Memory Impairment and Intelligence Retardation with Exposure to Fluoride and Arsenic

Due to the uneven distribution of geochemical elements and environmental pollution caused by industrial development, the environmental media in some areas are rich in fluorine and arsenic. High-fluorine, high-arsenic, and double high regions of both fluorine and arsenic exist widely in the world. The attention to the harm of endemic fluoride, arsenic and their combined poisoning on the intelligence, learning and memory of children has been paid. We herein reviewed the research results on the effects of fluorine, arsenic and their combined effects on learning and memory.<br>


EFFECTS OF FLUORIDE, ARSENIC AND THEIR COMBINED EFFECTS ON CHILDREN'S LEARN-ING AND MEMORY
Epidemiological studies have found that long-term drinking of high-fluorine and high-arsenic water can cause children's intellectual decline and adversely affect their learning and memory abilities. At the same time, it was also found that children with high arsenic and high fluoride coexisting disease areas suffered a certain degree of damage to their growth and development. Calderón et al. (3) surveyed children aged 6-8 years who drank high-fluorine water (water fluoride concentration of 1,500-3,000 μg/L) in San Luis Potosi, Mexico, and showed that urine fluoride levels were positively correlated with children's response time (r = 0.28, P = 0.04), which was negatively correlated with children's visual spatial organization ability (r = -0.27, P = 0.05). Drinking high fluoride water affected children's learning ability. Rocha-Amador et al. (4) analyzed the water fluoride in three regions of Mexico: Moctezuma, Salitral, and 5 de Febrero (fluorine concentrations were 800 ± 1,400 μg/L, 5,300 ± 900 μg/L, and 9,400 ± 900 μg/L. ), Children's urine fluoride content and IQ were measured. After adjusting for confounding factors, water fluoride and urine fluoride content were found to be negatively correlated with children's intelligence quotient (IQ), operational IQ, and total IQ. The IQ of children aged 6 to 11 in Makoo, Iran, who drank higher and medium concentrations of fluorine-containing water (fluorine concentrations of 5,200 ± 1 100 μg/L and 3 100 ± 900 μg/L, respectively) was significantly lower than those in the control group (water (Fluorine concentration is 800-300 μg/L) (5). The intelligence of 12-year-old children in Madhya Pradesh region of India is negatively correlated with water and urine fluoride levels (6). IQ tests were performed on children in areas with high fluoride (3,150 μg/L) and low fluoride (370 μg/L) in Tianjin, where the material life, education and cultural conditions were basically similar. Exposure affected children's intellectual development. Children's urine fluoride levels (4.99 ± 2.57 mg/L, 1.43 ± 0.64 mg/L, respectively) were negatively correlated with IQ (r = -0.32, P < 0.01) (7). Survey results from the Luliang and Datong basins in Shanxi (water concentrations of 4,120 μg/L and 8,300 μg/L, respectively) also indicate that high fluoride in drinking water has a negative effect on the IQ of children in the ward (8)(9). In addition, IQ of 7 to 14-yearold children drinking low-fluorine water (water concentration of 1,310 ± 1,050 μg/L) in Hulunbuir, Inner Mongolia was negatively correlated with urine fluoride content (0.10-3.55 mg/L). Increasing 1 mg/L reduced IQ    (10). These epidemiological studies from different countries have shown that exposure to fluoride from drinking water can impair children's intellectual development and that urine fluoride levels have a consistent negative correlation with IQ. A meta-analysis of the relationship between endemic fluorosis and children's intellectual development revealed that the children's intellectual development in the endemic fluorosis endemic areas was lagging behind that of the control group, suggesting that high fluoride caused some damage to children's intellectual development (11). Tang et al (12) used a meta-analysis of 16 case-control studies on the relationship between fluoride exposure in early life and Chinese children's intelligence, and found that children living in fluorosis areas were at risk of low IQ in non-fluorosis areas or mild Five times as many children as fluorosis. These studies indicate that high fluoride can impair children's intellectual development and affect their ability to learn and remember.

Effects of Arsenic Exposure on Children'S Learning and Memory
Calderon et al. (13) tested the neuropsychological development of 80 children aged 6-9 years exposed to arsenic using the Wechsler Intelligence Scale for Children (Revised in Mexico), analyzed the effects of environmental arsenic exposure on neuropsychological development, and found that children's speech IQ varies with As the urine arsenic content increased (62.9 ± 0.03 μg/L), it decreased significantly. It was also found that children with high urine arsenic content had lower long-term memory scores and language abstract scores. A study on the relationship between environmental arsenic exposure and cognitive ability of 557 6-8 year old children from 9 public elementary schools (all within 3.5 km from a metal smelter) in Torreon, Mexico, found children's memory and isocognitive ability was negatively correlated with urine arsenic content (58.1 ± 33.2 μg/L). The study also found that the effect of arsenic on cognitive ability is gender related. Only boys 'cognitive abilities such as visual spatial abilities, picture vocabulary, visual search, and alphabetical ranking scores were negatively related to urine arsenic, and only girls' recitation scores were negatively related to urine arsenic (14). Rocha-Amador et al. (4) analyzed the relationship between drinking water arsenic exposure and IQ of Mexican children aged 6-10 years, and found that children's ver-bal IQ, operating IQ, and total IQ were negatively correlated with water arsenic content, while only total IQ and urinary arsenic existed. Long-term drinking water arsenic exposure (water arsenic concentration of 131.2 ± 343.7 μg/L) can reduce adolescents' image memory and cognitive ability to switch attention (15). Children's verbal intelligence quotient and memory of words and stories and their hair from 11 to 13 years of age The arsenic content (average hair arsenic was 17.8 ± 14.1 ng/g) was negatively correlated (16). Wasserman et al. (17)(18) found that 10-year-old and 6-year-old children with reduced arsenic exposure in drinking water were exposed to arsenic in Bangladesh, and their arsenic levels were reduced (water arsenic concentrations were 117.8 ± 145.2 μg/L and 120.1 ± 134.4 μg/L) Negative correlation. A study from the Bangladesh region of India showed that there was a weak link between decreased intelligence in school-age children and urinary arsenic content (urine arsenic concentration of 78 ± 61 μg/L). No arsenic concentration in water during pregnancy and childhood (59 ± 133 μg/L) was associated with children's intelligence (19). Urinary arsenic concentration can reflect the amount of arsenic intake from different sources (including food and water), but only reflects short-term exposure. Studies have found that the effect of arsenic on children's intelligence is related to gender. Hamadani (20) reported that drinking water was exposed to arsenic early in life, and the total IQ and verbal IQ of 5-year-old girls were negatively related to their urinary arsenic content, while the total IQ and verbal IQ of boys were not found to be related to their urinary arsenic content. Kang Jiaqi and others analyzed the relationship between the intellectual development and arsenic concentration of water (130 μg/L) in 268 primary school students in areas with high arsenic drinking water in Hangjinhouqi, Inner Mongolia. The impact of intelligence is more pronounced. From the above epidemiological research results from different countries, it can be concluded that arsenic can damage children's intellectual development and learning and memory, and there is a negative correlation between urinary arsenic content and children's intellectual function. However, in the latest prospective cohort study of a large sample (2,112 young children) from Bangladesh, it was not found that exposure to arsenic through drinking water during early life, including pregnancy and 18 months after birth, affects growth and development of young children and adverse effects on the intellectual development. This suggests that the Review SI 2020; Vol. 32, No. 1 www.bonoi.org 120 adverse effects of arsenic exposure in early life on growth and development may be manifested in childhood (22).

Effects of Combined Exposure of Fluoride and Arsenic on Children's Learning and Memory
There are few reports on the epidemiological survey of children with high fluoride and arsenic disease. Salitral in Mexico with high fluorine and high arsenic area (5,300 ± 900 μg/L in water fluorine concentration, 169 ± 0.9 μg/L in water arsenic) and 5 de Febrero (9,400 ± 900 μg/L water fluoride concentration, water arsenic) The concentration of high fluoride and arsenic in the region with a concentration of 194 ± 1.3 μg/L) has adverse effects on children's IQ, but this study did not analyze the impact of coexistence of high fluoride and high arsenic on children's IQ (4). Wang et al. (9) conducted research on high fluoride disease areas in Shanxi Province (water fluoride concentration of 8,300 ± 1,900 μg/L, water arsenic concentration of 3 ± 3 μg/L), and high arsenic disease areas (water fluoride concentration of 900 ± 500). μg/L, water arsenic concentration is 190 ± 183 μg/L), medium arsenic area (water fluoride concentration is 1,700 ± 1 100 μg/L, water arsenic concentration is 142 ± 106 μg/L), and control area (water fluoride Children aged 8 to 12 with a concentration of 500 ± 200 μg/L and a water arsenic concentration of 2 ± 3 μg/L were tested for intelligence. The results showed that the children's IQ scores were ranked from high to low in the control group, high fluoride group; compared with the middle arsenic group and the high arsenic group, the IQ difference between the latter three groups and the control group was statistically significant. The IQ scores of children in the high arsenic group were negatively correlated with their urinary arsenic levels, and the IQ scores of the children in the high fluoroscopy group were also negatively correlated with their urinary fluorination levels. These results suggest that high arsenic and high fluoride exposure can affect children's intelligence; especially the effect of high arsenic is more obvious. significantly lower than that of the high-fluoride and control groups (water arsenic concentration of 30 μg/L, water fluoride concentration is 580 μg/L), but there is no statistically significant difference between the high fluoride group and the control group, suggesting that high fluoride and low arsenic have little effect on IQ. Caused by high arsenic; the IQ of children in the high arsenic and high fluoride group at the age of 10 years was significantly lower than that of the control group, and there was no statistical difference between the high arsenic and high fluoride group and the high fluoride group, but due to the sample size Too small, not very representative. At present, there are few epidemiological studies on the effects of combined exposure of fluoride and arsenic on children's intelligence, learning and memory function, and it is not clear how the interaction of high fluoride and arsenic on children's intelligence, learning and memory function needs to be further studied.

EFFECTS OF FLUORINE, ARSENIC AND THEIR COMBINED EFFECTS ON LEARNING AND MEMORY OF EXPERIMENTAL ANIMALS
In recent years, researches on the effects of chronic fluoride and arsenic poisoning on the learning and memory abilities of experimental animals have gradually increased.

Effects of Fluoride Exposure on Learning and Memory in Experimental Animals
Chioca et al. (24) used open field test and two-way active avoidance test to evaluate the effect of sodium fluoride on memory in rats, and found that the 50 mg/L and 100 mg/L sodium fluoride groups had impaired habituation ability, and 100% In the mg/L sodium fluoride group, the number of avoidance reactions in the active avoidance task was significantly reduced. These results indicate that moderate levels of sodium fluoride poisoning have a potentially damaging effect on learning and memory. Wu et al. (25) reported that the learning and memory ability of rats exposed to fluoride (100 mg/L sodium fluoride) in free drinking water was impaired for 30, 60 and 90 days. Compared with the control group, the learning and memory ability of the offspring of the high-fluoride group (100 mg/L sodium fluoride) was reduced (26 periments and Y-maze to evaluate the learning and memory ability of fluoride-exposed mice. The results of open field experiments found that the medium fluoride group (5 mg/L sodium fluoride) and the high fluoride group (10 mg/L The number of standing legs and the number of moving grids on the hind legs of the mice were less than those of the control group and the lowfluoride group (1 mg/L sodium fluoride), and the changes were highest in the high-fluoride group. The results of the Y-maze experiment found that as the fluorine concentration (1, 5, 10 mg/L sodium fluoride) increased, the number of training sessions required for the mice to reach the learning standard increased gradually. The mice in the 10 mg/L sodium fluoride group trained The number of times was nearly doubled than that of the control group, indicating that fluorosis can significantly reduce the learning ability of mice. No high fluoride has been found to affect the memory retention of Y-maze discrimination learning in mice, which is similar to their 2001 (28) and Reports in 2003 (29) were consistent. Pathological changes in synaptic structures in the hippocampal CA3 region, which are closely related to learning and memory, have been observed (28,30). Xu et al. (31) 8 weeks after the mice were exposed to free drinking water, Y-maze was used to determine the effect of fluorine on the ability of mice to distinguish learning and memory. The number of trainings required by the standard has increased significantly, indicating that fluorine is an essential element, and lack of fluoride will affect the normal physiological function of the mouse brain; while low (3 mg/L sodium fluoride), medium (6 mg/L sodium fluoride), High fluoride group (10 mg/L sodium fluoride) 3 fluorine-exposed groups. With the increase of fluorine exposure dose, the number of training times required for mice to reach the learning standard gradually increased. The number of training required to learn the standard is significantly more than that of the control group, which indicates that fluorosis can significantly reduce the learning ability of mice, which is consistent with the report of Zhang et al. (27)(28)(29)(30)(31).

Effects of Arsenic Exposure on Learning and Memory in Experimental Animals
At present, synaptic plasticity is considered to be the neurophysiological basis of learning and memory. Stimulation under certain conditions can lead to rapid and continuous enhancement of synaptic activity, known as long-term potentiation (LTP). LTP is a method of information storage at the synaptic level, which is learned and memorized Electrophysiological indicators are also a sign of synaptic plasticity. Krüger et al. (32) found that sodium arsenite significantly inhibited LTP in hippocampal brain slices of adult rats (2 to 4 months) and young rats (14 to 21 days), thereby inhibiting learning and memory. The activity of arsenic-exposed rats decreased, a large number of errors in cognitive behavioral expression, and their learning and memory abilities decreased significantly (33). Chronic arsenic-exposed rats took a longer time to acquire operational learning abilities than the control group (34). Li et al. (35) performed a double-box electric shock method on neurobehavioral tests in experimental rats and found that compared with the control group, the memory of the arsenic-treated rats was significantly reduced, indicating that arsenic compounds can significantly affect the memory function of rats. Nervous behavior has some impact. Xiao et al. (36) found that chronic arsenic-stained rats from embryonic stage had significantly lower learning and memory performance than the control group through water maze experiments, suggesting that chronic arsenic-stained embryos could reduce spatial learning and memory ability of rats. This study also observed that chronic arsenic exposure can inhibit the induction and maintenance of LTP in the hippocampal dentate gyrus of offspring rats, further indicating that chronic arsenic exposure can impair hippocampal learning and memory function. Shu et al. (37) observed that arsenic exposure to drinking water had a toxic effect on the neurobehavior and learning and memory of young rats. Luo et al. (38) used Morris water maze to detect the spatial learning and memory ability of arsenic-stained rats. The results showed that compared with the control group, the escape latency of rats in the 68 mg/L sodium arsenite group was significantly longer than in the control group. neurons, glial cells and synapses in rats (39)(40), and these changes may affect learning and memory abilities.

Effects of Combined Exposure of Fluoride and Arsenic on Learning and Memory in Experimental Animals
The study found that with the increase of the dose, the learning and memory abilities of rats exposed to fluoride and arsenic combined were significantly reduced, and the number of nerve cells, irregular nuclear morphology, organelle lesions, and significantly reduced synaptic numbers were observed by electron microscopy. Physiological changes indicate that fluoride and arsenic have obvious damage to the offspring's nervous system (41). The rats were given 50 mg/L arsenite and 100 mg/L sodium fluoride by free drinking water route. The learning and memory ability of the rats was tested by a stepby-step method. Both the number of single errors and the number of second errors were higher than those of the control group, but the difference between the rats in the combined group and the control group was statistically significant (25), suggesting that the combination of fluoride and arsenic exposure has a certain degree of learning and memory in rats Damage, but the study did not conduct an interaction analysis of the effects of fluoride and arsenic on learning and memory in rats.

POTENTIAL MECHANISMS OF FLUORIDE, AR-SENIC AND THEIR COMBINED EFFECTS ON LEARNING AND MEMORY
The central nervous system is more sensitive to toxic effects than other tissue systems, especially the develop-ing central nervous system. Studies have shown that excess fluoride and arsenic can accumulate in the brain tissue through the placental barrier or the blood-brain barrier, which can affect brain development and the synthesis and secretion of neurotransmitters, and therefore have an adverse effect on the normal development of the nervous system and children's intelligence. Fluoride and arsenic lead to decreased learning and memory functions, and its mechanism has not been fully elucidated. It may be related to fluoride and arsenic-induced changes in the morphology and structure of nerve cells, oxidative damage to the central nervous system, neuronal apoptosis, changes in certain enzymes, DNA damage and affect the center neurotransmitters and their changes in gene regulation.

PERSPECTIVES
The above findings indicate that chronic exposure to fluoride and arsenic can cause decreased intelligence and learning and memory, but most epidemiological studies have targeted higher concentrations of fluorine (water fluoride concentration> 3,000 μg/L), arsenic exposure (water arsenic concentration> 100 μg/L) and children's intelligence, learning and memory, there is currently lack of research results on the lower levels of water fluoride, arsenic exposure and children's intelligence, learning and memory. In addition, there are few reports on the effects of the combined effects of fluoride and arsenic on learning and memory, and the interaction between fluorine and arsenic. Due to the interaction of fluorine and arsenic, the impact on health is more complex and needs to be thoroughly investigated with further studies.■