Molecular and immunohistochemical alterations in fluoride-induced neurological impediment in adult rats.

Fluoride, a naturally occurring element, has been extensively used in public health programs worldwide to prevent dental caries. Fluoride is used in drinking water, toothpaste, and mouth rinses to provide the desired preventive effect [1]. However, over the years, research has suggested that the benefits of fluoride may not outweigh the potential harm it can cause, particularly cognitive and neurological alterations.

Fluoride pollution is a global issue now since the amounts of fluoride present in groundwater in North and South America, Sri Lanka, China, Italy, the West Indies, Spain, and Holland are often higher than what is considered bearable [2]. World Health Organization (WHO) suggested that the ideal fluoride concentration for drinking water is between 0.7 and 1.2?ppm. This level has been beneficial without negatively impacting the health [3], [4]. However, in some areas, the level of fluoride in drinking water can exceed this recommended limit, leading to excessive fluoride exposure. Several studies have reported high fluoride levels in drinking water in various regions of India, including Rajasthan, Bihar, Jharkhand, Chhattisgarh, Karnataka, Andhra Pradesh, Telangana, Gujarat, and Tamil Nadu. These studies have also identified several risk factors associated with fluoride toxicity, including age, sex, socioeconomic status, and dietary habits [2], [5]. The district in the southwestern part of West Bengal has high fluoride levels in its groundwater. As a result, many people in the community have been affected by fluorosis, with dental and skeletal fluorosis being common [6]. Moreover, studies have suggested that fluoride can affect the brain’s neurotransmitter systems, alter neuronal plasticity, and interfere with oxidative stress and antioxidant defense mechanisms. These alterations can lead to neurological and cognitive impairments, including lower I.Q. scores, memory deficits, and learning disabilities [7], [8], [9].

Fluoride permeates the blood-brain barrier (B.B.B.), which can build up the concentration of fluoride in the brain. This emphasizes the importance of comprehending the possible health consequences of excessive fluoride exposure, especially in susceptible populations like children [10], [11]. According to the previous analysis, the I.Q. level of children who live in fluoride-endemic areas is reduced five times than the I.Q. level of children who reside in an area with a moderate amount of fluoride in water [9]. Fluoride reduced locomotor activity, as evidenced by the behavioral assessment and the active avoidance task carried out in rats. The result also suggests that fluoride may adversely affect memory and learning [12], [13]. At high fluoride levels, individuals may experience symptoms such as nausea, vomiting and diarrhea. Acute fluoride toxicity can lead to seizures, coma, and even death [11], [14], [15].

According to the United States Environmental Protection Agency (E.P.A.), four ppm fluoride in drinking water is allowed as a Maximum Contaminant Level (MCL); this level is considered safe for long-term consumption by most people [16]. However, exposure to fluoride levels above four ppm can lead to acute toxicity with symptoms such as nausea, vomiting, abdominal pain, and diarrhea.

The mechanisms underlying fluoride-induced neurotoxicity are not fully understood, but several hypotheses have been proposed. One theory suggests that fluoride can influence the levels of neurotransmitters in the brain, leading to changes in brain function. Another hypothesis suggests that fluoride may cause oxidative stress, leading to cellular damage and neurodegeneration [17], [18], [19]. On the other hand, imbalance between the production of reactive oxygen species (R.O.S.) and antioxidants in the cells is the leading cause of fluoride-induced toxicity. R.O.S. can harm biological components like D.N.A., enzymes, and lipids, resulting in cell death [17], [20]. Mitochondrial dysfunction is another pathway by which fluoride can induce apoptosis. Mitochondria are the cell’s powerhouses responsible for generating energy through oxidative phosphorylation. Mitochondrial dysfunction can increase the production of R.O.S., leading to oxidative stress and the activation of apoptotic pathways [21], [22]. Activation of proapoptotic signaling pathways is another mechanism by which fluoride can induce apoptosis. Bcl-2 is a family of proteins that can promote or prevent apoptosis and control the intrinsic apoptotic process. Fluoride can activate apoptotic pathways by decreasing the expression of antiapoptotic Bcl-2 proteins and increasing the expression of proapoptotic Bax proteins, according to studies [23] Fluoride-induced apoptosis can also occur through the inflammatory response pathway by stimulating the immune system and release of pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF- ?). These cytokines can induce apoptosis by activating caspases and upregulating proapoptotic factors such as Bax.

This study explores the mechanisms by which fluoride induces apoptosis and helps to develop strategies to prevent or treat fluoride-induced neurotoxicity.