# Mechanisms of Fluoride Toxicity: From Enzymes to Underlying Integrative Networks
## 4 The Implication of Fluoride Toxicity on Human Health
### Melatonin  
Melatonin, the hormone produced by the pineal gland at night, regulates large numbers of life processes, such as the sleep-wake cycle, reproduction, development, and aging. It is also a modulator of mitochondrial metabolism, digestive functions, and immunity (Figure 5). Because of its radical scavenging actions melatonin reportedly restrains cancer development and growth [119].  
[PERSON] studied the effect of fluoride from drinking water on gerbils during sexual maturation [120]. Animals excreted less melatonin metabolite in their urine and took a shorter time to reach puberty. [PERSON] also analyzed the pineal glands from 11 human corpses and found that fluoride in the apatite crystals averaged about 9000 ppm [121]. Based on this evidence fluoride is likely to cause decreased melatonin production and to have other effects on normal pineal function, which in turn could contribute to a variety of effects in humans [122].  
The Newburgh-Kingston caries-fluoride study compared the development of girls aged 7-18 years in fluoridated Newburgh (1.2 mg F/L) with girls in fluoride-free Kingston. The investigators found  
Figure 5: Physiological functions of melatonin and fluoride interventions. File melatonin has been used from the Wikimedia Commons according to the GNU Free Documentation License.  
that girls in Newburgh had menarche earlier than girls in Kingston [123]. The authors suggested an analogy with [PERSON]'s observations in gerbils [120].  
Melatonin has been recognized by the European Medicines Agency (EMA) since 2007 for primary insomnia in adults over 55 years of age. Pooled data demonstrate that exogenous melatonin lowers sleep onset latency and increases total sleep time, whereas it has little if any effect on sleep efficiency [124]. Children and young people with significant sleep issues are often prescribed melatonin, namely the subjects with ASD [102]. Insomnia and sleep disorders occur in 50-80% of ASD patients [125; 126]. The disruption of the serotonin-N-acetyl serotonin-melatonin pathway has been found in a group of 278 patients with ASD [127; 128; 129]. [PERSON] et al. suggested the levels of plasma melatonin, whole-blood serotonin, and platelet N-acetyl serotonin as biomarkers for ASD. They found a deficit in melatonin in 51% as well as hyperserotonemia in 40% of ASD patients. [127; 128]. Serum serotonin was also increased in a cohort of healthy children drinking water containing 2.5 ppm fluoride, as compared to controls [102; 129].  
The study of fluoride exposure and sleep patterns among a sample of adolescents living in the USA shows that fluoride exposure may be a risk factor for sleep disturbances [130]. The authors found that each 0.52 mg/L increase in tap water fluoride concentration was associated with 1.97 times higher odds of participants reporting snorting, gasping, or stopping breathing while sleeping at night.  
Two melatonin receptors have been identified in humans. They are both GPCRs and can be affected by AlFx. Regardless of mechanism of the effect of fluoride on melatonin, whether this is primary via melatonin receptors or secondary through pineal calcification, its intervention could have the wide spectrum of pathological effects [119]. Additional prospective human studies are needed to explore the impact of fluoride on melatonin for healthy physical and mental development and aging [131; 132].