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Fluoride Exposure Increases the Activity of the Cystine/Glutamate Exchanger in Glia Cells.
| Neurochemical Research | Ocharán-Mercado A, Loaeza-Loaeza J, Hernández-Sotelo D, Cid L, Hernández-Kelly LC, Felder-Shmittbuhl MP, Ortega A. | 50(2):105.
Glia cells Brain Mechanisms of Cellular Toxicity Neurodevelopmental Cell Study
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Abstract

Fluoride exposure in drinking water has been widely related to impairment of cognitive function. Even though this ion has been described as neurotoxic for more than two decades, the molecular mechanisms of fluoride neurotoxicity are not fully understood, however, increasing evidence suggests that glial cells are the site of early injury in fluoride neurotoxicity. Nevertheless, a convergence point of many studies is the effect on glutamatergic neurotransmission and the generation of reactive oxygen species. In this context, we evaluated here the expression and regulation of the cystine/glutamate exchanger upon fluoride exposure since this transporter is in the interface between excitotoxicity and the antioxidant response. We demonstrate here the functional expression of the cystine /glutamate exchanger in both the U373 human glioblastoma cells and chick cerebellar Bergmann glia cells. Using a [3H]-L-Glutamate uptake assay, we demonstrate that fluoride increases the activity of the exchanger in a time and dose-dependent manner. This augmentation is mitigated by the antioxidant Trolox. To gain insight into fluoride neurotoxicity mechanisms, we evaluated its effect on human antigen R, a RNA binding protein, that binds to the 3′-UTR region of exchanger mRNA increasing its half time life. An increase in human antigen R protein was recorded after a 6 h fluoride exposure, suggesting that this ion regulates the exchanger through this RNA-binding protein. Furthermore, we show that fluoride exposure increases both the exchanger and human antigen R mRNAs half-life. These results provide insights into fluoride neurotoxicity mechanisms and support the notion of a central role of glial cells in neuronal glutamatergic transmission disruption that leads to neuronal cell death…

Conclusion

Our data supports the idea of a critical involvement of glial cells in F– toxicity. Work currently under progress in our group is aimed at the characterization of the signaling pathways that regulate HuR function under F– exposure as a preliminary step to further understand the complexity of the molecular mechanisms of F– toxicity.

FULL-TEXT STUDY ONLINE AT https://link.springer.com/article/10.1007/s11064-025-04358-2

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Authors and Affiliations

  1. Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro, Zacatenco, 07360, México

    Andrea Ocharán-Mercado, Jaqueline Loaeza-Loaeza, Luis Cid, Luisa C. Hernández-Kelly & Arturo Ortega

  2. Laboratorio de Epigenética del Cáncer, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas 88, 39086, Chilpancingo, Guerrero, México

    Daniel Hernández-Sotelo

  3. Centre National de La Recherche Scientifique, Institut Des Neurosciences Cellulaires Et Intégratives (UPR 3212), Université de Strasbourg, Strasbourg, France

    Marie-Paule Felder-Shmittbuhl

Funding

This study was supported by a Conahcyt grant (CF2023-I-935) to AO. A O-M was supported by a Conahcyt-Mexico scholarship (No. 779191).