Impact of Fluoride Exposure on Reproductive Health: Insights into Molecular Mechanisms and Health Implications.

Abstract

Introduction

Reproductive toxicology plays a vital role in safeguarding reproductive health against the detrimental effects of various toxicants. It delves into how pharmaceuticals and environmental contaminants can disrupt the reproductive functions of males and females, affecting the development of embryos and fetuses [21]. Heavy metals like lead, mercury and cadmium threaten reproductive health by impairing sperm parameters and oocyte development [11]. Additionally, fluoride has increasingly been recognized as a reproductive toxicant, contributing to hormonal imbalances and oxidative stress, which further compromise fertility.[169], [170], [171], [18].

Fluoride contamination in groundwater is a growing public health concern, particularly in several countries where natural fluoride levels exceed safe limits. Certain countries, such as Bangladesh, China, Indonesia, India, Sri Lanka, and Iran face significant challenges due to high fluoride concentrations in groundwater. These elevated levels threaten fertility and overall health[57]. In certain parts of India, including Telangana, Rajasthan, Gujarat, Andhra Pradesh, and Karnataka, concerns have risen over elevated fluoride levels in groundwater and their potential impacts on reproductive health. These states in India are gravely affected by high fluoride levels in drinking water, with concentrations ranging from traces to as high as 9.75 mg/L [109]. Research has increasingly highlighted the link between fluoride exposure and adverse reproductive outcomes, including reduced fertility rates and pregnancy complications, raising significant public health concerns. Regions with high fluoride levels in drinking water, specifically with fluoride content exceeding 2.0 ppm, are significantly affected by changes in semen quality [116], [54], [89]. A pilot case-control study in Sri Lanka linked chronic high-fluoride exposure to lower sperm count, motility, and viability among men in the affected region, also noting higher serum fluoride levels and prolonged liquefaction time [46]. Research indicates its potential to disrupt reproductive functions in both males and females[151], [152], [35]

Fluoride exposure has been increasingly linked to adverse effects on reproductive health, particularly in both male and female fertility. In males, fluoride induces oxidative stress, disrupts thiol/disulfide balance, reduces sperm motility and density, and causes structural alterations in testicular tissue [19]. Similarly, in females, fluoride negatively impacts oogenesis, leading to a decline in mature oocyte count, impaired development and maturation, hindered fertilization, and disruptions in gene expression and epigenetic modifications [158]. At a molecular level, fluoride acts as a cell signal activator, stimulating G-proteins and triggering key downstream signaling pathways such as protein kinase A (PKA), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), calcium-dependent pathways, and the mitogen-activated protein kinase (MAPK) system. These signalling disruptions play a crucial role in fluoride-induced reproductive toxicity, ultimately compromising fertility and overall reproductive health[3].

Despite fluoride’s potential threats to reproductive health, research suggests several interventions to mitigate these risks. Antioxidants such as vitamin C, E, and selenium have shown promise in reducing oxidative stress induced by fluoride exposure [6]. Strategies involving mitophagy, the selective removal of damaged mitochondria, and promoting mitochondrial biogenesis are critical for maintaining healthy mitochondrial function amidst fluoride-induced dysfunction (S. [66]). Furthermore, dietary adjustments play a vital role; adequate intake of calcium and magnesium can help reduce fluoride absorption, while maintaining sufficient iodine levels may mitigate its negative effects on the thyroid gland [59]. This article further investigates the molecular level alterations caused by fluoride on reproductive health and their interventions using various therapeutic approaches.(Fig. 1)

Section snippets

DNA Damage and Repair Mechanisms

Fluoride Impact on the Male Reproductive System…

Fluoride exposure in regions affected by fluorosis has been shown to impact the male reproductive system negatively. According to clinical research, increased fluoride levels lead to reduced fertility rates [101]. Heindel et al. demonstrated that doses of NaF at 27 mg/kg for rats and 29 mg/kg for rabbits per day did not adversely affect embryonic and foetal development. However, in a clinical study, male patients with skeletal fluorosis showed significantly lower testosterone levels [133].

Fluoride Impact on the Female Reproductive System

High fluoride concentrations are directly linked to multiple primary and secondary organ developmental disorders in females, most prevalent in regions like India, China and other parts of Asia. Fluorosis, characterised by deformities and degradation of reproductive organs, poses significant health risks. A study by Chongqing Medical University in 2012 shows that exposure to Sprague Dawley rats fluoride concentrations of 100 ppm (low), 150 ppm (moderate) and 200 ppm (high) via drinking water led…

Therapeutic Approach

Addressing fluoride-induced disruptions in the reproductive systems of males and females requires targeted therapeutic interventions. Chronic fluoride exposure disrupts reproduction through alterations in key molecular pathways. Research suggests antioxidants like vitamins C & E and NAC may offer mitigation by reducing oxidative stress (D. [39]; P. [103]). ROS are scavenged by antioxidants, protecting reproductive organs from oxidative damage and maintaining cellular function…

Conclusion

This review has highlighted the concerning potential of excessive fluoride exposure to disrupt reproductive health in both males and females. Evidence suggests that fluoride exerts its detrimental effects through a multifaceted approach, from direct DNA damage to triggering cascades of cellular disruptions compromising crucial physiological processes essential for successful reproduction. Chronic fluoride exposure disrupts reproductive homeostasis in mammals, as comprehensively analysed in this

Abbreviation

Acknowledgement

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