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Effects of Long-Term Fluoride Exposure: Systematic Review and Meta-Analysis on Anxiety and Depression in Animal Models.
| Biological Trace Element Research | Enríquez-Sánchez FM, Pérez-Vega MI, Miranda-Beltrán ML, Valdez-Jiménez L. |
Animal-depression Systematic review Behavior Animal Study

Abstract

Studies have shown that long-term fluoride ingestion affects the structure and functioning of the central nervous system, altering cognitive functions of exposed individuals and mood disorders. The aim of this study is to present a systematic review and meta-analysis on the effects of experimental fluoride poisoning on anxiety and depression in animal models. The systematic review was performed according to PRISMA methodology, using the terms “fluoride and depression”, “fluoride and anxiety” in PubMed, Scopus and International Society for Fluoride Research databases, on studies published between 2013–2025. Subsequently, a meta-analysis was conducted, and the risk of bias was evaluated using the SYRCLE methodology. The results demonstrated that prolonged fluoride exposure instigates substantial behavioral alterations in animal models, manifesting a pro-depressant effect in the tail suspension test (B=1.53, p<0.001) with an evident dose–response relationship (B=0.069 per ppm, p=0.0004). The analysis revealed a higher susceptibility in males (B=2.68, p=0.010) and rats exhibit different response patterns compared to mice (B=-1.72, p=0.043). In anxiety tests, non-significant trends were observed in the elevated maze (B=-0.65, p=0.108), but a significant reduction of rearing was observed in the open field (B=-0.85, p=0.033). Despite considerable heterogeneity among the studies, the findings remained consistent in sensitivity analyses, indicating that fluoride exerts a differential effect on neural circuits implicated in emotional regulation. This observation carries significant ramifications for the assessment of neurobehavioral risks in exposed populations.

Supplementary information

Supplementary file1 (PDF 110 KB)

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Corresponding author

Correspondence to Liliana Valdez-Jiménez.

References

  1. Ponikvar M (2008) Exposure of Humans to Fluorine and Its Assessment. Fluorine Health: Mol Imaging Biomed Mater Pharmaceut 487–549. https://doi.org/10.1016/B978-0-444-53086-8.00012-6

  2. Fordyce FM (2011) Fluorine: human health risks. In: Encyclopedia of environmental health. pp 776–785

  3. Zuo H, Chen L, Kong M et al (2018) Toxic effects of fluoride on organisms. Life Sci 198:18–24. https://doi.org/10.1016/J.LFS.2018.02.001

    Article  CAS  PubMed  Google Scholar

  4. World Health Organization (WHO) (2006) Fluoride in drinking-water. IWA Publishing, London, UK

    Google Scholar

  5. Hidalgo-Gato Fuentes I, Duque de Estrada Riverón J, Mayor Hernández F, Zamora Díaz JD (2007) Revista cubana de estomatología. Editorial Ciencias Médicas

  6. Ranjan R, Ranjan A (2015) Fluoride toxicity in animals. Springer, Cham

    Google Scholar

  7. Khan SA, Singh RK, Navit S et al (2015) Relationship between dental fluorosis and intelligence quotient of school going children in and around Lucknow district: a cross-sectional study. J Clin Diagn Res 9:ZC10–5. https://doi.org/10.7860/JCDR/2015/15518.6726

  8. Rocha-Amador D, Navarro ME, Carrizales L et al (2007) Decreased intelligence in children and exposure to fluoride and arsenic in drinking water. Cad Saude Publica 23(Suppl 4):S579–S587. https://doi.org/10.1590/s0102-311×2007001600018

    Article  PubMed  Google Scholar

  9. Choi AL, Sun G, Zhang Y, Grandjean P (2012) Developmental fluoride neurotoxicity: a systematic review and meta-analysis. Environ Health Perspect 120:1362–1368. https://doi.org/10.1289/ehp.1104912

    Article  CAS  PubMed  PubMed Central  Google Scholar

  10. Agalakova NI, Nadei OV (2020) Inorganic fluoride and functions of brain. Crit Rev Toxicol 50:28–46. https://doi.org/10.1080/10408444.2020.1722061

    Article  CAS  PubMed  Google Scholar

  11. Chan JT, Qiu CC, Whitford GM et al (1989) The distribution of fluoride of prenatal origin in the rat–a pilot study. Arch Oral Biol 34:885–888. https://doi.org/10.1016/0003-9969(89)90145-3

    Article  CAS  PubMed  Google Scholar

  12. Dec K, ?ukomska A, Maciejewska D et al (2017) The influence of fluorine on the disturbances of homeostasis in the central nervous system. Biol Trace Elem Res 177:224–234. https://doi.org/10.1007/s12011-016-0871-4

    Article  CAS  PubMed  Google Scholar

  13. De Witte NAJ, Mueller SC (2017) White matter integrity in brain networks relevant to anxiety and depression: evidence from the human connectome project dataset. Brain Imaging Behav 11:1604–1615. https://doi.org/10.1007/s11682-016-9642-2

    Article  PubMed  Google Scholar

  14. G?owacka M, Przyby?a N, Huma?ska M, Kornatowski M (2024) Depression and anxiety as predictors of performance status and life satisfaction in older adult neurological patients: a cross-sectional cohort study. Front Psychiatry. https://doi.org/10.3389/fpsyt.2024.1412747

    Article  PubMed  PubMed Central  Google Scholar

  15. Dean J, Keshavan M (2017) The neurobiology of depression: an integrated view. Asian J Psychiatr 27:101–111. https://doi.org/10.1016/j.ajp.2017.01.025

    Article  PubMed  Google Scholar

  16. Page MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. https://doi.org/10.1136/bmj.n71

    Article  PubMed  PubMed Central  Google Scholar

  17. Kilkenny C, Browne WJ, Cuthill IC et al (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e1000412. https://doi.org/10.1371/journal.pbio.1000412

    Article  CAS  PubMed  PubMed Central  Google Scholar

  18. Hooijmans CR, Rovers MM, de Vries RBM et al (2014) SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 14:43. https://doi.org/10.1186/1471-2288-14-43

    Article  PubMed  PubMed Central  Google Scholar

  19. McGuinness LA, Higgins JPT (2020) Risk-of-bias VISualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. https://doi.org/10.1002/jrsm.1411

    Article  PubMed  Google Scholar

  20. Liu F, Ma J, Zhang H et al (2014) Fluoride exposure during development affects both cognition and emotion in mice. Physiol Behav 124:1–7. https://doi.org/10.1016/j.physbeh.2013.10.027

    Article  CAS  PubMed  Google Scholar

  21. Balaji B, Kumar EP, Kumar A (2015) Evaluation of standardized Bacopa monniera extract in sodium fluoride-induced behavioural, biochemical, and histopathological alterations in mice. Toxicol Ind Health 31:18–30. https://doi.org/10.1177/0748233712468018

    Article  PubMed  Google Scholar

  22. Bartos M, Gumilar F, Bras C et al (2015) Neurobehavioural effects of exposure to fluoride in the earliest stages of rat development. Physiol Behav 147:205–212. https://doi.org/10.1016/j.physbeh.2015.04.044

    Article  CAS  PubMed  Google Scholar

  23. Lu F, Zhang Y, Trivedi A et al (2019) Fluoride related changes in behavioral outcomes may relate to increased serotonin. Physiol Behav 206:76–83. https://doi.org/10.1016/j.physbeh.2019.02.017

    Article  CAS  PubMed  PubMed Central  Google Scholar

  24. Uyar H, Oto G (2020) The effect of chronic exposure to fluorine and 7,12-dimethylbenz(A)anthracene on anxiety, locomotor activity, spatial learning, and memory consolidation in rats. Fluoride 53:52–76

    CAS  Google Scholar

  25. Zhou G, Hu Y, Wang A et al (2021) Fluoride stimulates anxiety- and depression-like behaviors associated with SIK2-CRTC1 signaling dysfunction. J Agric Food Chem 69:13618–13627. https://doi.org/10.1021/acs.jafc.1c04907

    Article  CAS  PubMed  Google Scholar

  26. Cao Q, Wang J, Hao Y et al (2022) Exercise ameliorates fluoride-induced anxiety- and depression-like behavior in mice: role of GABA. Biol Trace Elem Res 200:678–688. https://doi.org/10.1007/s12011-021-02678-2

    Article  CAS  PubMed  Google Scholar

  27. Karademir B (2023) The assessment of effectiveness of a novel antidepressant, Agomelatine on anxiety and depression induced by fluoride intoxication by means of Open-Field and Hot-Plate tests in mouse model (BalB-C). Ankara Üniversitesi Veteriner Fakültesi Dergisi 70:123–130. https://doi.org/10.33988/auvfd

  28. Kumar S, Swamy RS, Bhushan R et al (2024) Molecular and immunohistochemical alterations in fluoride-induced neurological impediment in adult rats. J Trace Elem Med Biol 86:127511. https://doi.org/10.1016/j.jtemb.2024.127511

    Article  CAS  PubMed  Google Scholar

  29. Owumi SE, Oluwawibe BJ, Chimezie J et al (2024) An in vivo and in silico probing of the protective potential of betaine against sodium fluoride-induced neurotoxicity. BMC Pharmacol Toxicol 25:87. https://doi.org/10.1186/s40360-024-00812-z

    Article  CAS  PubMed  PubMed Central  Google Scholar

  30. Qi M, Wu Y, Shi H et al (2024) Effect of voluntary wheel running on anxiety- and depression-like behaviors in fluoride-exposed mice. Biol Trace Elem Res. https://doi.org/10.1007/s12011-024-04433-9

    Article  PubMed  Google Scholar

  31. Swamy RS, Kumar N, Shenoy S et al (2024) Effect of naringin on sodium fluoride-induced neurobehavioral deficits in Wistar rats. Biomed Rep 20:97. https://doi.org/10.3892/br.2024.1785

    Article  CAS  PubMed  PubMed Central  Google Scholar

  32. Ahuja T, Begum F, Kumar G et al (2025) Exploring the protective role of metformin and dehydrozingerone in sodium fluoride-induced neurotoxicity: evidence from prenatal rat models. 3 Biotech 15:36. https://doi.org/10.1007/s13205-024-04175-4

    Article  PubMed  PubMed Central  Google Scholar

  33. Hosokawa M, Iwasaki Y, Someya A, Tanigawa T (2025) Effects of low concentration of fluoride exposure during fetal on behavior and neurotransmitters in adult mice. Biomed Rep 22:81. https://doi.org/10.3892/br.2025.1959

    Article  PubMed  PubMed Central  Google Scholar

  34. Javanbakht P, Talebinasab A, Asadi-Golshan R et al (2025) Effects of quercetin against fluoride-induced neurotoxicity in the medial prefrontal cortex of rats: a stereological, histochemical and behavioral study. Food Chem Toxicol 196:115126. https://doi.org/10.1016/j.fct.2024.115126

    Article  CAS  PubMed  Google Scholar

  35. Yang L, Jin P, Wang X et al (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

    Article  CAS  PubMed  Google Scholar

  36. Bartos M, Gumilar F, Gallegos CE et al (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

    CAS  PubMed  Google Scholar

  37. Chen L, Ning H, Yin Z et al (2017) The effects of fluoride on neuronal function occurs via cytoskeleton damage and decreased signal transmission. Chemosphere 185:589–594. https://doi.org/10.1016/j.chemosphere.2017.06.128

    Article  CAS  PubMed  Google Scholar

  38. Organización Panamericana de la Salud (2017) Depresión y otros trastornos mentales comunes. Estimaciones sanitarias mundiales. Pan American Health Organization/World Health Organization

  39. Ennaceur A, Chazot PL (2016) Preclinical animal anxiety research – flaws and prejudices. Pharmacol Res Perspect 4. https://doi.org/10.1002/prp2.223

  40. Belovicova K, Bogi E, Csatlosova K, Dubovicky M (2017) Animal tests for anxiety-like and depression-like behavior in rats. Interdiscip Toxicol 10:40–43. https://doi.org/10.1515/intox-2017-0006

    Article  PubMed  Google Scholar

  41. Acikgoz B, Dalkiran B, Dayi A (2022) An overview of the currency and usefulness of behavioral tests used from past to present to assess anxiety, social behavior and depression in rats and mice. Behav Processes 200:104670. https://doi.org/10.1016/j.beproc.2022.104670

    Article  PubMed  Google Scholar

  42. Sun Z, Zhang Y, Xue X et al (2017) Maternal fluoride exposure during gestation and lactation decreased learning and memory ability, and glutamate receptor mRNA expressions of mouse pups. Hum Exp Toxicol 37:87–93. https://doi.org/10.1177/0960327117693067

    Article  CAS  PubMed  Google Scholar

  43. Valdez Jiménez L, López Guzmán OD, Cervantes Flores M et al (2017) In utero exposure to fluoride and cognitive development delay in infants. Neurotoxicology 59:65–70. https://doi.org/10.1016/j.neuro.2016.12.011

    Article  CAS  PubMed  Google Scholar

  44. Niu R, Chen H, Manthari RK et al (2018) Effects of fluoride on synapse morphology and myelin damage in mouse hippocampus. Chemosphere 194:628–633. https://doi.org/10.1016/j.chemosphere.2017.12.027

    Article  CAS  PubMed  Google Scholar

  45. Li X, Zhang J, Niu R et al (2019) Effect of fluoride exposure on anxiety- and depression-like behavior in mouse. Chemosphere 215:454–460. https://doi.org/10.1016/j.chemosphere.2018.10.070

    Article  CAS  PubMed  Google Scholar

  46. Black CN, Bot M, Scheffer PG, Penninx BWJH (2017) Oxidative stress in major depressive and anxiety disorders, and the association with antidepressant use; results from a large adult cohort. Psychol Med 47:936–948. https://doi.org/10.1017/S0033291716002828

    Article  CAS  PubMed  Google Scholar

  47. Salim S (2014) Oxidative stress and psychological disorders. Curr Neuropharmacol 12:140–147. https://doi.org/10.2174/1570159X11666131120230309

    Article  CAS  PubMed  PubMed Central  Google Scholar

  48. Adkins EA, Yolton K, Strawn JR et al (2022) Fluoride exposure during early adolescence and its association with internalizing symptoms. Environ Res 204:112296. https://doi.org/10.1016/j.envres.2021.112296

    Article  CAS  PubMed  Google Scholar

  49. Yu F-F, Luo K-T, Wang G-Q et al (2025) Association between fluoride exposure and psychiatric disorders in adults. Int J Environ Health Res 35:1018–1027. https://doi.org/10.1080/09603123.2024.2378950

    Article  PubMed  Google Scholar

  50. Wong CK, Mak RY, Kwok TS et al (2022) Prevalence, incidence, and factors associated with non-specific chronic low back pain in community-dwelling older adults aged 60 years and older: a systematic review and meta-analysis. J Pain 23:509–534. https://doi.org/10.1016/j.jpain.2021.07.012

    Article  PubMed  Google Scholar

  51. Guth S, Hüser S, Roth A et al (2020) Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses. Arch Toxicol 94:1375–1415. https://doi.org/10.1007/s00204-020-02725-2

    Article  CAS  PubMed  PubMed Central  Google Scholar

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Acknowledgements

The authors acknowledge the Universidad de Guadalajara for the facilities and support received to accomplish this project, and the Secretaría de Ciencia, Humanidades, Tecnología e Innovación (SECIHTI) for the scholarship granted with support number 837904.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Author information

Authors and Affiliations

  1. Laboratorio de Ciencias Biomédicas, Departamento de Ciencias de La Tierra y de La Vida, Centro Universitario de los Lagos (CULagos), Universidad de Guadalajara, Lagos de Moreno, México

    Fernanda Marlen Enríquez-Sánchez, María Isabel Pérez-Vega & María de la Luz Miranda-Beltrán

  2. Laboratorio de Neuropsicología, Departamento de Humanidades, Artes y Culturas Extranjeras, CULagos, Universidad de Guadalajara, Paseo del Leñador 58, Paseos de La Montaña, Lagos de Moreno, Jalisco, 47463, México

    María Isabel Pérez-Vega & Liliana Valdez-Jiménez

Contributions

F.M.E.S. Contributed to the conception and design of the work, and the acquisition, analysis and interpretation of data. M.I.P.V. Contributed to the acquisition, analysis, interpretation and writing of the document M.L.M.B. Contributed to the critical analysis and interpretation of the data. L.V. J. Contributed to the manuscript design, analysis and critical data interpretation. All authors have given final approval and agree to be accountable for all aspects of the work ensuring integrity and accuracy.

Competing interest

The authors declare no competing interests.

ABSTRACT ONLINE AT https://link.springer.com/article/10.1007/s12011-025-04755-2