Tregs are key mediators of renal dysfunction induced by low-dose fluoride exposure.

Since the 1950s, the risks and benefits of drinking fluoridated water have been debated worldwide [1]. The World Health Organization (WHO) recommends a maximum fluoride concentration of 1.5 mg/L in drinking water [2]. As research on fluoride has advanced, fluoride intake from water has been identified as a potential contributor to several diseases of unknown etiology and is associated with an increased risk of systemic diseases [3]. With the recognition of these findings, countries and regions worldwide have established regulations and standards to limit fluoride levels in water [4]. According to WHO statistics on global drinking water quality regulations and standards, 102 countries and regions have set limits for fluoride concentration limit for drinking water. Among these, 8 countries or regions have fluoride concentration standards exceeding the WHO recommended limit (1.5 mg/L), with a maximum allowable of 4.0 mg/L, while 77 countries have adopted the WHO guideline value [5]. Currently, areas with high fluoride exposure (>4.0 mg/L) are gradually decreasing, making research on the health effects of low-to-moderate fluoride exposure more increasingly important [6].

Fluoride exhibits nephrotoxicity and acts as a toxin to both glomeruli and renal tubules. Environmental fluoride exposure can impair the kidney’s ability to concentrate urine and increase N-acetyl-B–d-glucosaminidase (NAG) excretion [7]. One defining characteristic of renal disease progression is its insidious nature. The prolonged latency period and the lack of reliable clinical biomarkers for renal diseases significantly increase the difficulty of early screening [8]. Simultaneously, impaired renal function reduces the kidney’s ability to excrete fluoride. Without proper intervention, the continuous accumulation of fluoride exacerbates renal structural abnormalities and functional impairment, creating a vicious cycle [9]. Initially, it was believed that reducing fluoride exposure in natural environments could delay renal dysfunction. However, a cohort study demonstrated that even in environments with low-dose water fluoride exposure (<1.5 mg/L), fluoride still remains a risk factor for renal dysfunction [10,11]. Therefore, exposure to fluoride at concentrations below 1.5 mg/L has become the primary form of natural exposure. Under these conditions, focusing on renal injury biomarkers in susceptible populations, closely monitoring at-risk individuals, and adopting early preventive measures may help mitigate the risk of progression to irreversible renal damage.

The kidney and immune system are interdependent, and this interaction renders the kidney susceptible to immune homeostasis imbalance [12,13]. Clinical data and experimental models have demonstrated that immune cell subsets serve as potential injury biomarkers and therapeutic targets for immune-mediated kidney diseases [14,15]. Regulatory T cells (Tregs) are crucial for maintaining immune homeostasis and have been shown to exert protective effects in the initial injury phase across various kidney disease models [16]. Our previous research found that low-to-moderate fluoride exposure induces peripheral Tregs recruitment while impairing their suppressive function [17,18]. Consequently, whether Tregs can serve as biomarkers for early renal injury mediated by low-level fluoride exposure has become a focal point of our investigation. Additionally, stability of both Tregs quantity and suppressive function is a critical factor in promoting renal tissue repair and delaying disease progression [14]. Given the complex characteristics of tissue-resident Tregs, further investigation is needed to elucidate their molecular mechanisms.

This study investigates the role of Tregs in renal dysfunction mediated by low-dose fluoride exposure using a cross-sectional survey of drinking-water fluorosis in China and a rat model of fluorosis. The research aims to explore the potential of Tregs as biomarkers for fluoride-induced renal injury, identify the molecular mechanisms underlying fluoride-induced imbalance in Tregs proportions, and evaluate the therapeutic potential of Tregs in renal injury.