| Background and Objective As an environmental poisons and production poisons, Cadmium was identified as one of the carcinogens by the international agency for research on cancer(IARC) in the 1990 s. It brings about acute or chronic damage, and systemic disease of the bodies mainly through inhalation smoke or cadmium dust, but its detail poison mechanism was unclear. It is currently recognized that Cd was initially accumulated in the liver and induce the liver cells to synthesize Metallothionein(MT), and they binds together to generate Cd-MT complex into the kidneys through blood circulation. to the kidneys by glomerular filtration and tubular absorption into proximal tubular segments S1 and calm, the lysosomal degradation into Cd2+ transport protein function caused by changes in oxidative damage and mitochondrial respiratory failure, renal tubular cells induced apoptosis. During the chronic cadmium exposure, Cd mainly accumulated in the kidney within the body, and leading to kidney damage and renal failure through the oxidative damage, calcium channel disorders, etc. Therefore, the treatment of chronic cadmium poisoning is mainly considered kidney cadmium removal and kidney repair. Numerous studies have indicated that the clinical commonly used heavy metals(lead, mercury, etc.) of poisoning Chelators which have no effect on chronic cadmium poisoning. New drive cadmium complexation agent GMDTC in dithiocarbamate esters(DTC), on the basis of using glucose, amino- a sulfur amino replace DTC, methionine replace R1, D-glucosamine base to replace R2 and synthesis of new compounds. Early researches of this topic have shown that GMDTC have good displacement effect of cadmium, can effectively through the cell membrane into the cell. GMDTC effect on acute cadmium poisoning has good displacement cadmium, cadmium content of cadmium can substantially reduce thekidney, liver, cadmium through the blood brain barrier, and not cause renal toxicity caused by cadmium has good protective effect, low toxicity and GMDTC, oral LD50 was greater than 5000 mg/Kg. Due to cadmium mainly by chronic exposure to accumulate in the body, the harm is greater than the acute poisoning caused chronic poisoning. Although previous studies have shown that GMDTC effect on acute cadmium poisoning has good displacement cadmium, low toxicity. But because of past research to a single dose, animals less sample size, and the gender of the single is not enough to fully evaluate the efficacy and safety of GMDTC. Therefore, this study GMDTC treatment for chronic cadmium poisoning as a starting point, using multiple doses, a variety of animals, both sexes and multiple time points more fully explore GMDTC curative effect of chronic cadmium poisoning and its toxicity. Chronic cadmium poisoning rats and mice as object, using in vivo animal experiment research, explore GMDTC from two kinds of animals on the therapeutic effect of chronic cadmium poisoning, the general toxicity, acute toxicity and subacute toxicity, comprehensive evaluation GMDTC treatment the curative effect of chronic cadmium poisoning and toxicity, and to provide theoretical basis for study of the next step of cadmium GMDTC flooding.Methods 1 Experimental Methods 1.1 GMDTC treatment of chronic cadmium poisoning mice test The 120 SPF adult NIH mice, male and female each 60, were randomly divided into control group and model group, respectively. The model group mice were daily given 0.6 μmol/m L Cd Cl2 +12 μmol/mlβ2-Mercaptoethanol(ME, ip) for 5 days. 35 days later, they were randomly divided into model control group, low- GMDTC group, middle- GMDTC group, high- GMDTC group and EDTA treatment group, respectively, each 20 mice. The control group and model control group were injected with saline, the GMDTC treatment groups were injected with 108.3, 216.5 and 433 mg/Kg GMDTC solution, respectively, and EDTA group were treated with 93.6 mg/Kg EDTA solution, 1/d, 5 days/week; male mice were administered for 5 weeks, and female mice were administered continuously for 6 weeks. 1.2 GMDTC treatment of chronic cadmium poisoning rat testThe 60 SPF adult SD rats, male and female each 30, were randomly divided into control group and model group, respectively. The model group rats were daily given 0.3 μmol/m L Cd Cl2 +60 μmol/mlβ2-Mercaptoethanol(ME, ip) for 5 days. 35 days later, they were randomly divided into model control group, low- GMDTC group, middle- GMDTC group, highGMDTC group and EDTA treatment group, respectively, each 10 rats. The control group and model control group were injected with saline, the GMDTC treatment groups were injected with 108.3, 216.5 and 433 mg/Kg GMDTC solution, respectively, and EDTA group were treated with 93.6 mg/Kg EDTA solution, 1/d, 5 days/week; were administered for 8 weeks. 1.3 Acute toxicity test Acute toxicity by abdominal injection test using the up and down method by intraperitoneal injection of one-time give 0.51g/m L GMDTC solution; acute oral toxicity test using the method of maximum limit of disposable gavage to give 1.01g/m L GMDTC solution. Infected animal poisoning manifestations,every day after death, continuous observation for 14 days, and weigh in d0, d3, d7 and d14, respectively. 2 Statistical methods Data were described as mean ± S.D. SPSS17.0 software was used for statistical analysis. The differences between groups were analyzed by using One-Way ANOVA, the Dunnett method for further comparison between the experimental group and control group, and Bonferroni method or further comparison between two experimental groups. Statistical differences of P-values at the level of 0.05 or less were.Results 1 GMDTC of chronic cadmium poisoning in mice and rats cadmium displacement effect 1.1 GMDTC curative effect of chronic cadmium poisoning in mice After GMDTC treatment of chronic cadmium poisoning mice, the male mice kidneys Cd content were significantly lower than those in the control group and the EDTA group(P <0.05), which drive cadmium ratio 23.8% 31.8%, 47.9% respectively; GMDTC in and high-dose groups of female mice kidneys Cd content lower than the model group and EDTAgroup(P <0.05), which drive cadmium ratio 11.2%, 21.4% and 41.7%, respectively. Cd urine test results have shown that, GMDTC treated mice 24 h urine total Cd content higher than the model group(P <0.05); after the end of treatment compared with the total amount of 24 h urine Cd content was significantly higher than the end after modeling(P <0.05). Cd blood results showed significantly higher in the model control group and the treatment group of male mice GMDTC blood Cd, and EDTA group was significantly higher than that of the model group(P <0.05). The liver, brain and testes Cd showed no significant change. It was indicated that GMDTC treatment of chronic cadmium poisoning, can cause kidney cadmium excreted in urine within the same time without causing Cd transfer to other organs. 1.2 GMDTC curative effect of chronic cadmium poisoning in rats After GMDTC treatment of chronic cadmium poisoning rats, treatment of the GMDTC groups kidney Cd were significantly reduced, and GMDTC high dose group was significantly lower than those in the control group(P <0.05); male rat kidney cadmium driving rates were 19.4%,10.7% and 33.6%; the rate of female rats kidney cadmium drive 18.2%,12.5% and 32.9% respectively. The results showed that urinary Cd, GMDTC treated mice 24 h urine total Cd content higher than the model group(P <0.05); 24 h after the end of treatment compared with the total amount of Cd in urine was significantly higher than before treatment(P <0.05). The results showed that blood Cd, model control group and the treatment group GMDTC male rats significantly reduced blood Cd, Cd female rats no difference in blood. In addition, the change did not differ(P> 0.05), brain, liver and testes of rats after cadmium content GMDTC treatment. It was indicated that when GMDTC treatment of chronic cadmium poisoning in rats shows that not only gender-related, but also with the dose. 1.3 The correlation cadmium of liver, kidney, blood and urine The results show that; GMDTC after treatment, male mice kidney Cd and liver Cd decreased with increasing GMDTC dose, in GMDTC relationship was a positive correlation between the three groups, the correlation coefficient was 0.861, 0.777 and 0.661, respectively.Female mice kidney and liver Cd Cd does not exist. GMDTC chronic cadmium poisoning rats after treatment, the male rat liver between Cd and renal Cd content in three doses showed a trend of high, low, high, but the correlation is not obvious; Female rat liver and kidney Cd Cd content in GMDTC, there was a positive correlation between the high dose relationship(P < 0.05). 24 h urine Cd along with the increase of GMDTC dose increases, blood Cd with GMDTC dose not change significantly increased, and renal Cd there is no correlation(P > 0.05), while cadmium displacement rate and are in completely negative correlation between the kidney cadmium content(P < 0.05). 2 The side effects of GMDTC on mice and rats 2.1 GMDTC impact on growth and development in mice and rats The animal weight results have shown that, GMDTC no effect on weight gain in mice, and 93.6mg/Kg body weight of EDTA slight growth in female mice leads to lower(P <0.05); GMDTC no effect on weight gain in female rats given a high long-term GMDTC dose male and EDTA inhibit growth(P <0.05) body weight of rats. GMDTC little effect on the mouse organ weight, but the dose GMDTC female mice have a greater impact on organ index. GMDTC after the treatment of chronic cadmium poisoning male mice, 10% in middle and high dose groups mice hepatic lesions and 10% kidney disease in mice. Cadmium poisoning model of female mice liver pathological changes in 50%, 60% in renal pathological changes, and pathological changes of the liver and kidney after GMDTC treatment are mitigated. It was suggests that Cd in male and female mice kidney pathological damage is not the same, the same dose male serious degree of female mice poisoning, and GMDTC treatment can reduce the change of cadmium poisoning. 2.2 GMDTC influence on essential elements in mice GMDTC treatment of chronic cadmium poisoning male mice after 25 days, GMDTC high dose group of kidney Ca, Cu and zinc content is higher than the blank control group and model group(P < 0.05). GMDTC treatment of chronic cadmium poisoning female mice after 30 days, model group and treatment group kidney Ca content is slightly lower than blank control group(P < 0.05); Model control group blood Cu is higher than the blank controlgroup(P < 0.05), blood Cu GMDTC high-dose group is lower than the model control group(P < 0.05); The model control group and GMDTC treatment group mind Ca content is lower than the blank control group; GMDTC high dose group and EDTA brain Cu and Mg content than ck and the model control group; GMDTC high dose group and EDTA mind zinc content is lower than the blank control group(P < 0.05). The Ca content in liver model control group and treatment group were lower than blank control group(P < 0.05); Cu content in the model group the liver is lower than the blank control group, while GMDTC high dose group and EDTA Cu content in liver is higher than that of model control group(P < 0.05). It was suggests that cadmium can cause the Ca content in brain and liver of mice, and high dose GMDTC and EDTA has a slight effect on mice of zinc, Cu slightly affected. 3 Acute and sub-chronic toxicity of GMDTC in mice and rats Acute toxicity test method and the maximum use of the upper and lower limits law, oral gavage and rats by intraperitoneal injection had no deaths. Acute toxicity of chemicals based on the evaluation criteria to judge that GMDTC large mouse acute oral LD50>10g/Kg; intraperitoneal injection of acute LD50>5g/Kg, its low toxicity or toxic chemical agents.Conclusion 1 It was suggested that GMDTC of chronic cadmium poisoning rats and mice cadmium displacement effect is good, prompting renal cadmium from urine in vitro metabolic cycles, the redistribution of without lead cadmium. 2 It was indicated that GMDTC little side effects on mice and rats, hair and essential elements for the growth of animals, small effects of renal injury caused by cadmium has certain protective effect. 3 It was suggested that GMDTC in mice and rats through the mouth poison of LD50>10g/kg,and By intraperitoneal injection of sharp poisonous LD50>5 g/Kg, the acute toxicity of graded as low toxicity or actual non-toxic chemical medicine. |
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