Lo and behold, shortly after sending out yesterday’s bulletin on fluoride & oxidative stress, I received the latest issue of the excellent quarterly journal FLUORIDE (2004; volume 37, issue 2). In this latest issue, there are a number of new studies (1-4) very relevant to the discussion of fluoride and oxidative stress.

Of particular interest was a study by Dr NJ Chinoy and colleagues from India, looking at fluoride and arsenic’s impact on the brain of mice (1).

As with Dr. Guan’s team at the Karolinska Institute (5, 6), and other researchers (7-12), Chinoy’s team found that fluoride increased the level of oxidative stress in brains of the fluoride-treated animals (1). The three main findings of the study were:

1. Fluoride treatment decreased the level of anti-oxidant enzymes in the brain (e.g. catalase, GSH-PX and SOD). Anti-oxidant enzymes provide the body a natural defense against oxidative stress.
2. Fluoride treatment increased the level of lipid peroxidation in the brain. Lipid peroxidation is an indicator of oxidative stress.
3. These toxic effects were reduced by simultaneous treatment with antioxidant vitamins (vitamins C and E).

A possible connection with fluoride’s impact on Pineal Gland?

While not discussed by Chinoy (1), nor the other research teams investigating this issue (5-12), it is conceivable that some of the increased oxidative stress observed in fluoride-treated animals is related to fluoride’s impact on the pineal gland.

As was brought to light by a 1997 PhD dissertation from Jennifer Luke (from the University of Surrey in England) the pineal gland is a major magnet for fluoride accumulation within the body (13, 14). The heightened vulnerability of the pineal gland lies in the fact that it contains small crystals of a substance known as hydroxyapatite (the same substance found in bone and well known to accumulate fluoride). This is significant because the pineal gland, which is not protected by the blood brain barrier, has a very high perfusion rate of blood – hence the hydroxyapatite crystals within the pineal gland are continually exposed to fluoride circulating in the bloodstream.

Based on these factors, Luke hypothesized in the mid-1990s that the pineal gland would in fact be a target for fluoride accumulation. To test this hypothesis she analyzed the fluoride content of pineal glands taken from 11 human cadavers in England. Sure enough, when she conducted the analysis, she found very high – an average of 9000 parts per million (ppm) and up to 21,000 ppm! – levels of fluoride in the crystals of the gland (13, 14). Luke’s work was a breakthrough because prior to her analysis this fact had never before been known, if even considered.

But that’s only half the story. The other half involves the animal research that Luke conducted after finding the high levels in humans. Naturally, Luke was interested to find out what this high level of accumulation within the pineal gland may be doing to the functioning of this tiny, yet important, gland. In research Luke later conducted on mongolian gerbils (13), she found that fluoride exposure reduced the levels of melatonin in the gerbils (as measured by the metabolites of melatonin in the gerbils’ urine).

Melatonin, a hormone that regulates many activities within the body, including potentially the onset of puberty (15), is regulated in part by the pineal gland. Hence, Luke’s animal findings suggested that the fluoride accumulation within the gland, may in fact be interfering with the gland’s function – in particular its regulation of melatonin.

So, how does this potentially relate to the issue of oxidative stress in the brain?

Of melatonin’s many functions, one of it’s most important may be it’s role as a powerful anti-oxidant for the brain and other tissues – to help ward off and reduce oxidative stress (16-19). Thus, anything which can reduce the melatonin level in the body, would – by logical deduction – be expected to reduce the body’s defense against oxidative stress in the brain.

The potential significance of this can be glimpsed in the following statement from a recent review (18) concerning melatonin’s anti-oxidant’s properties:

“Since melatonin, the hormone secreted from the pineal gland has a remarkable anti-oxidant property and whose rate of production declines with increase in age, has prompted many to suggest that this hormone plays a crucial role in the genesis of neurodegenerative diseases.”

Of course, I am engaging in conjecture here, but the fluoride/pineal/oxidative stress connection may well be worth examining in future research. Can fluoride indeed reduce melatonin levels (13), and if so, is this related to a subsequent increase in oxidative stress? If yes, to what extent has this factor been involved in the repeatedly observed relationship (1, 4, 6, 7-12, 20-33) between fluoride and oxidative stress, both in animals and in humans?

References:

1) Chinoy NJ, et al. (2004). Biochemical effects of sodium fluoride and arsenic trioxide toxicity and their reversal in the brain of mice. Fluoride 37: 80-87.

2) Jhala DD, et al. (2004). Reversible toxicity of fluoride and arsenic in ovary of mice. Fluoride 37: 71-79.

3) Nair SB, et al. (2004). Beneficial effects of certain antidotes in mitigating fluoride and/or arsenic induced hepatoxicity in mice. Fluoride 37: 60-70.

4) Wang A, et al. (2004). Antagonistic effect of selenium on oxidative stress, DNA damage, and apoptosis induced by fluoride in human hepatocytes. Fluoride 37: 107-116.

5) Shan KR, et al. (2004). Decreased nicotinic receptors in PC12 cells and rat brains influenced by fluoride toxicity-a mechanism relating to a damage at the level in post-transcription of the receptor genes. Toxicology 200: 169-77.

6) Guan ZZ, et al (1998). Influence of chronic fluorosis on membrane lipids in rat brain. Neurotoxicology and Teratology 20: 537-542.

7) Shen X, Zhang Z, Xu X. (2004). [Influence of combined iodine and fluoride on phospholipid and fatty acid composition in brain cells of rats]. Wei Sheng Yan Jiu. 33(2):158-61.

8) Shivarajashankara YM , et al. (2002). Brain lipid peroxidation and antioxidant systems of young rats in chronic fluoride intoxication. Fluoride 35: 197-203.

9) Lakshmi Vani M, Pratap Reddy K. (2000). Effects of fluoride accumulation on some enzymes of brain and gastrocnemius muscle of mice. Fluoride 33: 17-26.

10) Shao Q, et al. (2000). [Influence of free radical inducer on the level of oxidative stress in brain of rats with fluorosis]. Zhonghua Yu Fang Yi Xue Za Zhi 34(6):330-2.

11) Wang Y, et al. (1997). [Changes of coenzyme Q content in brain tissues of rats with fluorosis]. Zhonghua Yu Fang Yi Xue Za Zhi. 31: 330-3.

12) Shashi A. (1992). Studies on alterations in brain lipid metabolism following experimental fluorosis. Fluoride 25(2):77-84.

13) Luke J. (1997). The Effect of Fluoride on the Physiology of the Pineal Gland. Ph.D. Thesis. University of Surrey, Guildord.

14) Luke J. (2001). Fluoride deposition in the aged human pineal gland. Caries Research 35:125-128.

15) Reiter RJ. (1998). Melatonin and human reproduction. Annals of Medicine 30: 103-8.

16) Kaptanoglu E, et al. (2003). Different responsiveness of central nervous system tissues to oxidative conditions and to the antioxidant effect of melatonin. Journal of Pineal Research 34: 32-5.

17) Ortega-Gutierrez S, et al. (2002). Melatonin improves deferoxamine antioxidant activity in protecting against lipid peroxidation caused by hydrogen peroxide in rat brain homogenates.Neuroscience Letters 323: 55-9.

18) Srinivasan V. (2002). Melatonin oxidative stress and neurodegenerative diseases. Indian Journal of Experimental Biology 40: 668-79.

19) Cabrer J, et al. (2001). Autoxidation and toxicant-induced oxidation of lipid and DNA in monkey liver: reduction of molecular damage by melatonin. Pharmacology and Toxicology 89: 225-30.

20) Shanthakumari D, et al. (2004). Effect of fluoride intoxication on lipid peroxidation and antioxidant status in experimental rats. Toxicology 204: 219-28.

21) Inkielewicz I, Krechniak J. (2004). Fluoride effects on glutathione peroxidase and lipid peroxidation in rats. Fluoride 37: 7-12.

22) Shen X, Zhang Z, Xu X. (2004). [Influence of combined iodine and fluoride on phospholipid and fatty acid composition in brain cells of rats]. Wei Sheng Yan Jiu. 33(2):158-61.

23) Guo X, et al. (2003). Oxidative stress from fluoride induced hepatotoxicity in rats. Fluoride 36: 25-29.

24) Shivarajashankara YM, et al. (2003). Lipid peroxidation and antioxidant systems in the blood of young rats subjected to chronic fluoride toxicity. Indian Journal of Experimental Biology 41: 857-60.

25) Wang A, et al. (2003). Effects of selenium and fluoride on apoptosis and lipid perioxidation in human hepatocytes. Fluoride 36: 45-46.

26) Yur F, et al. (2003). Changes in erthrocyte parameters of fluorotic sheep. Fluoride 36: 152-156.

27) Ghosh D, et al. (2002). Testicular toxicity in sodium fluoride treated rats: association with oxidative stress. Reproductive Toxicolology 16(4):385.

28) Shivashankara AR, et al. (2002). Lipid peroxidation and antioxidant defense systems in liver of rats in chronic fluoride toxicity. Bulletin of Environmetnal Contamination and Toxicology 68: 612-6.

29) Shivashankara YM, et al. (2001). Oxidative stress in children with endemic skeletal fluorosis. Fluoride 34: 103-107.

30) Shivashankara YM, et al. (2001). Effect of fluoride intoxication on lipid peroxidation and antioxidant systems in rats. Fluoride 34: 108-113.

31) Guan ZZ, et al. (2000). Changed cellular membrane lipid composition and lipid peroxidation of kidney in rats with chronic fluorosis. Archives of Toxicology 74: 602-8.

32) Wang YN, et al. (2000). Effect of long term fluoride exposure on lipid composition in rat liver. Toxicology 146: 161-9.

33) Guan ZZ, et al. (1989). An experimental study of blood biochemical diagnostic indices for chornic fluorosis. Fluoride 22: 112-128.