Neglected parathyroids: Fluoride’s trigger for skeletal fluorosis and endocrine domino effect.

Abstract

Introduction

Fluoride is an essential micromineral which is physiologically essential for the development of humans [1]. Fluorides can get into water resources through weathering of rocks contaminating the water resources and reach human body via drinking water and food. Fluoride is found in the atmosphere, water, soil, coal, food, dental and industrial uses [2]. Fluoride in minimal amount helps in proper growth of bones and teeth but in larger concentrations it causes toxicity and life-threatening diseases like dental and skeletal fluorosis [3]. Fluorosis, a chronic condition resulting from excessive fluoride consumption, is a significant health concern in various regions globally. It affects nearly 22 countries, where it is recognized as an endemic public health issue [4], [5], [6]. There is generally a dose response relationship between fluorosis and fluoride intake, meaning that, with increased fluoride intake, the prevalence and severity of fluorosis also increase [7]. Ingestion of fluoride in excessive amounts for longer durations of time can cause damage to various organs, major clinical manifestations being dental fluorosis, skeletal fluorosis and non-skeletal tissue alterations [8], [9]. Fluoride levels between 0.5 and 1.5 mg/L are good for dental health, 1.5–4 mg/L can cause dental fluorosis, 4–10 mg/L might cause dental and skeletal fluorosis and over 10 mg/L can cause crippling fluorosis [10], [11], [12], [13] (Fig. 1).

Long-term fluoride consumption has numerous degenerative effects on soft tissues due to increased oxidative stress [14]. Fluoride affects a variety of soft tissues like brain [15], kidney [16], liver [17], gastrointestinal tract [18], reproductive organs [19], [20] and various endocrine organs such as pancreas [21], adrenal [22], thyroid [23] and parathyroid [24]. A variety of gastrointestinal effects, including nausea, vomiting, diarrhea, and abdominal pain have been reported in cases of acute fluoride toxicity [25]. Systemic exposure to fluoride causes calcification of ligaments, bone deformities, fractures, functional restrictions, a disrupted mineral balance and occasional pseudo-hyperparathyroidism [26], [27]. Fluorosis disrupts the dynamic balance between bone formation and resorption by interfering with the function of osteoblasts and osteoclasts [28]. Fluoride also disrupts thyroid function as an endocrine disruptor, inhibiting iodine uptake via Na K-ATPase and sodium-iodide symporter (NIS) blockade, reducing T3/T4 levels, elevating TSH, and inducing oxidative stress with downregulated antioxidants (SOD, CAT, GPx, Nrf2). These thyroid alterations parallel parathyroid changes, where fluoride modulates PTH secretion, chief cell hyperplasia, and calcium homeostasis, often exacerbated by shared risk factors like iodine/calcium deficiency in endemic fluorosis areas [23].

Parathyroid glands are the most important endocrine regulator to maintain the calcium homeostasis in the circulation [29]. The parathyroid glands of the rat consist of a single type of secretory cell called the chief cell [30]. Within this single chief cell category, inactive or light cells and active or dark cells have been described as representing different stages of secretory activity [31], [32]. The parathyroid chief cells synthesize and secrete parathyroid hormone (PTH), a straight chain polypeptide consisting of 84 amino acids. PTH regulates calcium homeostasis with calcitonin and calcitriol (active forms of vit. D). Chief cells sense the changes in extra cellular calcium and accordingly produce PTH to maintain normal blood calcium levels [33]. PTH levels are significantly altered in case of fluoride exposure, as fluoride can disrupt calcium homeostasis in the body.

Parathyroid plays an underexplored but central role among the endocrine targets of fluoride toxicity, as it regulates the key physiological axis linking fluoride exposure to skeletal pathology i.e. calcium homeostasis [24], [26]. PTH regulates the calcium homeostasis alongwith calcitonin and active vit. D. Calcium-sensing receptors (CaSR) on parathyroid chief cells sense the reduced extracellular calcium levels under normal physiological conditions and result in PTH secretion to restore calcium by intestinal absorption, renal reabsorption and bone resorption [34], [35]. But fluoride disrupts this close-knit system by often causing hypocalcaemia via formation of insoluble fluoride complexes thus reducing the bioavailable calcium and altering calcium transport mechanisms [36], [37]. This decrease in calcium levels primarily results in compensatory PTH secretion, directly linking fluoride exposure to parathyroid activation [24]. A vicious cycle stems from this interaction as elevated PTH levels increase bone resorption to restore serum calcium, while fluoride also stimulates osteoblast activity and promotes new bone formation, it simultaneously inhibits osteoclast-mediated bone resorption, leading to abnormal bone remodeling and mineral deposition [27], [28], [38]. Continuous calcium mobilization under sustained PTH influence promotes secondary hyperparathyroidism, which further aggravates skeletal damage and mineral imbalance [26], [39].

Several in-vitro, in-vivo and population studies on the parathyroid gland have shown various direct alterations caused by fluoride like increased number and size of parenchymal cells, aggregation of glycogen granules in chief cells, reduction in intercellular space, increased number of Golgi complexes and hyperplastic parathyroid [40], [41], [42], [43]. Elevated PTH levels, osteocalcin levels, alkaline phosphatase (ALP) levels and activity and inhibition of cAMP accumulation were also reported [24], [44], [45], [46], [47], [48], [49], [50] (Fig. 2). This review emphasizes the importance of understanding the effects of fluoride on the parathyroid gland and the larger implications for calcium homeostasis and endocrine health.