Arsenic Exposure Caused Damage To Liver,Kidney And Intestine And Disturbance Of Lipid Metabolism In Mice

Arsenic（As）is a toxic metalloid element that is present in air,water and soil.The effects of arsenic have been widely concerned.Humans can be exposed to arsenic through the air,food and water.Drinking water is the main way of arsenic exposure.Chronic exposure to arsenic is associated with multiple diseases,such as skin lesions,peripheral neuropathy,gastrointestinal symptoms,diabetes,renal system effects and cardiovascular disease.Several epidemiological studies have also documented exposure of different arsenicals to cancers.At present,studies suggested that these toxic effects of arsenic are closely related to oxidative stress.In our study,in order to provide experimental basis for the prevention and treatment of health problems caused by arsenic,mice were selected as experimental materials,the oxidative stress and lipid metabolism were measured.The main research contents and results are as follows:（1）The effects of subchronic arsenic exposure on mice.Subchronic arsenic exposure model was established using ICR mice.The mice in the control group drank sterilized distilled water.The mice in two arsenic exposure groups were exposed to 5 mg/L and 15 mg/L sodium arsenite（Na As O₂）respectively for 56 days.The results showed that compared with the control group,there were no significant changes in water consumption,final body weight and organ coefficients of liver and kidney in the two arsenic exposure groups.The average daily arsenic consumption of 5mg/L and 15 mg/L arsenic group was 1.02 mg/kg·BW and 2.43 mg/kg·BW,respectively;in the two arsenic groups.Compared with the control group,the contents of hydrogen peroxide（H₂O₂）and malondialdehyde（MDA）in liver,kidney and intestine were increased,the contents of reduced glutathione（GSH）were decreased,and the activities of total superoxide dismutase（T-SOD）were decreased in the two arsenic groups.Meanwhile,the oxidative stress indexes of 15 mg/L arsenic group were significantly changed compared with the control group.At the same time,the pathological damage of liver,kidney and intestine were observed in the two arsenic groups.These results suggested that subchronic arsenic exposure could lead to oxidative stress and oxidative damage in a dose-dependent manner.In addition,the inflammatory cells were observed in the liver tissue sections of 15 mg/L arsenic group.RT-q PCR showed that the expression of TNF-αwas increased,suggesting that the ROS burst induced by arsenic exposure could also cause the inflammatory reaction in the liver tissue of mice.Detection of lipid levels in serum and lipid metabolism related gene expression in liver found that 5 mg/L arsenic group had no significant changed,while in the 15 mg/L arsenic group,total cholesterol（T-CHO）and low density lipoprotein cholesterol（LDL-C）were significantly increased,and high density lipoprotein cholesterol（HDL-C）were decreased.The RT-q PCR results showed that the expression of peroxisome proliferator activated receptor-γ（PPARγ）was increased in the arsenic group,while the expression of carnitine palmitoyl transferase-1（CPT-1）and peroxisome proliferator activated receptor-α（PPARα）were decreased.These results suggested that the disorder of lipid metabolism induced by arsenic exposure is related to the expression of related genes.（2）The effects of chronic arsenic exposure on mice.C57BL/6 mice were selected as experimental materials.The mice in the control group drank sterilized distilled water freely and in two arsenic groups were exposed to 5mg/L and 50 mg/L Na As O₂solution respectively for 150 days.The results showed that compared with the control group,the body weight of mice in the arsenic groups decreased significantly,and the organ coefficients of liver and kidney did not change significantly.The water consumption of mice in the arsenic groups decreased significantly;the daily average arsenic intake in arsenic groups was 1.42 mg/kg·BW and 3.56 mg/kg·BW,respectively.Compared with the control group,the contents of H₂O₂and MDA in liver,kidney and intestine were increased,while the levels of SOD and GSH were decreased in the arsenic groups.The changes of oxidation index in 50 mg/L arsenic group were more significantly than that in 5 mg/L arsenic group.At the same time,the pathological damage was also found in the liver,kidney and intestine of mice in the two arsenic exposure groups,and the damage of 50 mg/L arsenic group was more serious than 5 mg/L arsenic group.These results indicated that chronic arsenic exposure could cause oxidative stress and oxidative damage in tissues,and this effect shows a dose effect relationship.Then,the level of lipid and the expression of lipid metabolism related genes in the liver were determined.The results showed that compared with control group,TG content in liver of 5 mg/L arsenic group was significantly increased,T-CHO was not significantly changed,while in 50 mg/L arsenic group,the contents of T-CHO and TG were significantly increased.The previous studies of our team showed that 5 and 50 mg/L arsenic exposure for 5 and 6 months resulted in impaired glucose homeostasis and decreased glucose regulation ability in mice.The above results suggested that chronic arsenic exposure could cause disorder of glycolipid metabolism.The expression of lipid metabolism genes in liver was detected by RT-q PCR.The results showed that compared with the control group,the expressions of SREBP-1c and PPARγwere significantly increased,and the expressions of CPT-1 and PPARαwere significantly decreased in the arsenic group.These results suggested that arsenic exposure could cause lipid metabolism disorder by affecting the expression of genes related to lipid synthesis and lipolysis.In conclusion,arsenic exposure could induce oxidative stress and oxidative damage in liver,kidney and intestine of different strains of mice（ICR and C57BL/6）.Moreover,prolonging the exposure time and increasing the concentration of arsenic can significantly enhance the toxic effect of arsenic,that is,the damage of arsenic to the body is dose and time-dependent.In addition,the accumulation of ROS also leads to inflammatory reaction and disturbance of lipid metabolism in liver.Arsenic induced dyslipidemia may be related to up regulation of SREBP-1c and PPARγand down regulation of CPT-1 and PPARα.Comparing the experimental results of 5 mg/L arsenic group in subchronic and chronic arsenic exposure experiments,we found that:in the subchronic experiment,the water consumption and body weight of mice in 5 mg/L arsenic group had no significant changed,while in the chronic arsenic exposure experiment,that were significantly decreased.It was inferred that with the extension of arsenic exposure time,arsenic intake could damage the digestion and absorption function of mice,cause abnormal metabolism,and lead to weight loss.In addition,subchronic arsenic exposure led to the occurrence of lipid metabolism disorder,but the glucose homeostasis was not affected.However,in chronic arsenic exposure experiment,glucose and lipid metabolism were abnormal.It is suggested that the arsenic induced glucose and lipid metabolism disorder may have a sequence,and the lipid metabolism disorder may occur before,and the glucose metabolism disorder may occur after.