelly Brunst