Effects Of Subchronic Arsenite And Fluoride Exposure On Cardiotoxicity And Expression Of Autophagy Related Genes In Rats

Objectives:In this study,we tested the toxic effects caused by sub-chronic exposure to high-dose As,F,or their combination on cardiotoxicity injury.We explore how autophagy participates in the process of cardiotoxicity induced by As and/or F exposure,which contribute to theoretical basis for clarify the mechanism of the cardiotoxicity in offspring.Methods:The offspring rats were randomly divided into four groups:control group receiving sterile water and exposure groups receiving 100 mg/L NaF（F group）,50 mg/L NaAsO₂（As group）,and 100 mg/L NaF+50 mg/L NaAsO₂（F+As group）in drinking water,respectively,from gestation to puberty.The offspring rats were exposed to three months,we tested cardiac function indicators:blood pressure,heart rate,electrocardiogram and echocardiography.We collected biological samples:serum,blood,femur,and heart tissue.We performed histopathological observation of rat heart tissue（light microscope and electron microscopy）.The activity of myocardial enzymes CK and LDH were detected in serum,and detected oxidative stress related indicators（SOD,MDA,GSH-PX）and ATPase enzyme in tissues.The distribution and expression of autophagosomes in cardiac tissues were observed and detected by electron microscopy,qRT-PCR and Western-blot.One-way ANOVA and factorial analysis were performed on the experimental data by using SPSS22.0.Result:1.Changes in cardiac function:As,F,or their combination increased systolic pressure and diastolic pressure and changed parameters of heart rate,electrocardiogram and ultrasonic cardiogram in offspring rats.2.Changes in cardiac pathology and ultrastructure:on the one hand,HE staining observed disorder of myocardial fibrosis,myocardial cell that occurred swelling and even degeneration;on the other hand,electron microscopy observed mitochondria,muscle fibers,intercalated disc and the nucleus that occurred different degrees of damage in the exposed group.3.Changes in myocardial injury markers:As,F,or their combination exposure increased the activity of LDH in serum;and inhibited the activity of myocardial antioxidant enzymes（SOD,MDA,GSH-PX）and ATPase;accumulated the levels of myocardial lipid peroxidation product MDA.4.Distribution of autophagosomes in cardiac tissue and expression of autophagy-related genes:As,F,or their combination exposure increased the number of autophagosomes in cardiomyocytes and significantly increased the mRNA and protein expression of autophagy-related genes LC3,Beclin1,and p62.Conclusions:Sub-chronic exposure to high-dose As,F,or their combination induced cardiotoxicity,changed cardiac function and cardiac pathology and ultrastructure,affected the level of myocardial injury markers.Autophagy is involved in the process of cardiac toxicity induced by As,F,or their combination exposure.