The Study Of Cardiovascular Toxicity Of Lead And Its Mechanism

?Objective?To explore the effect of lead acetate exposure on the cardiovascular system and oxidative stress in male rats by animal experiments.To investigate the effects of lead acetate on the cardiovascular and discuss the cardiovascular toxicity of lead acetate and its possible mechanism of toxic toxicity.To provide evidences for risk assessment of cardiovascular toxicity induced by lead exposure.?Methods?Forty male Wistar rats of of specific pathogen free(SPF)quality weighed between 170 and 180 g was randomly classificated in to four groups,control group(0mg/kg body weight),low(90mg/kg body weight),moderate(180mg/kg body weight)and high(360mg/kg body weight)dose groups.The rats were treated with lead acetate water solution by gavage(10ml/kg),once a day,five times a week for 8 weeks.Throughout the experiment,all animals were observed at least once daily clinical symptoms of toxicity lead acetate exposure.Blood pressure and heart rate of rats were determined by the tail cuff method after 12 hours of the the last exposure.After 24 hours of the last exposure,blood was collected,heart and thoracic aorta were separated and the organ weights and coefficients of the heart were determined as soon as rats were sacrificed.Blood lead level was determined by Graphite furnace atomic absorption spectrometry;Peripheral blood serum myocardial enzymes(creatine kinase isoenzymes,lactic acid dehydrogenase,hydroxybutyrate dehydrogena-se,aspartate aminotransferaselevels were measured by the automatic biochemical analyzer;The levels of blood plasma endothelin-1(ET-1),serum intercelllar adhesion molecule 1(ICAM-1)and interlekin 6(IL-6),interlekin 1 beta(IL-1),interlekin 8(IL-8)and tumor necrosis factor alpha(TNF alpha)of serum and heart tissue homogenate were examined by enzyme-linked immunosorbent method(ELISA);Take the serum and liver tissue homogenate to determine the markers of oxidative stress(glutathione,superoxide enzyme and malondialdehyde levels were measured by the oxidative stress kit;Pathological changes of rat's heart and thoracic aorta tissue were observed using HE staining.Take the tissue of rat's heart and thoracic aorta to observe the expression of Bax/Bcl-2 and Nrf2 protein by immunohistochemistry.?Results?1.The effect of lead acetate to the cardiovascular system in rats.During the experiment,it was found that the activity of the control group and the low-dose lead acetate group were normal and no obvious symptoms of poisoning were observed.Compared with the control group,the rats in the middle and high dose groups had symptoms such as reduced food intake,diarrhea and so on.The exposure groups have obviously higher systolic blood pressures(SBP)levels than the matched group(P<0.05);The levels of serum LDH and HBDH in the low,medium and high dose groups were significantly higher than those in the control group(P<0.05),and the levels of CKMB and CRP in the serum of middle and high dose groups were significantly higher;The levels of plasma ET-1 and serum ICAM-1 were increased with the increase of the dose of lead acetate;The myocardial tissue of the control group and the low-dose lead acetate group were normal,the structure of myocardial tissue is basic normal in medium-dose lead acetate group and cytoplasmic coagulation of the deep plaque and inflammatory cells can be seen in the part of the cardiomyocytes;myocardial fiber disorder,loose,partly myocardial fiber fracture;visible atrophy thinner and visible myocardial infiltration of inflammatory cells can be seen in the high-dose lead acetate group.The structure of the vascular tissue in the control group and the low,middle-dose lead acetate group was normal,the structure of each layer was clear and no obvious lesion,but the outer membrane can be seen a lot of inflammatory cells infiltration in the high-dose lead acetate group.2.The mechanism of cardiovascular toxicity of lead acetateCompared with the matched group,the levels of serum GSH of the low,middle dose groups and high dose groups was obviously lower(P<0.05),the level of serum ROS and MDA in the middle and high dose groups were significantly increased;the level of heart tissue homogenate ROS in middle and high dose groups and the level of heart tissue homogenate MDA in high dose group.Compared with the matched group,the levels of serum IL-8 and TNF-? in the middle and high dose of lead acetate group were significantly increased(F=7.607,P=0.001;Welch=3.911,P=0.027);the level of serum IL-? in the high-dose lead acetate group was significantly increased(F=3.159,P=0.038);the level of IL-8 in cardiac tissue homogenate of high-dose lead acetate group was significantly higher than those in control group(Welch=4.228,P= 0.025).Compared with the control group,the average optical density of Bax and the Bcl-2 protein in thoracic aorta in low,medium and high dose group was exceeded than that of the matched group(P<0.05);the expression of Bax protein in the thoracic aorta of control group was lower than that of middle and big dose groups;the expression of Nrf2 protein in the heart and thoracic aorta was higher than that in the control group(P<0.05).And it showed a positive correlation between the level of ROS in the heart tissue homogenate and the level of the serum CKMB and LDH,the correlation coefficient was 0.661 and 0.599(P<0.05).?Conclusions?1.Under the experimental conditions,cardiovascular function and cardiovascular sy stem pathology changed after lead acetate exposure and inflammatory damage and apop tosis can be seen in the cardiovascular tissues,suggesting that lead acetate can lead to cardiovascular damage.2.The results of correlation analysis of ROS content and cardiac function in rat heart tissue suggest that the exposure of lead acetate can rise the level of ROS,and the change expression of the Nrf2 protein suggests that lead acetate exposure can act ivate the antioxidant capacity of Nrf2/ARE signaling pathway.When the level of ROS increases beyond the antioxidant capacity of the Nrf2/ARE signaling pathway,the rest ROS can lead to depletion of the antioxidant system and consequent oxidative damage to the cardiovascular system.