Abstract
Fluoride, a pollutant present in contaminated ground water, oral care products, food, and pesticides, has deleterious effects in the structure and function of the central nervous system. Among the established neurological defects described in the exposed population, a reduced score in intelligence quotient tests in children of contaminated areas has gained attention over the past years. Maternal fluoride exposure during gestation decreases learning and memory abilities that correlate with a significant diminution of glutamate receptors expression. Since the involvement of glia cells in the maintenance and regulation of glutamatergic synapses is well-documented, in this contribution, we characterized the effect of fluoride exposure in the regulation of glia glutamine transporters. To this end, we used the Müller glia cell line, Mio-M1, and through the use of [3H]L-Glutamine uptake experiments and a Western blot approach, we demonstrate here the functional expression of system N of glutamine transporters, SNAT3 and SNAT5, in this model of human retina radial glia cells. Furthermore, these transporters interact with the glutamate transporter excitatory amino acid transporter 1, in an activity-dependent manner. Fluoride treatment reduces glutamine uptake and cell membrane [3H]glutamine surface binding, in good correlation with a decrease in SNAT3 and 5 protein levels. These results demonstrate that glia cells respond to the presence of fluoride reducing glutamine mobilization and by these means decreases glutamate turnover suggesting a disruption of glutamatergic transmission.
*Original absract online at https://link.springer.com/article/10.1007/s12640-020-00263-4
References
Barbier O, Arreola-Mendoza L, Del Razo LM (2010) Molecular mechanisms of fluoride toxicity. Chem Biol Interact 188:319–333. https://doi.org/10.1016/j.cbi.2010.07.011
Bartos M, Gumilar F, Gallegos CE, Bras C, Dominguez S, Mónaco N, Esandi MC, Bouzat C, Cancela LM, Minetti A (2018) Alterations in the memory of rat offspring exposed to low levels of fluoride during gestation and lactation: involvement of the ?7 nicotinic receptor and oxidative stress. Reprod Toxicol 81:108–114. https://doi.org/10.1016/j.reprotox.2018.07.078
Billups D, Marx MC, Mela I, Billups B (2013) Inducible presynaptic glutamine transport supports glutamatergic transmission at the calyx of Held synapse. J Neurosci 33:17429–17434. https://doi.org/10.1523/JNEUROSCI.1466-13.2013
Bringmann A, Biedermann B, Faude F, Enzmann V, Reichenbach A (2000) Na(+) currents through Ca(2+) channels in human retinal glial (Müller) cells. Curr Eye Res 20:420–429
Bringmann A, Pannicke T, Grosche J et al (2006) Müller cells in the healthy and diseased retina. Prog Retin Eye Res 25:397–424. https://doi.org/10.1016/j.preteyeres.2006.05.003
Buffo A, Rossi F (2013) Origin, lineage and function of cerebellar glia. Prog Neurobiol 109:42–63
Chouhan S, Flora SJS (2010) Arsenic and fluoride: two major ground water pollutants. Indian J Exp Biol 48:666–678
Chouhan S, Lomash V, Flora SJS (2010) Fluoride-induced changes in haem biosynthesis pathway, neurological variables and tissue histopathology of rats. J Appl Toxicol 30:63–73. https://doi.org/10.1002/jat.1474
Cresto N, Pillet LE, Billuart P, Rouach N (2019) Do astrocytes play a role in intellectual disabilities? Trends Neurosci 42:518–527. https://doi.org/10.1016/j.tins.2019.05.011
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105
Danbolt NCC, Furness DNN, Zhou Y (2016) Neuronal vs glial glutamate uptake: resolving the conundrum
Dienel GA (2019) Brain glucose metabolism: integration of energetics with function. Physiol Rev 99:949–1045. https://doi.org/10.1152/physrev.00062.2017
Ding Y, YanhuiGao SH et al (2011) The relationships between low levels of urine fluoride on children’s intelligence, dental fluorosis in endemic fluorosis areas in Hulunbuir, Inner Mongolia, China. J Hazard Mater 186:1942–1946. https://doi.org/10.1016/j.jhazmat.2010.12.097
Flores-Méndez M, Ramírez D, Alamillo N, Hernández-Kelly LC, del Razo LM, Ortega A (2014) Fluoride exposure regulates the elongation phase of protein synthesis in cultured Bergmann glia cells. Toxicol Lett 229:126–133
Flores-Méndez M, Mendez-Flores OG, Ortega A (2016) Glia plasma membrane transporters: key players in glutamatergic neurotransmission. Neurochem Int 98:46–55
Gonçalves CA, Rodrigues L, Bobermin LD, Zanotto C, Vizuete A, Quincozes-Santos A, Souza DO, Leite MC (2018) Glycolysis-derived compounds from astrocytes that modulate synaptic communication. Front Neurosci 12. https://doi.org/10.3389/fnins.2018.01035
Grandjean P (2019) Developmental fluoride neurotoxicity: an updated review. Environ Health 18:110. https://doi.org/10.1186/s12940-019-0551-x
Hertz L, Rothman D (2017) Glutamine-glutamate cycle flux is similar in cultured astrocytes and brain and both glutamate production and oxidation are mainly catalyzed by aspartate aminotransferase. Biology (Basel) 6:17
Hu YH, Wu SS (1988) Fluoride in cerebrospinal fluid of patients with fluorosis. J Neurol Neurosurg Psychiatry 51:1591–1593. https://doi.org/10.1136/jnnp.51.12.1591
Leke R, Schousboe A (2016) The glutamine transporters and their role in the glutamate/GABA-glutamine cycle. In: Advances in neurobiology. Springer, Cham, pp 223–257
Lutzu S, Castillo PE (2020) Modulation of NMDA receptors by G-protein-coupled receptors: role in synaptic transmission, plasticity and beyond. Neuroscience. https://doi.org/10.1016/j.neuroscience.2020.02.019
Martínez-Lozada Z, Ortega A (2015) Glutamatergic transmission: a matter of three. Neural Plast 2015:1–11
Martínez-Lozada Z, Guillem AM, Flores-Méndez M, Hernández-Kelly LC, Vela C, Meza E, Zepeda RC, Caba M, Rodríguez A, Ortega A (2013) GLAST/EAAT1-induced glutamine release via SNAT3 in Bergmann glial cells: evidence of a functional and physical coupling. J Neurochem 125:545–554
Mondal P, Chattopadhyay A (2019) Environmental exposure of arsenic and fluoride and their combined toxicity: a recent update. J Appl Toxicol jat.3931. https://doi.org/10.1002/jat.3931
National Research Council (2006) Fluoride in drinking water: a scientific review of EPA’s standards. The National Academies Press, Washington, DC. https://doi.org/10.17226/11571
Olivares-Bañuelos TN, Chí-Castañeda D, Ortega A (2019) Glutamate transporters: gene expression regulation and signaling properties. Neuropharmacology 161:107550. https://doi.org/10.1016/j.neuropharm.2019.02.032
Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32:1152–1166. https://doi.org/10.1038/jcbfm.2011.149
Pochini L, Scalise M, Galluccio M, Indiveri C (2014) Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health. Front Chem 11:61
Reichenbach A, Bringmann A (2013) New functions of Müller cells. Glia 61:651–678. https://doi.org/10.1002/glia.22477
Reichenbach A, Derouiche A, Kirchhoff F (2010) Morphology and dynamics of perisynaptic glia. Brain Res Rev 63:11–25. https://doi.org/10.1016/j.brainresrev.2010.02.003
Rocha-Amador D, Navarro ME, Carrizales L, Morales R, Calderón J (2007) Decreased intelligence in children and exposure to fluoride and arsenic in drinking water. Cad Saude Publica 23:S579–S587. https://doi.org/10.1590/S0102-311X2007001600018
Saeed M, Malik RN, Kamal A (2020) Fluorosis and cognitive development among children (6–14 years of age) in the endemic areas of the world: a review and critical analysis. Environ Sci Pollut Res 27:2566–2579. https://doi.org/10.1007/s11356-019-06938-6
Saxena S, Sahay A, Goel P (2012) Effect of fluoride exposure on the intelligence of school children in Madhya Pradesh, India. J Neursci Rural Pract 3: 144 https://doi.org/10.4103/0976-3147.98213
Schneider CA, Rasband WS, Eliceiri KW (2012) NIH image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675
Somogyi P, Takagi H, Richards JG, Mohler H (1989) Subcellular localization of benzodiazepine/GABAA receptors in the cerebellum of rat, cat, and monkey using monoclonal antibodies. J Neurosci 9:2197–2209
Todd AC, Marx M-C, Hulme SR, Bröer S, Billups B (2017) SNAT3-mediated glutamine transport in perisynaptic astrocytes in situ is regulated by intracellular sodium. Glia 65:900–916
von Bartheld CS, Bahney J, Herculano-Houzel S (2016) The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol 524:3865–3895. https://doi.org/10.1002/cne.24040
Wang SX, Wang ZH, Cheng XT, Li J, Sang ZP, Zhang XD, Han LL, Qiao XY, Wu ZM, Wang ZQ (2007) Arsenic and fluoride expose in drinking water: Children’s IQ and growth in Shanyin Country, Shanxi Province, China. Environ Health Perspect 115:643–647. https://doi.org/10.1289/ehp.9270
Yan L, Liu S, Wang C, Wang F, Song Y, Yan N, Xi S, Liu Z, Sun G (2013) JNK and NADPH oxidase involved in fluoride-induced oxidative stress in BV-2 microglia cells. Mediat Inflamm 2013:1–10. https://doi.org/10.1155/2013/895975
Yang L, Jin P, Wang X, Zhou Q, Lin X, Xi S (2018) Fluoride activates microglia, secretes inflammatory factors and influences synaptic neuron plasticity in the hippocampus of rats. Neurotoxicology 69:108–120. https://doi.org/10.1016/j.neuro.2018.09.006
CAS Article PubMed Google Scholar
Zhou Y, Danbolt NC (2013) GABA and glutamate transporters in brain. Front Endocrinol (Lausanne) 4:165. https://doi.org/10.3389/fendo.2013.00165– Article Google Scholar
Zhou Z, Wang H, Zheng B, Han Z, Chen Y, Ma Y (2017) A rat experimental study of the relationship between fluoride exposure and sensitive biomarkers. Biol Trace Elem Res 180:100–109. https://doi.org/10.1007/s12011-017-0984-4
CAS Article PubMed Google Scholar
Acknowledgments
The technical assistance of Luis Cid and Blanca Ibarra is acknowledged.
Funding
This work was funded by a grant from Consejo Nacional de Ciencia y Tecnología (Conacyt-México) to A.O. (255087). A.L.G.L. was supported by a Conacyt-México fellowship (#455449).