Urinary proteomic biomarkers of systemic fluoride exposure in children

Abstract

While optimal fluoride (F) levels support oral health, chronic exposure to high concentrations can lead to skeletal and dental fluorosis, especially in children. Emerging evidence suggests that excessive fluoride intake may disrupt systemic physiology, yet the underlying mechanisms remain poorly understood. To address this gap, we performed a comparative urinary proteomic analysis using LC-MS/MS in schoolchildren residing in a high-fluoride region, categorizing participants into high-fluoride (HF) and low-fluoride (LF) groups based on urinary fluoride excretion. Among 460 quantified proteins, ten were differentially expressed in the HF group, six upregulated (PHPT1, SPP1, COLEC12, CST4, DCHS1, LDHB) and four downregulated (CTSH, NECTIN1, TNC, KLK1). Gene Ontology enrichment highlighted associations with cell adhesion, ossification, and tissue development. Notably marked alterations in osteopontin (SPP1) and tenascin-C (TNC), key regulators of bone remodeling and dental matrix organization, suggesting disrupted focal adhesion signaling, impaired matrix integrity, and dysregulated biomineralization. Additional changes in proteins associated with enamel formation, oxidative stress, and immune regulation suggest that high fluoride exposure may broadly disrupt extracellular matrix organization and trigger inflammatory pathways. These findings demonstrate that excessive fluoride exposure induces systemic molecular disturbances in children, with implications for bone and soft tissue homeostasis. This research adds to the body of human evidence concerning fluoride’s biological impact, advocating for vigilant exposure monitoring.