Fluoride Action Network


Pharmaceuticals are widely acknowledged to be a threat to aquatic life. Over the last two decades, the steady use of biologically active chemicals for human health has been mirrored by a rise in the leaking of these chemicals into natural environments. The aim of this work was to detect the toxicity of sodium fluoride (NaF) exposure and platinum-derived drugs in an ecological setting on aquatic organism development. From 24 to 96 h post-fertilization, zebrafish embryos were treated to dosages of NaF 10 mg/L-1 + cisplatin (CDDP) 100 uM, one with NaF 10 mg/L-1 + carboplatin (CARP) 25 uM, one with NaF 10 mg/L-1 + CDDP 100 uM + CARP 25 uM. Fluoride exposure in combination with Cisplatin and Carboplatin (non-toxic concentration) had an effect on survival and hatching rate according to this study. Additionally, it significantly disturbed the antioxidant defense system and increased ROS in zebrafish larvae. NaF 10 mg/L-1 associated with CDDP 100 uM and CARP 25 uM, increased the production of apoptosis-related proteins (caspase 3, bax, and bcl-2) and the downregulation of acetylcholinesterase (AChE) activity, while no effect was seen for the single exposure.

Keywords: fluoride; platinum-based antineoplastic drugs; zebrafish

*Full-text study online at https://www.mdpi.com/2305-6304/10/5/272/htm



1. Introduction

Fluoride is used in the production of fluoridated dental products as well as it is used in drinking water fluoridation processes [1,2]. The World Health Organization establishes an acceptable level for drinking water, which ranges from 0.7 to 1.0 mg/L-1. However, fluoride concentrations of up to 20 mg have been recorded in some countries [3]. Sodium fluoride NaF was reported to be present in water at a range of 9 mg L-1 to 17 mg L-1 [4] and concentrations between 1.5 mg L-1 and 7 mg L-1 varying from country to country [4,5]. Epidemiological studies reveal that populations living in areas with high fluoride levels are more susceptible to neurological or intellectual problems [6,7]. However, the toxic effects of high amounts of fluoride in the environment, do not only present a danger to humans, but also to the different species that inhabit the environments in which these substances accumulate [8]. Fluoride-related central nervous system (CNS) function has been shown to be sensitive in experimental tests [9,10,11]. Fluoride has been shown in experimental animals to produce neurotoxicity, including effects on learning and memory [12,13]. This chemical builds up in numerous parts of the brain, causing a variety of symptoms, including decreased synaptic cleft width [14]. According to available research, excessive fluoride can harm neurons and synapses by causing free radicals and lipid peroxidation, which may increase the vulnerability of neurons to excitotoxicity [15,16]. Reduced nicotinic acetylcholine (ACh) receptors and histological alterations in brain cells of rats with impaired learning and memory have been highlighted after fluoride exposure [11,17,18]. ACh is promptly cleaved into choline and acetate by acetylcholinesterase (AChE), which has been reported as a well-known biomarker for a variety of pollutants [19]. Zebrafish have emerged as an alternate perspective for understanding neurotoxicant chemicals in this context. Fluoride can pass the blood–brain barrier in zebrafish, causing detrimental effects on neural cells and eventually mental impairment [20,21] found that 72.12 mg/L-1 NaF changes the expression pattern of genes involved in inflammation, apoptosis, and DNA repair in zebrafish. Furthermore, NaF genotoxic and mutagenic potential has been attributed to it [22]. In the current study, we looked into whether fluoride-induced neurotoxicity was linked to oxidative stress changes under these experimental NaF exposure circumstances. The World Health Organization (WHO) lists anticancer drugs as one of the eight most often used types of medicine on the planet. In chemotherapy, platinum-based antineoplastic drugs are commonly utilized. They include cisplatin (CDDP), carboplatin (CARP), and oxaliplatin (OXA), which crosslink DNA strands or generate DNA-protein crosslinks in cancer cells [23,24]. Several studies have demonstrated that exposure to platinum or its derivatives, such as cisplatin, can cause genotoxic and teratogenic consequences in zebrafish embryonic development [25,26]. Several studies have found rising platinum group element concentrations in several areas of the water ecosystem, including drinking, ground, and surface waters [27]. The largest sources of platinum compounds in the environment are emissions from automotive catalytic converters and hospital effluents. A study on wastewater samples from cancer departments in hospitals reported high levels of carcinogenic platinum compounds including oxaliplatin, varying from 4.7 to 145 micrograms/liter [28]. There is a lot of ecotoxicological data on anticancer medications in the literature [29]. Unfortunately, there are limited data on acute antitumoral drug exposure as a pollutant in the environment and its effects on aquatic species, particularly the most vulnerable forms such as larvae [21]. The Danio rerio Fish Embryo Toxicity (FET) assay is a commonly used methodology for determining the toxicity of environmental pollutants [30,31]. Other consequences on development, such as morphological abnormalities, delayed development, pericardial edema, and yolk sac edema, can be shown in the FET test. This is a promising technology that proposes medicines (and other substances) and their toxicity processes could be studied using fish lines at lower concentrations because surface water contains minimal amounts of environmental contaminants. Furthermore, as a whole-animal drug screening platform, zebrafish can swiftly identify medicines with evident developmental toxicity or absorption difficulties [27]. Fluoride is ubiquitous in the environment and is always present in plants, soils, and phosphate fertilizers [32]. It has been shown that a large proportion of the total F in ash is apparently soluble in the digestive system of grazing animals [33]. Thus, even if at concentrations below the toxicity threshold, the interaction of NaF with other pollutants could give harmful effects. In particular, the overwhelming incidence of carcinomas treated with platinum derivative therapies leads to increased levels of these drugs at appreciable environmental levels. Therefore, the increased presence of anticancer drugs in the environment and the high presence of NaF could present a potential toxic crosslink for animal species living there and consequently for human health.

5. Conclusions

Finally, NaF and CDDP/CARP co-exposure resulted in altered antioxidant defenses as well as enhanced lipid peroxidation, whereas separate exposures had no significant effects when compared to the control group. In contrast to single concentrations that had no harmful effects, co-exposure of NaF and CDDP or CARP caused not only problems in embryonic development, as well as an imbalance in antioxidant defenses, but also an increase in the apoptotic process. The massive presence of NaF in the environment, and other anthropogenic contaminants, such as platinum-derived anticancer drugs, pose a major health risk to both humans and the various animal species that come into contact with them. Future studies will be needed to elucidate the synergistic toxicity of these contaminants in aquatic species and consequently to humans.


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