内质网应激在邻苯二甲酸二异癸酯诱导大鼠自身免疫性甲状腺炎中的作用

Role of endoplasmic reticulum stress in autoimmune thyroiditis induced by diisodecyl phthalate among rats

目的探讨邻苯二甲酸二异癸酯(DIDP)诱发自身免疫性甲状腺炎的分子机制。方法88只SPF级雌性Wistar大鼠随机分为溶剂对照组(生理盐水)、0.15、1.5、15 mg/kg DIDP组(0.15、1.5、15 DIDP组)、甲状腺球蛋白组(TG)、0.15 DIDP+TG组、1.5 DIDP+TG组、15 DIDP+TG组、4-苯基丁酸钠(4-PBA)组、TG+4-PBA组、15 DIDP+TG+4-PBA组,连续处理42 d。检测血清中抗甲状腺球蛋白抗体(TGAb)和游离三碘甲腺原氨酸(FT3)水平,观察各组大鼠甲状腺组织病理学变化,检测甲状腺组织中维甲酸相关孤核受体γt(RORγt)、叉头框蛋白P3(FoxP3)和转录共激活因子(TAZ)表达变化。结果DIDP单独作用不能引起血清TGAb水平的显著增加;但与甲状腺球蛋白组比较,15 DIDP+TG组的组织病理学变化加重、血清TGAb水平升高,FT3水平下降,甲状腺组织RORγt和TAZ水平上调、FoxP3水平下降;而与15 DIDP+TG组相比,15DIDP+TG+4-PBA组其各项指标都有了明显的改善。结论DIDP可以激活大鼠内质网应激途径,扰乱组织Th17-Treg免疫平衡,恶化自身免疫性甲状腺炎的发生,导致甲状腺功能减退。

Objective To understand the mechanism of diisodecyl phthalate(DIDP)-induced autoimmune thyroiditis.Methods Eighty-eight SPF grade female SD rats were randomly divided into control group(saline)and three DIDP-exposed groups(0.15,1.5 and 15 mg/kg),thyroglobulin group(TG),0.15 DIDP+TG group,1.5 DIDP+TG group,15 DIDP+TG group,4-phenylbutyrate sodium(4-PBA)group,TG+4-PBA group and 15 DIDP+TG+4-PBA group,the experiment lasted for 42 days.Serum levels of thyroglobulin antibody(TGAb)and free triiodothyronine(FT3)were detected.The pathological examination of thyroid was done,and the expressions of retinoid-associated lonuclear receptorγt(RORγt),forkhead frame protein P3(FoxP3)and transcriptional coactivator(TAZ)in thyroid tissue were detected.Results DIDP alone exposure didn’t induce significant increase of serum TGAb.However,aggravated histopathological changes,higher TGAb level and lower FT3 level in serum,higher RoRγt and TAZ levels and lower Foxp3 level in thyroid were observed in 15 DIDP+TG group compared with control.Compared with the 15 DIDP+TG group,all indicators in 15 DIDP+TG+4-PBA group were significantly restored.Conclusion DIDP can disturb the Th17-Treg immune balance by activating the endoplasmic reticulum stress pathway,thereby exacerbate autoimmune thyroiditis and lead to hypothyroidism.