Effects of Long-Term Fluoride Exposure: Systematic Review and Meta-Analysis on Anxiety and Depression in Animal Models.

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 (&#x3b2;&#x2009;=&#x2009;1.53, p&#x2009;<&#x2009;0.001) with an evident dose-response relationship (&#x3b2;&#x2009;=&#x2009;0.069 per ppm, p&#x2009;=&#x2009;0.0004). The analysis revealed a higher susceptibility in males (&#x3b2;&#x2009;=&#x2009;2.68, p&#x2009;=&#x2009;0.010) and rats exhibit different response patterns compared to mice (&#x3b2;&#x2009;=&#x2009;-1.72, p&#x2009;=&#x2009;0.043). In anxiety tests, non-significant trends were observed in the elevated maze (&#x3b2;&#x2009;=&#x2009;-0.65, p&#x2009;=&#x2009;0.108), but a significant reduction of rearing was observed in the open field (&#x3b2;&#x2009;=&#x2009;-0.85, p&#x2009;=&#x2009;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.