The dopamine transporter (DAT) regulates the dimension and duration of dopamine transmission. DAT expression, its trafficking, protein–protein interactions, and its activity are conventionally studied in the CNS and within the context of neurological diseases such as Parkinson’s Diseases and neuropsychiatric diseases such as drug addiction, attention deficit hyperactivity and autism. However, DAT is also expressed at the plasma membrane of peripheral immune cells such as monocytes, macrophages, T-cells, and B-cells. DAT activity via an autocrine/paracrine signaling loop regulates macrophage responses to immune stimulation. In a recent study, we identified an immunosuppressive function for DAT, where blockade of DAT activity enhanced LPS-mediated production of IL-6, TNF-α, and mitochondrial superoxide levels, demonstrating that DAT activity regulates macrophage immune responses. In the current study, we tested the hypothesis that in the DAT knockout mice, innate and adaptive immunity are perturbed. We found that genetic deletion of DAT (DAT^−/−) results in an exaggerated baseline inflammatory phenotype in peripheral circulating myeloid cells. In peritoneal macrophages obtained from DAT^−/− mice, we identified increased MHC-II expression and exaggerated phagocytic response to LPS-induced immune stimulation, suppressed T-cell populations at baseline and following systemic endotoxemia and exaggerated memory B cell expansion. In DAT^−/− mice, norepinephrine and dopamine levels are increased in spleen and thymus, but not in circulating serum. These findings in conjunction with spleen hypoplasia, increased splenic myeloid cells, and elevated MHC-II expression, in DAT^−/− mice further support a critical role for DAT activity in peripheral immunity. While the current study is only focused on identifying the role of DAT in peripheral immunity, our data point to a much broader implication of DAT activity than previously thought. This study is dedicated to the memory of Dr. Marc Caron who has left an indelible mark in the dopamine transporter field.

Background/Objectives: Urinary fluoride (UF) is the most well-established biomarker for fluoride exposure, and understanding its distribution can inform risk assessment for potential adverse systemic health effects. To our knowledge, this study is the first to report distributions of UF among youth according to sociodemographic factors in a nationally representative United States (US) sample. Methods: The study included 1191 children aged 6-11 years and 1217 adolescents aged 12-19 years from the National Health and Nutrition Examination Survey (NHANES) 2015–2016. We examined UF according to sociodemographic variables as well as Spearman correlations between UF and plasma fluoride. Survey-weighted quantile regression examined associations between tap water fluoride and UF levels adjusted for covariates. Results: The average age of participants was 12.5 years. The median (IQR) UF and water fluoride concentrations were 0.52 (0.50) mg/L and 0.39 (0.54) mg/L, respectively. Children had higher UF levels than adolescents and males had higher UF levels than females. UF differed according to race/ethnicity among both children and adolescents. Specifically, non-Hispanic Black youth tended to have higher UF levels than all participants except for those classified as other race/multiracial. UF and plasma fluoride were moderately correlated for children and adolescents. Higher water fluoride levels were associated with higher UF levels, and the magnitudes of association were larger at higher quantiles of UF (β = 0.14, p < 0.001; β = 0.20, p< 0.001 at the 25th and 50th quantiles, respectively). The magnitude of association between water fluoride and UF was the largest for non-Hispanic Black participants (predictive margin = 0.3, p < 0.001). Conclusions: Non-Hispanic Black youth in the US may have greater fluoride exposure and receive more of their fluoride intake from tap water than youth of other races/ethnicities. Factors contributing to potential racial/ethnic disparities in fluoride exposure within the US warrant further investigation so that they can be mitigated to reduce the potential for harm.