2003 - Effects of fluoride and iodine on brain function

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2003 - Effects of fluoride and iodine on brain function

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125. 许晓路,章子贵,申秀英.氟与碘对脑功能影响的研究进展[J].中国公共卫生,2003,19(1):99-100
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Xu et al. - "Review of fluoride and iodine effects on brain function" China Public Health 19(1):99-100 (2003)
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氟与碘均是人体的必需元素,但摄入过量或不足均会产生疾病.人体摄氟过多会产生氟斑牙、氟骨症等,不足则会导致龋齿;人体摄碘不足或过多则会产生甲状腺肿大、克汀病等碘缺乏病或碘中毒.又由于氟和碘同为卤族元素,具有相似的地球化学性质,两者间可以产生置换作用,并且能转换含氢氧根化合物中的[OH-].近期的研究提示,碘和氟对有关靶器官的影响在一定条件下可能有竞争作用[1],由于过量氟可通过血脑屏障进入脑组织,对神经系统产生直接的损害作用,碘摄入异常能影响甲状腺的发育和甲状腺激素的正常分泌,从而影响中枢神经细胞的生长发育.因此,近年来氟、碘对脑功能的影响及其机制成了研究者们关注的热点.本文结合我们近年来的研究成果,将国内这一研究领域的研究做一总结探讨.……
基金项目:浙江省自然科学基金(301467);省教委基金和省大型仪器测试基金资助
作者简介:许晓路(1966-),男,教授,硕士生导师,主要从事环境生态毒理学、环境地学的教学和科研工作.
作者单位:许晓路(浙江师范大学生命与环境科学学院,金华,321004) 
     章子贵(浙江师范大学生命与环境科学学院,金华,321004) 
     申秀英(浙江师范大学生命与环境科学学院,金华,321004) 
参考文献:
[1]赵文元.碘、氟在实验性高碘甲状腺肿和氟中毒发病联合作用的初步研究[J].中华预防医学杂志,1988,3:146-148.
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[8]于燕妮,杨文秀,董仲,等.地方性氟病区胎儿大脑神经递质与受体的变化[J].中国地方病学杂志,1996,15(5):257-258.
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[10]赵西龙,高文华,赵忠良,等.氟化钠对大鼠脑突触体膜Ca2+,Mg2+-ATP酶活性影响的研究[J].中华预防医学杂志,1994,28(5):264-266.
[11]王淑秋,陶佳南,孟丹,等.实验性甲状腺功能低下大鼠脑神经细胞超微结构变化[J].中国地方病学杂志,1996,15(4),219-220.
[12]孙素菊,尹桂山,冯忠军,等.过量碘对仔鼠海马组织烯醇化酶活性的影响[J].中华预防医学杂志,2000,34(1):39-40.
[13]杨长春,尹桂山,朱惠民,等.高碘对路鼠脑和甲状腺细胞凋亡影响的实验研究[J].中国地方病学杂志,19(5):342-344.
[14]末建良,赵祟,宋学文,等.碘缺乏对大鼠神经元特异烯醇化酶基因表达的影响[J].中国地方病学杂志,1996,15(3);129-131.
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Both fluorine and iodine are essential elements for the human body, but excessive or insufficient intake can cause diseases. Excessive intake of fluoride by the human body will cause dental fluorosis, bone fluorosis, etc., and insufficient intake of iodine will lead to dental caries; insufficient or excessive intake of iodine by the human body will cause iodine deficiency diseases such as goiter, cretinism, or iodine poisoning. Also, because fluorine and iodine are both halogen elements, they have similar geochemical properties, and substitution can occur between them, and can convert [OH - ] in hydroxide-containing compounds. Recent studies suggest that the effects of iodine and fluorine on relevant target organs may have a competitive effect under certain conditions [ 1 ] , because excessive fluoride can enter the brain tissue through the blood-brain barrier, causing direct damage to the nervous system. Abnormalities can affect the development of the thyroid and the normal secretion of thyroid hormones, thereby affecting the growth and development of central nervous cells. Therefore, in recent years, the effects of fluorine and iodine on brain function and their mechanisms have become the focus of researchers' attention. Based on our recent research results, this paper summarizes and discusses the domestic research in this research field.

1. Effects of fluorine and iodine on brain function
1.1 The effect of fluoride on children's IQ
Studies have shown that high fluoride environment leads to children's IQ development disorder. Compared with non-fluorine pollution and light fluoride pollution areas, more children with moderate pollution and severe pollution have IQs < 70, and IQs are between 90~109 and 110~119. The IQs of children in moderately polluted areas and high-pollution areas changed very little with age, which was caused by fluoride pollution in early childhood (the period of rapid nervous system development) [ 2 ] ] . Zhao et al [ 3 ] investigated the average IQ of children whose drinking water contains 4.12 mg/L of fluoride in a certain area of ​​Shanxi Province, and the average IQ was 97.69, which was significantly lower ( P < 0.02) than that of children in villages with normal drinking water fluoride content (IQ=105.21, F =0.91 mg/L). Randomly selected 320 children aged 7-14 who were born in the survey area when their mothers were pregnant (the mothers drank high-fluoride water before birth), their IQ has a significant impact, and with the increase of age, although the children's IQ is also rising , but the rate of increase is slow, that is, the inherent adverse effects do not disappear rapidly with age. This is because fluorine can penetrate the maternal blood-brain barrier and enter the fetal brain tissue before birth, thereby affecting children's IQ. The results of this study further showed that the IQ development of children in moderately and severely polluted areas was significantly adversely affected by fluoride, and their IQs were significantly lower than those in mild and non-fluorosis areas. The development of IQ of children in mildly polluted areas has a low correlation with fluorine pollution, and there is no correlation between the age and IQ of children in moderately and heavily polluted areas, and high fluoride pollution causes children to suffer from high fluoride pollution when brain cells differentiate and develop the fastest in embryonic and early childhood. Impaired IQ. Therefore, active and comprehensive measures should be taken to reduce the absorption of fluoride by the body in areas with heavy and medium fluoride pollution, especially for pregnant women and young children.

1.2 The effect of iodine on children's IQ
From 1985 to 1987, Chang Cunshi et al [ 4 ] conducted a comparative study on the IQ of children born in iodine-deficient areas and non-disease areas since the 1970s, and found that the average IQ of children in ward areas was 73.70±12.59, which was significantly lower than that of non-disease areas. 83.83±11.66 ( P < 0.05) in the ward, and up to 34.58% of the rural children in the ward had an IQ < 69. In 1982, 1/30,000 of table salt was added with iodine and gradually improved to strengthen iodine supplementation. The survey results in early 1999 showed that there was no significant difference in total IQ, verbal IQ (UIQ), and performance IQ (PIQ) between the experimental group and the control group. The above results indicate that iodine is necessary for the development of children's IQ, and iodine deficiency can affect the development of children's IQ.

1.3 Effects of fluorine and iodine on learning and memory in mice
In order to further explore the effect of iodine on brain function, the researchers used rats or mice as animal models to study the effect of fluoride on the higher brain function-learning and memory ability. The results of Sun Zengrong et al. [ 5 ] showed that drinking water with high fluoride for 6 months can significantly affect the learning and memory ability of offspring mice. With the increase of fluoride intake, the learning ability of the animals in each high fluoride group became more and more backward. The research of our group also shows that long-term high fluoride intake (10mg/L) can significantly damage the optical resolution learning ability of the mouse brain [ 6 ] . Long-term intake of excessive iodine can also reduce the learning and memory ability of mice [ 7 ] .

2. The mechanism of the effect of iodine and fluorine on brain function
In order to explore the mechanism of the effect of iodine and fluorine on brain function, many scholars have observed and studied the structure of nerve cells, neurotransmitters, enzymes, genes, etc. using mice or rats.

2.1 The effect of fluoride on brain cell structure and neurotransmitters
The fluoride content in the fetal brain tissue in the fluorosis area was higher than that in the fetal brain tissue in the non-diseased area. In addition to the increase in fluoride content in the fetal brain tissue in the fluorosis area, the mitochondria of cortical neurons were enlarged, the rough endoplasmic reticulum was enlarged, and the chromatin was enlarged. Edge aggregation, nuclear membrane rupture, reduction in the number of synapses and abnormal synaptic function, which in turn affect the intellectual development of the fetus after birth [ 8 ] . Abnormal changes in microstructure and neurotransmitters. The analysis of the fetuses induced by chronic fluorosis patients (fetuses in the fluorosis area) showed that the content of norepinephrine, serotonin and L1-receptor in the fetal brain were significantly lower than those of the fetuses in the non-fluorosis area, while the content of epinephrine was significantly lower. Significantly increased, the difference was significant ( P < 0.05). It is suggested that the accumulation of excess fluoride in the brain tissue can cause the synthesis of certain receptors and transmitters in nerve cells to decrease, resulting in developmental disorders or damage of nerve cells [ 8 ] .

2.2 The effect of fluoride on the activity of some enzymes in the brain
Fluorosis affects the activity of certain enzymes involved in the transmission of nerve messages. Xu Shunqing et al [ 9 ] used chemiluminescence analysis to measure the activity of nitric oxide synthase in rat brain tissue. The experimental results showed that fluorine can make the activity of nitric oxide synthase (NOS) in vivo or in vitro. Increase. The NOS activity in the brain tissue of fluoride-exposed rats was higher than that of the control group. When sodium fluoride was directly added to the NOS reaction, the NOS activity was also increased. Research by Zhao Xilong et al. [ 10 ] showed that fluorine can inhibit the activity of ATPase in rat brain synaptic membrane, which plays an important role in maintaining high calcium ion concentration in nerve cells.

2.3 The effect of iodine on brain cell structure, some enzyme activities and neuronal apoptosis rate
Iodine is an essential component for the synthesis of thyroid hormones, and low or high levels of iodine can have significant effects on brain development. Electron microscope observation showed that iodine deficiency degenerates the endoplasmic reticulum in part of rat nerve cells, and nucleosomes are lost and freed; mitochondria are enlarged and disappear; nuclear chromatin is dissolved and reduced, and phagosomes are increased, indicating neuromorphology. Significant changes [ 11 ] . Excessive long-term intake of fenugreek can cause the brain tissue quality, protein content and RNA content of offspring mice to be significantly reduced, thereby reducing the learning and memory ability of mice [ 7 ] . Enolase (NSE) is a marker of neuronal maturation. Sun Suju et al [ 12 ] replicated the high iodine thyroid abscess animal model with high iodine water, and used enzyme-linked immunosorbent assay to measure the hippocampal nerves of the first and second offspring of mice with high iodine goiter at 7, 14, 21, and 30 days old. The results showed that the activity of NSE in the high-iodine group (3 000 μg/L) and the second-generation offspring from birth to 30 days was higher than that in the iodine-appropriate control group (5 μg/L). L) decreased, and the NSE activity in the hippocampus of the 14-day-old offspring in the second-generation high-iodine group was significantly lower than that in the first-generation offspring, indicating that high iodine can reduce the NSE activity in the brain of the offspring, suggesting that high iodine can interfere with NSE by affecting the brain. The energy supply in the brain, thereby affecting the development of nerve cells, causing brain dysfunction. Transmission electron microscope observation showed that the apoptosis rates of cerebral cortex, hippocampus and thyroid cells in the experimental high iodine group were significantly higher than those in the appropriate iodine group, and the apoptosis rate of the high iodine II group was significantly higher than that of the high iodine I group, suggesting that high iodine induced brain The occurrence of apoptosis and thyroid cell apoptosis is related to the concentration of iodine. The higher the concentration of iodine, the higher the apoptosis rate of brain and thyroid cells [ 13 ] . Excessive apoptosis of brain cells will inevitably cause damage to the central nervous system, thereby affecting its learning, memory and intelligence.

2.4 The effect of iodine on the growth of neurons in neonatal rat cerebral cortex and the expression of proto-oncogene product C-fos
An appropriate amount of iodine has a certain relationship with the physiological development of many parts of the human body. Gene probes were prepared from NSE cDNA, and the relative contents of NSE and mRNA were detected by Northern blot method. The results showed that low iodine could hinder the gene expression of NSE at the transcriptional level, reduce its synthesis, and then affect the energy supply of the brain and nerves. cell development [ 14 ] . Wang Xue et al. [ 15 ] used the primary culture method of neonatal rat cerebral cortex neurons to observe the effects of different concentrations of iodine (40, 80, 120 mg/L) on the morphology of neurons, and the results showed: low, medium and high iodine addition The volume of nerve cells in each group was larger than that of the control group ( P < 0.001), and the length of the neurites was also longer than that of the control group ( P < 0.05). The high-concentration iodine group (120 mg/L) had a more significant effect on the growth and morphology of nerve cells, manifested in dense growth, larger cell bodies, large nuclei, intact nuclear membranes, longer and more processes, and interconnected into a dense network . It is suggested that with the increase of iodine concentration, iodine can promote the growth and development of nerve cells in a dose-dependent manner. After the samples were processed by immunohistochemical procedures, 15 nerve cells were randomly selected from each group for image analyzer measurement. Nuclei were dark yellow with weak light transmission and reduced gray value. P < 0.01).

Based on the research results over the years, researchers have put forward many theories on the mechanism of fluorine-induced brain damage. In recent years, the role of free radicals in fluorine neurotoxicity has attracted attention. The free radical theory of fluorosis believes that fluorine is a very active element in chemical properties. After the body ingests excessive fluorine, fluorine can directly attack oxygen, interfere with oxygen metabolism and lead to the increase of oxygen free radicals; at the same time, fluorine may also attack trace amounts of antioxidant enzymes. element, which reduces the activity of antioxidant enzymes, and also leads to the increase of oxygen free radicals; while SOD is an important enzyme in the body's anti-lipid peroxidase enzymatic defense system, which can effectively remove superoxide cation free radicals generated by biological oxidation It has the effect of terminating free radical chain reaction. Due to the accumulation of free radicals in the body due to high fluorine, SOD is excessively consumed in the process of scavenging free radicals, causing a series of free radical reactions in the polyunsaturated fatty acids of membrane structural lipids, reducing the composition of polyunsaturated fatty acids and unsaturated fatty acids. Fatty acids increase the fragility of the membrane and increase the static K + permeability, thereby causing cell damage [ 16 ] . Shao Qianli et al. [ 17 ] analyzed and measured the fatty acid composition in the brain of rats after drinking different fluorinated water freely for 5 months, and found that the composition of polyunsaturated fatty acids in the brain tissue of rats with experimental fluorosis decreased, while the saturated fatty acids The composition increased, especially in the high-dose fluoride group. The results of the F test showed that there were significant differences in the results of pairwise comparison of fatty acid types in each group ( P < 0.05). Numerous studies have shown that experimental fluorosis animals and patients with endemic fluorosis have increased lipid peroxide levels, and decreased or compensatory changes in the levels of antioxidant enzymes or antioxidant substances. Studies have also shown that free radical damage aggravates the direct damage of high iodine to brain tissue [ 18 ] .

3. The effects of iodine and fluorine on advanced brain functions

Up to now, there are few reports on the effects of iodine-fluoride combined use on brain damage. Our research group Shen Xiuying et al conducted a correlation study using mice as an animal model and optical resolution learning and memory as an indicator of brain function and found that long-term high fluoride intake (10 mg/L) would affect the normal physiological function of the brain of mice, and high fluoride intake Concentrations of iodine (0.12 mg/L) and high fluoride have synergistic toxic effects, which can significantly impair the optical resolution learning ability of mice, and lower concentrations of iodine (0.04 mg/L) affect the growth and development of thyroid glands in mice The light-resolved learning ability of the mice, appropriate concentration of iodine (0.08 mg/L) can antagonize the learning ability damage of mice caused by high fluoride, and the brain function changes of these mice correspond to the activity of antioxidant enzymes in the brain and learning ability. Some ultrastructural changes in the synaptic interface of memory-related brain regions were also observed.

The development of molecular biology and the application of genetic recombinant DNA technology provide us with the possibility to further explore the effects of iodine and fluorine on brain function and their mechanisms at the molecular level. Of course, the effects of iodine and fluorine on brain function are extensive, and the mechanism of action is complex. In particular, little is known about their mechanism of action at the molecular level. A lot of basic research work is still needed in the future.


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