Thyroid Disruption Induced By Iodoacetic Acid

In recent years,the iodo-disinfection byproducts is a new class of disinfection byproducts found in drinking water,have been known that the content of iodo-disinfection byproducts in water is microgram level,however,it has strong toxicity,the cell toxicity,genetic toxicity and potential carcinogenicity of iodoacetic acid are much more stronger than the corresponding chlorine and bromine disinfection byproducts.In recent years,the hot spot of the scholar's research change from the cell toxicity,genetic toxicity and potential carcinogenicity to endocrine disrupting effects of drinking water disinfection byproducts.Drinking water disinfection byproducts have the effects of endocrine disruptors,thyroid interference effects of disinfection byproducts is considered to be one of the potential influencing factors of the endocrine system anomalies.Early research has shown that IAA might has the thyroid interference effects,however it still lacks a system evaluation on the thyroid interference effects.Therefore,in this research,we preliminarily explored the thyroid interference effects of IAA through the in vivo and in vitro experiments,so that we can provide a scientific basis to health risk assessment,effective control and national water quality standardsof the IAA.1 Thyroid disruption by IAA in vivoObjective:Adopt 28 days continuously through the mouth of rats by gastric infected subjects,to evaluate the thyroid endocrine disrupting effects of IAA.Methods:Acute toxicity was experimented by using Horn to assess the IAA median lethal dose of SD rats,according to the volume of 1 ml/100 g-bw,the rats were respectively gavaged in 46.4,21.5,10.0,21.5 mg/ml of IAA,observed two weeks after gavaged,recorded the performance of the rats,calculated LD50 according to the animal deaths.28-days of continuously gavaged method references the OECD TG407,respectively gavaged rats by ultrapure water,6 mg/kg·bw,12 mg/kg·bw,24 mg/kg·bw IAA solution,for 28 consecutive days.The rats were killed after the last 24 hours gavaged,and weighed the rats and the organs of rats;Checked the rat's liver function;detection the thyroid function related to genes TRs,Dios,NIS,TSHR,Tg,TPO mRNA and protein expression level;detection the rat's serum TSH,TRH,Tg,TPO protein expression;detection of rat's serum TT3,TT4,FT3,FT4 hormone levels;the histopathological examination thyroid related organs in rats.Result:1.Acute toxicity experiment shows that LD50 of male rats is 126 mg/kg·bw,95%confidence limit is 92.6?171.0 mg/kg·bw;LD50 of female rat is 147 mg/kg·bw,95%confidence limit is 95.1?227.0 mg/kg·bw.2.Male and female rats weight in each dose group of IAA have no statistical difference compared with the control group(P>0.05).IAA 12 mg/kg·bw and 24 mg/kg·bw dose group male rats livers and body weight ratio are lower compared with control group(P<0.05).Each dose group of IAA male rats thyroids and body weight ratio have no statistical difference compared with control group(P>0.05).Each dose group of IAA,female rats livers,thyroids and body weight ratio have no statistical difference compared with control group(P>0.05).3.IAA 6 mg/kg-bw dose group,the concentrations of male rats AST?AST/ALT have statistical differences compared with the control group(P<0.05).IAA 24 mg/kg-bw dose group,the concentrations of male rats TP,GLO,A/G,ALP have statistical differences compared with the control group(P<0.05).The concentrations of male rats TbiL,ALB,ALT have no statistical difference compared with control group(P>0.05).IAA 24 mg/kg·bw dose group,the concentrations of female rats GLO,A/G have statistical differences compared with the control group(P<0.05).Each dose group of IAA,the concentrations of female rats ALT,AST have statistical differences compared with the control group(P<0.05).The concentrations of female rats TbiL,TP,ALB,AST/ALT,ALP have no statistical difference compared with control group(P>0.05).4.IAA 12 mg/kg-bw dose group,Liver thra mRNA levels of male rats are lower compared with control group(P<0.05).IAA 24 mg/kg-bw dose group,Liver thrb mRNA levels of male rats are higher compared with control group(P<0.05).Each dose group of IAA,liver Diol mRNA levels of male rats is higher compared with control group(P<0.05).Liver Dio3 mRNA levels of male rats have no statistical difference in each dose group of IAA compared with control group(P>0.05).IAA 6 mg/kg·bw dose group,Liver thra mRNA levels of female rats are higher compared with control group(P<0.05).IAA 6 mg/kg-bw and IAA 12 mg/kg·bw dose group,Liver Dio1 mRNA levels of female rats are higher compared with control group(P<0.05).Liver thrb and Dio3 mRNA levels of female rats have no statistical difference in each dose group of IAA compared with control group(P>0.05).Each dose group of IAA,thyroid NIS mRNA levels of male rats are lower compared with control group(P<0.05).Thyroid TSHR mRNA levels of male rats have no statistical difference in each dose group of IAA compared with control group(P>0.05).IAA 12 mg/kg·bw and IAA 24 mg/kg·bw dose group,thyroid Dio1 mRNA levels of male rats are lower compared with control group(P<0.05).IAA 12 mg/kg·bw dose group,thyroid Tg and TPO mRNA levels of male rats are higher compared with control group(P<0.05).Thyroid NIS mRNA levels of female rats in each dose group of IAA are lower compared with control group(P<0.05).Thyroid TSHR,Tg,TPO mRNA levels of female rats have no statistical difference in each dose group of IAA compared with control group(P>0.05).IAA 12 mg/kg·bw and IAA 24 mg/kg·bw dose group,thyroid Dio1 mRNA levels of female rats are lower compared with control group(P<0.05).5.Each dose group of IAA,thyroid NIS and TSHR protein levels of male and female rats are lower compared with control group(P<0.05).Thyroid Tg and TPO protein levels of male and female rats have no statistical difference in each dose group of IAA compared with control group(P>0.05).6.IAA 12 mg/kg·bw and IAA 24 mg/kg·bw dose group,the concentrations of male rats TSH,Tg,TPO are higher compared with control group(P<0.05).The concentrations of male rats TRH in each dose group of IAA have no statistical difference compared with control group(P>0.05).The concentrations of female rats TSH in each dose group of IAA have no statistical difference compared with control group(P>0.05).IAA 6 mg/kg·bw dose group,the concentration of female rats TRH are lower compared with control group(P<0.05).IAA 12 mg/kg·bw and IAA 24 mg/kg·bw dose group,the concentration of female rats Tg and TPO are higher compared with control group(P<0.05).7.The concentrations of male rats TT3,TT4,FT3,FT4 in each dose group of IAA have no statistical difference compared with control group(P>0.05).IAA 24 mg/kg·bw dose group,the concentrations of female rats TT3 are lower compared with control group(P<0.05).The concentrations of TT4 of female rats in each dose group are higher compared with control group(P<0.05).IAA 12 mg/kg·bw dose group,the concentration of female rats FT4 is higher compared with control group(P<0.05).8.Male and female rats liver tissue pathology in each dose group of IAA shows slight liver cell edema,thyroid tissue pathology visible follicular epithelial cells after stratification,lymphocytes invasion and change.Conclusion:IAA can induce male rat liver and body weight ratio significantly lower,liver function test results show that IAA can lead to liver function damage in rats,IAA can affect the thyroid endocrine function by damaging the liver.IAA can reduce thyroid tissue NIS gene mRNA and protein expression levels in both male and female rats,and affect the level of rats serum TH cycle.IAA can reduce male and female rats thyroid tissue Diol gene mRNA expression level,block the cycle of T3.IAA can also cause the male rats thyroid Tg,TPO gene mRNA expression change,and cause male and female rats serum Tg,TPO concentration change,directly affect the synthesis of TH.IAA can increase male rats serum TSH concentrations and female rats serum TT3,TT4 concentrations change,interfere the normal level of TH and synthetic function.IAA can lead to male and female rats thyroid lesions.In vivo tests show that IAA has endocrine disrupting effects of the thyroid.2 Thyroid disruption by IAA in vitroObjective:Explore the thyroid hormone interference effects of IAA through GH3 cell proliferation experiment.Methods:Detecte the best proliferation concentration of T3,and the dose range of IAA cytotoxicity,then determine the effection of GH3 cell proliferation by T3 and IAA common affected through CCK-8 kit.Result:1 nM T3 can induce the expression of GH3 cells which relative to the solvent control 3.8 times,11?M IAA can make GH3 cell survival rate less than 80%.1 nM T3 and 3-10 ?M IAA common infected GH3 cells,as long as concentration of IAA is more than 3 ?M,it will suppress the GH3 cell proliferation induced by 1 nM T3.Conclusion:IAA has the ability to inhibit thyroid hormone activity.