Health Implications of Proinflammatory Cytokine Activity at Different Levels of Fluoride Exposure: A Systematic Review

ABSTRACT The chronic intake of excessive fluoride (F − ) (>  1.5 mg/L) affects several tissues, organs, and systems. This represents a worldwide issue due to the presence of the compound in nature, with drinking water being the main source of exposure. The underlying mechanisms by which F − is toxic are not completely understood, but proinflammatory cytokine activity is implicated in these events. The aim of this study was to perform a systematic review of the health implications of proinflammatory cytokine activity at different levels of F − exposure. The search for original studies in which the activity of proinflammatory cytokines was assessed under exposure to F − was performed using the PubMed, Scopus, Springer, EBSCO, and Google Scholar databases by applying the Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) guidelines. The study protocol was registered with PROSPERO (CRD42024546726). Sixteen studies were analyzed in the present review. Tumor necrosis factor‐alpha (TNF‐α), interleukin (IL)‐1 beta (β), IL‐6, IL‐2, IL‐12, IL‐17, IL‐18, C‐reactive protein, and transforming growth factor‐β (TGF‐β) were the proinflammatory cytokines identified in the included reports. Alterations in cytokine activity were observed in response to varying levels of F − exposure, implicating an increased risk of toxicity and damage to the evaluated structures by highlighting the role of inflammation in the progression of these processes. Hence, the activity of proinflammatory cytokines at different levels of F − exposure has important implications for health, where inflammation plays a relevant role in the underlying mechanisms related to the resulting toxicity.