Hepatotoxicity And Its Mechanism Of Tris-(2,3-Dibromopropyl) Isocyanurate Via Death Receptor Signaling Pathway

Nowadays,environmental problems have been paid more and more attention.Among many environmental pollution problems,persistent organic pollutants(POPs)have attracted more and more attention.From 2001 to 2013,the conference of the parties chaired by the United Nations Environment Program(UNEP)for many times,decide to prohibit or restrict the use polychlorinated biphenyls,fluorooctanoic acids and organic pollutants.Polychlorinated biphenyls and perfluorooctanoic acids have been widely used as flame retardants,plasticizers,rubber sealants and other fields.However,with the gradual prohibition of such organic pollutants,safer,harmless and more environment-friendly flame retardants has also become one of the most important target in t environmental science.Tri-(2,3-dibromopropyl)isocyanuratse(TBC)is a new type of flame retardant,which is widely added to plastics,rubber and fibers,which is mainly produced in China,and its production and consumption are increasing year by year.It has the ability of environmental pollution and bioaccumulation in some organisms for a long time.With the application of TBC in many fields,people are inevitably exposed to TBC through direct or indirect ways.Herein,it is important to verify the toxic effects of TBC on the environment and organisms.The in vivo experiment was firstly used to explore the toxic target organs of TBC in Wistar rats through the pathological examination of the main organs and the whole blood test in this study,the target organ liver was clarified.Gene abundance and related protein expression of death receptor apoptosis pathway was detected to discuss its hepatotoxicity mechanism.Firstly,pre-experiment of acute toxicity in mice and in rats indicated that there was no death after 24 hours of exposure.Herein,the acute toxicity of TBC to experimental rats was non-toxic.To determine the target organ,28-day chronic toxicity feeding experiment was performed.80 Wistar rats,male and female half to half,were randomly divided into control group and TBC exposure dose groups with three doses.Slow weight growth,hair loss of luster and mental state depression were appeared after one week exposure.The pathological examination of liver,testis,ovary,brain,heart,lung,spleen and kidney showed that TBC had an obvious effect on liver,including liver swelling,inflammatory infiltration,loose cytoplasm and dark color.Also,there were phenomena such as increasing bubbles between lungs and pulmonary edema observed in lung.Other organs also showed inordinately phathological change.Liver was the target organ of TBC combined with hematological examination.The apoptosis gene FADD,FAS,FASLG,CASP8,CASP3,CASP6,CASP7,TNF,TNFRSF11B,TNFRSF10B,TNFRSF1B,TNFRSF1A,TRADD,TRAF2,XIAP mRNA abundance expression upregulated with the increase of TBC exposure dose(P<0.05).The mRNA abundance of TBC exposure group 1.250 g/(kg·bw)was significantly higher than that in the other three groups(P<0.05).Furthermore,the expression of proteins TRAIL,DR4,FAS,DR5,Caspase-8,FADD upregulated with the increase of TBC exposure dose(P<0.05),and the protein expression of 1.250 g/(kg·bw)was higher than that of the other three groups(P<0.05).Each exposure group showed a dose-response relationship.The genes and proteins of death receptor signaling pathway up-regulated with the increase of TBC exposure dose,and the key genes of apoptosis pathway were significantly correlated with proteins(P<0.05).Most of these genes were significantly correlated with trail and Fas proteins closer ties.TBC induced apoptosis related pathway factors,induced and activated TNF family,CASP family and Fas family in cell death receptor signal pathway,and then affected the corresponding protein FAS,TRAIL and Caspase family after mRNA expression,resulting in cell death.