Fluorine is one of the most reactive elements with high electronegativity and the second-highest electron affinity. It has an oxidation number of ^–1 and exists as either inorganic fluorides or organofluorine compounds [1,2]. F^– exposure in humans occurs majorly from consuming water contaminated by F^– from various natural and anthropogenic sources such as volcanic eruptions, mining residues, industrial effluents, phosphorus fertilizers, and certain domestic activities [3,4]. F^– is considered a double-edged sword, having both beneficial and adverse effects on humans as well as other animals. F^– is beneficial to human health by promoting bone development and preventing tooth decay and dental caries at low levels. However, prolonged exposure to higher levels can cause F^– toxicity or “fluorosis”. Although fluorosis is generally characterized by dental mottling and skeletal deformities, cellular and functional damages in multiple organ systems are also observed [[5], [6], [7]]. Therefore, the level of F^– consumption becomes critical to human health, which is why the World Health Organization (WHO) has set the maximum permissible limit of F^– in drinking water at 1.5 ppm (1.5 mg/L) [8].

Being a chemically active ion, F^– affects the oxygen metabolism and induces oxygen-free radicals enhancing oxidative stress in the blood [9,10]. This free radical generation and resulting oxidative stress have been identified to catalyze the harmful effects of F^– both at the cellular and molecular levels [11]. F^– induced generation of reactive oxygen species (ROS) such as superoxide anion (O₂^–), hydrogen peroxide (H₂O₂), peroxynitrite (ONOO^–), hydroxyl radical (OH), and nitric oxide (NO) affects cell functions [12]. Excessive ROS generation alters the cellular redox homeostasis, subsequently inhibiting the activities of antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). Further, it also decreases the levels of non-enzymatic antioxidants such as glutathione (GSH), vitamin A, E, and C [[13], [14], [15]], adding to the prevailing oxidative stress conditions [16]. F^– induced oxidative stress has been reported in many studies associated with F^– toxicity [[17], [18], [19], [20], [21]]. Hence, the altered levels of endogenous antioxidants due to excessive generation and accumulation of cellular ROS under oxidative stress conditions can be considered the major mechanism in F^– pathogenesis [[22], [23], [24]].

F^– induced intracellular ROS generation also alters the mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (MPTP) at the membrane. Once the MPTP is open, cytochrome c (Cyt c) is released activating caspase proteins (Caspases 3/7), resulting in the proteolysis of apoptotic cells [25,26]. This mechanism is depicted in various studies in different experimental models such as rat kidney [27,28], mice spleen [29,30], chicken and pig liver [31,32], and broiler cecal tonsil [33,34], suggesting apoptosis to be another key mechanism involved in fluorosis. Cellular signaling pathways like mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), nuclear factor kappa B (NF-kB), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways are also disturbed by excessive accumulation of F^–, leading to F^– toxicity [[35], [36], [37]]. Notably, F^– can activate or inhibit the transcription factors and regulate gene expression. This evidence revealed that F^– increases ROS levels and activates downstream pathways. Despite the numerous studies on F^– induced oxidative stress and apoptotic cell death, the role of ROS-mediated oxidative stress-induced cell death mechanisms in fluorosis is elusive. Hence the present review is focused on understanding the ROS-mediated oxidative stress-induced cellular signal transduction pathways and cell death mechanism in fluorosis.