Apoptosis And Disordered Autophagy Flux Contribute To The Neurotoxicity Induced By High Iodine In SD Rats

Objective:Iodine is an essential trace element for the body,but high iodine intake can lead to many diseases.Accumulated evidences have shown that the intake of high iodine can induce goiter,hyperthyroidism,hypothyroidism and autoimmune thyroid disease.In recent years,the detrimental effects of high iodine on intelligence are gaining more and more attention,but the relationship between high iodine and neurotoxicity is controversial.In this study,using the model of potassium iodate-administrated Sprague-Dawley rats,we aimed to examine the influence of high iodine on intelligence and explored the roles of apoptosis and autophagy in this scenario.Method:A total of 36 Sprague-Dewley rats（210²50 g,female:male=2:1）were randomly divided into four group as follow:one control group（tap water,iodine concentration was less than 10μg/L）,and three KIO₃-treated groups（KIO₃ was administered at 500,2500,5000μg/L via drinking water）.The rats were randomly taken from different groups（female:male=2:1）for mating.Each pregnant rat was placed in separate cage and following corresponding exposure throughout the gestation and subsequent weaning of pups.Ten female pups were randomly selected from each group,and re-caged on the twenty-first day after the birth,and given the corresponding levels of KIO₃ for 4 months after birth.Urine iodine concentrations in female rats were detected by arsenic cerium catalytic spectrophotometry.The learning and memory abilities of female rats were measured by MWM test.Nissl staining and TEM were utilized to examine the hippocampal morphology change.The TUNEL anylysis was used to determine the apoptosis of rat hippocampal neurons.Western blot and IHC were applied to detect the expression of key indicators of apoptosis and mitochondrial apoptosis,as well as autophagy key proteins,such as PARP,P53,Caspase-3,Bcl2,BAX,Cyt c,Atg7,Beclin1,p62,LC3-II expression in rats hippocampus.Results:Compared to the control group,urine iodine concentrations of 4 month female rats in three KIO₃-treated groups was significantly elevated（P<0.05）.The brain coefficient of three KIO₃-treated groups was significantly less than the control group（P<0.05）.For the PNT of MWM test,the escape latency of KIO₃-treated group female rats was longer than the control group on day 2-4（P<0.05）.And the KIO₃-treated group female rats swam longer distance to the fixed platform than the control group in each day（P<0.05）.The results of SPT showed that the frequencies of platform crossing of 2500 and 5000μg/L KIO₃-treated group female rats were significantly lower than the control（P<0.05）.Furthermore,the percentage of swimming time/distance spent in the target quadrant by the female rats of the 2500and 5000μg/L KIO₃-treated groups were significantly declined compared with the control（P<0.05）.The number of nissl bodies in three KIO₃-treated groups was significantly reduced as compared to the control（P<0.05）.High iodine exposure caused many histopathological abnormalities in hippocampus,as confirmed by homogenization and margination of nuclear chromatin,and numerous autophagosomes and demyelination of nerve fibers,as well as dilated endoplasmic reticulum and swollen mitochondria with the disappearance of cristae.The TUNEL-positive incidence in 2500 and 5000μg/L KIO₃-treated groups were remarkably higher than the control.The result of western blot showed that the expression levels of PARP,P53 and Cleaved caspase-3 were dramatically increased in2500 and 5000μg/L KIO₃-treated female rat hippocampus when compared with the control（P<0.05）.Elevated Bax,Cyt c and declined Bcl2 were also detected in 2500and 5000μg/L KIO₃-treated groups（P<0.05）.The expression levels of Atg7,Beclin1,p62 and LC3-II were significanly elevated（P<0.05）.Meanwhile,the results obtained from IHC were consistent with the above findings of western blot.Conclusion:High iodine exposure induces neurotoxicity of female rats,impairing the learning and memory abilities.Furthermore,high iodine exposure can cause apoptosis in female rat hippocampus and activate mitochondrial apoptosis.At the same time,high iodine exposure can not only increase the production of autophagosomes in rat hippocampus,but also inhibite the degradation of autophagosomes,resulting in disorder of autophagic flow.In summary,excessive apoptosis and autophagic flow disorders are involved in the high iodine-induced neurotoxicity.