Fluoride is a ubiquitous exposure and evidence of its potential developmental neurotoxicity is rising. Increased fluoride exposure has been linked to cognitive deficits, attention deficit hyperactivity disorder (ADHD), and mood abnormalities. Our previous work indicates fluoride may impact internalizing symptoms such as anxiety and depression. Despite evidence of fluoride's impact on neurobehavioral outcomes, the chemical's influence on brain structure is unclear. Additionally, we know little about sex-specific effects.
This project leveraged neurobehavioral assessments, neuroimaging, and childhood urinary fluoride (CUF) data from the Cincinnati Combined Childhood Cohort (C4) study. We used validated neurobehavioral assessments to examine associations between CUF and neurobehavioral outcomes. These outcomes included externalizing (attention and hyperactivity-related symptoms) and internalizing (anxiety/depression symptoms) behaviors (Chapter 2). Using magnetic resonance imaging (MRI) we examined the relationship between CUF and brain structure, including regional brain volumes and cortical thickness (Chapter 3). Moreover, this study explored whether CUF impacts neurobehavior and brain structure in a sex-specific manner.
We hypothesize that adolescents with higher CUF concentrations will exhibit more anxiety, depression, and ADHD-related behaviors and decreased brain volume and cortical thickness in areas related to emotion regulation and executive function in a sex-specific manner. We employed multiple statistical approaches, primarily relying on regression modeling using the generalized linear model (GLM) framework.
Increased CUF was associated with more internalizing symptoms including those related to obsessive-compulsive disorder (β = 2.3, 95% CI 0.73 to 3.9, p = 0.0040), somatization (β = 2.1, 95% CI 0.26 to 4.0, p = 0.026), and separation anxiety (β =1.5, 95% CI 0.034 to 2.9, p = 0.045). Increased CUF was also associated with increased odds of sub-clinically elevated symptoms related to panic attack/agoraphobia (OR = 2.3, 95% CI 1.3 to 4.5, p = 0.0080), obsessive-compulsive disorder (OR = 2.0, 95% CI 1.0 to 3.9, p = 0.047), and total anxiety (OR = 2.1, 95% CI 1.0 to 4.1, p = 0.041). However, these findings did not hold up after correction for multiple comparisons.
Increases in CUF were associated with increases in cortical thickness among several brain regions including the left entorhinal cortex (β = 0.40, 95% CI 0.18 to 0.62, p = 0.0010), left inferior temporal gyrus (β = 0.41, 95% CI 0.19 to 0.69, p < 0.0010), and right fusiform gyrus (β = 0.36, 95% CI 0.14 to 0.58, p = 0.0010, pBH = 0.033). Sex-specific analyses revealed that females exhibited a greater number of increases in cortical thickness throughout the brain compared to their male counterparts. While increases in several brain volumes were associated with CUF, the remaining associations did not hold up after correction for multiple comparisons.
Our findings suggest that CUF is associated with more internalizing symptomology and increases cortical thickness across multiple regions of the brain, with females seeing more generalized increases in cortical thickness. Although it is unclear the impact of the directionality and timing of fluoride-related changes in volume/cortical thickness on behavior, deviations from normal trajectories of development could impact cognition and risk of mental health disorders.