PCB153、P，P’-DDE单独及联合对新生期大鼠甲状腺激素的干扰作用及机制探讨
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摘要
甲状腺干扰物(Thyroid disrupting chemicals, TDCs)是指能够作用于下丘脑-垂体-甲状腺轴或直接作用于甲状腺激素受体(Thyroid Hormones Receptor,TR),影响体内甲状腺激素(Thyroid Hormones, THs)代谢及作用的外源性化合物。PCB153是生物和人体组织中含量最高的PCBs同系物,其含量与机体总PCB负荷具有很好的相关性;p,p'-DDE是DDT在环境和机体内存留时间最持久、浓度最高的代谢产物,是环境中DDT长残留期的标志物。PCBs和p,p'-DDE对人和实验动物甲状腺功能具有明显的干扰作用。
本研究以PCB153和p,p'-DDE作为受试物,以新生期SD大鼠作为研究对象,给予不同低剂量的PCB153和p,p'-DDE,建立大鼠暴露模型；本研究主要观察PCB153和p,p'-DDE单独或联合染毒对大鼠甲状腺生长发育,血清THs的影响,并探讨与THs合成、分泌、代谢密切相关的机制,旨在为进一步研究此类TDCs对甲状腺系统的毒性作用及其机制提供科学依据。
第一部分、PCB153和p,p'-DDE单独及联合染毒对大鼠甲状腺及THs的影响
目的：PCB153和p,p'-DDE单独或联合染毒对大鼠甲状腺及THs的影响。
方法：对新生期的仔鼠从出生后第3天至第15天进行染毒,隔天一次,共7次。按照1ml/kg体重的剂量,经口灌胃进行染毒。PCB153单独暴露实验：溶剂对照组,0.025mg/kg PCB153,0.25mg/kg PCB153,2.5mg/kg PCB153。p,p'-DDE单独及与PCB153联合暴露实验：溶剂对照组,0.1mg/kg,p'-DDE,1mg/kg,p'-DDE,10mg/kg p'-DDE,0.25mg/kg PCB153+1mg/kg p,p'-DDE,2.5mg/kg PCB153+10mg/kg p,p'-DDE。每次染毒前,称取动物体重(哺乳期)；染毒结束后,每周称取动物体重一次。所有动物处死后分离甲状腺、大脑、肝等器官,称重后计算脏器系数。采用ELISA试剂盒检测血清中TT4、FT4、TT3、FT3、TSH、TRH。 Morris水迷宫定位航行实验、空间探索实验衡量动物空间学习记忆能力。
结果：与对照组相比,2.5mg/kg PCB153组大鼠定位航行实验的潜伏期和总路程明显增加,差异有统计学意义(P<0.05)。在出生后21天时,与对照组相比：0.25mg/kg PCB153、2.5mg/kg PCB153组甲状腺脏器系数,差异有统计学意义(P<0.05)。与对照组相比:p,p'-DDE单独及与PCB153联合组甲状腺脏器系数、2.5mg/kg PCB153+10mg/kg p,p'-DDE组肝脏脏器系数升高,差异有统计学意义(P<0.05)。对大鼠出生后21天(PND21)血清甲状腺激素影响：与对照组相比,0.25mg/kg PCB153、2.5mg/kg PCB153组大鼠血清TT4、FT3、TT3水平、各染毒组TRH水平明显下降,差异有统计学意义(P<0.05)。与对照组相比,各暴露组大鼠血清TT4,FT3(除0.1mg/kg p,p-DDE暴露组)明显下降,差异有统计学意义(P<0.05)。在出生后50天时,与对照组相比,各暴露组大鼠血清TT4、TT3、FT4(2.5mg/kg PCB153组)、FT3(0.25mg/kg PCB153、2.5mg/kg PCB153)、TSH (0.25mg/kg PCB153、2.5mg/kg PCB153)水平明显下降,差异有统计学意义(P<0.05)。与对照组相比,各PCB153组大鼠血清TRH水平明显上升,差异有统计学意义(P<0.05)；与对照组相比,大鼠血清TT4(各暴露组)、FT4(10mg/kg p,p'-DDE组)水平明显下降,差异有统计学意义(P<0.05)。与PCB153同剂量单独暴露组相比：大鼠血清TT3、FT3水平在0.25mg/kg PCB153+lmg/kg p,p'-DDE、2.5mg/kg PCB153+10mg/kg p,p'-DDE组明显升高,差异有统计学意义(P<0.05)。析因分析表明PCB153与p,p'-DDE联合对大鼠(PND50)血清FT3水平影响存在交互作用(F=9.49,P<0.05)。
结论：PCB153、p,p'-DDE单独和／或联合暴露,会对大鼠甲状腺的生长发育产生影响。PCB153、p,p'-DDE单独和／或联合暴露后,大鼠体内甲状腺激素稳态的遭到破坏。PCB153可能会对大鼠的学习、空间记忆能力产生不良影响。
第二部分、PCB153和p,p'-DDE单独及联合染毒甲状腺干扰机制探讨
目的：研究探讨PCB153和p,p'-DDE单独及联合染毒对甲状腺的干扰机制。
方法：采用ELISA试剂盒检测血清中NIS、TG、TPO、TTR, ROS、MDA、 GSH-PX、SOD水平。用Real time RT-PCR技术检测出生50天后大鼠肝脏组织中TR (TRα1、TRβ1、TRβ2),脱碘酶(D1,D2),肝组织代谢酶(CYP1A1、 CYP2B3、 UGT1A1、UGT1A9)、甲状腺激素跨膜转运蛋白(MCT8)、视黄醇类X受体(RXRα)、ERK1/2信号通路(Kras1、KRaf1、 MEK1、ERK1、ERK2)等基因mRNA表达情况,用Western blot检测出生50天后大鼠肝脏组织中TRβ1、RXRα、总ERK1/2、磷酸化ERK1/2的蛋白表达情况。
结果：21天时,与对照组相比：大鼠血清TPO(各PCB153组)、NIS(0.25mg/kg PCB153、2.5mg/kg PCB153组)水平明显下降,差异有统计学意义(P<0.05)。PCB153染毒对大鼠血清TG、TTR水平有性别差异,与对照组同性别相比,雄与雌性大鼠在0.25mg/kg PCB153、2.5mg/kg PCB153组TG、TTR水平明显下降,差异有统计学意义(P<0.05)。与对照组相比,各PCB153染毒组大鼠血清ROS、MDA水平上升,差异有统计学意义(P<0.05)；0.25mg/kg PCB153、2.5mg/kg PCB153组GSH-PX、SOD水平明显下降,差异有统计学意义(P<0.05)。与对照组相比,各染毒组大鼠血清ROS(除0.1mg/kg p,p'-DDE暴露组)水平明显上升,差异有统计学意义(P<0.05)。50天时,与对照组相比,大鼠血清TPO水平在各PCB153组,TG水平在10mg/kg p,p'-DDE组明显下降,差异有统计学意义(P<0.05)；PCB153染毒TTR水平影响有性别差异,与对照组同性别相比,雌性大鼠在0.25mg/kg PCB153、2.5mg/kg PCB153组大鼠血清TTR水平明显下降,差异有统计学意义(P<0.05)。与对照组相比,各PCB153暴露组大鼠血清ROS、MDA水平上升,差异有统计学意义(P<0.05)；各PCB153暴露组大鼠血清GSH-PX、SOD水平明显下降,差异有统计学意义(P<0.05)。
与对照组同性别相比：雄性大鼠中,肝脏组织TRα1mRNA表达水平在各PCB153、10mg/kg p,p'-DDE, TRβ1mRNA表达水平在各PCB153(除0.25mg/kg PCB153组)、p,p'-DDE组(除1mg/kg p,p'-DDE组),TRβ2mRNA表达水平在各p,p'-DDE组中及联合组明显上升,差异有统计学意义(P<0.05)；雌性大鼠中,TRα1mRNA表达水平在2.5mg/kg PCB153组、TRβ1mRNA表达水平在10mg/kg p,p'-DDE中,TRβ2mRNA表达水平在2.5mg/kg PCB153,各p,p'-DDE(除1mg/kg p,p'-DDE组)组及联合组明显上升,差异有统计学意义(P<0.05)析因分析表明,p,p'-DDE与PCB153联合对雄性大鼠(PND50)肝脏组织TRβ1mRNA表达水平的影响存在交互作用(F=10.00,P<0.05)。
与对照组同性别相比,雄性大鼠肝脏组织D1mRNA表达水平在各PCB153组中、p,p'-DDE单独及与PCB153联合组中,D2mRNA表达水平在2.5mg/kg PCB153组中明显上升,差异有统计学意义(P<0.05)；雌性大鼠肝脏组织,D2mRNA表达水平在0.25mg/kg PCB153、2.5mg/kg PCB153、1mg/kg p,p'-DDE、 lOmg/kg p,p'-DDE、2.5mg/kg PCB153+10mg/kg p,p'-DDE组中明显上升,差异有统计学意义(P<0.05)。
与对照组同性别相比,雄性大鼠肝脏组织CYP1A1mRNA表达水平在各PCB153组、UGT1A1mRNA表达水平在各PCB153组、各p,p'-DDE单独组,UGT1A9mRNA表达水平在0.025mg/kg PCB153、2.5mg/kg PCB153组、各p,p'-DDE组中,CYP2B3mRNA表达水平在0.025mg/kg PCB153、2.5mg/kg PCB153组、各p,p'-DDE单独组中明显上升,差异有统计学意义(P<0.05)。雌性大鼠肝脏,CYP1A1mRNA表达水平在各p,p'-DDE单独组,UGT1A1mRNA表达水平在2.5mg/kg PCB153组中、UGT1A9mRNA表达水平在2.5mg/kg PCB153、10mg/kg p,p'-DDE组中明显上升,差异有统计学意义(P<0.05)。析因分析表明,p,p'-DDE与PCB153联合对雄性大鼠(PND50)肝脏组织CYP1A1mRNA表达水平的影响存在交互作用(F=10.28,P<0.05)。
与对照组同性别相比,雄性大鼠肝脏组织MCT8在各PCB153组中、1mg/kg p,p'-DDE、10mg/kg p,p'-DDE组中,RXRα mRNA表达水平在各PCB153组,10mg/kg p,p'-DDE组中明显上升,差异有统计学意义(P<0.05)；雌性大鼠肝脏组织,MCT8mRNA表达水平在10mg/kg p,p'-DDE组中明显下降,差异有统计学意义(P<0.05),RXRα mRNA表达水平在各个PCB153组中明显上升,差异有统计学意义(P<0.05)。
与对照组同性别相比,雄性大鼠肝脏组织Kras1mRNA表达水平在10mg/kg p,p'-DDE组中、Krafl mRNA表达水平在0.25mg/kg PCB153、10mg/kg p,p'-DDE组,ERK1mRNA表达水平在10mg/kg p,p'-DDE组,ERK2mRNA表达水平在0.1mg/kg p,p'-DDE、10mg/kg p,p'-DDE暴露组中明显上升,差异有统计学意义(P<0.05)；而MEK1mRNA表达水平在各PCB153暴露组中表达水平明显下降,差异有统计学意义(P<0.05),在10mg/kg p,p'-DDE组中表达水平明显上升,差异有统计学意义(P<0.05)。雌性大鼠肝脏组织Kras1mRNA表达水平在lmg/kg p,p'-DDE组中,Krafl mRNA表达水平在2.5mg/kg PCB153组,MEK1mRNA表达水平在1mg/kg p,p'-DDE组中明显上升,差异有统计学意义(P<0.05)。析因分析表明,p,p'-DDE与PCB153联合对雄性大鼠(PND50)肝脏组织Kraf1、 Kras1、MEK1mRNA表达水平的影响存在交互作用(F=8.33、6.53、8.19,P<0.05)。
与对照组同性别相比,雄性大鼠肝脏组织总ERK1/2蛋白表达水平在0.025mg/kg PCB153、2.5mg/kg PCB153、10mg/kg p,p'-DDE组中,p-ERK1/2蛋白表达水平在2.5mg/kg PCB153、10mg/kg p,p'-DDE组中,TRβ1蛋白表达水平在2.5mg/kg PCB153、01mg/kg p,p'-DDE组中,RXRα蛋白表达水平在0.25mg/kg PCB153+lmg/kg p,p'-DDE蛋白表达水平明显上升,差异有统计学意义(P<0.05)。雌性大鼠肝脏组织中RXRa蛋白表达水平在2.5mg/kgPCB153+10mg/kg p,p'-DDE组中明显上升,差异有统计学意义(P<0.05)。
结论：
1) PCB153单独暴露可以抑制TPO、NIS、TG,而p,p'-DDE则对TPO产生抑制作用,对合成THs产生影响。
2) PCB153抑制大鼠体内TTR水平,影响大鼠体内甲状腺激素转运。
3) PCB153和p,p'-DDE能上调雄性大鼠MCT8表达。
4)PCB153和p,p'-DDE能上调脱碘酶和代谢酶的基因表达,干扰THs代谢。
5) PCB153和p,p'-DDE(?)干扰肝脏TR及核受体RXRα,干扰THs稳态。
6) PCB153和p,p'-DDE能改变机体氧化应激状态,并激活ERK1/2信号通路,调节基因表达。
Thyroid disrupting chemicals (TDCs) are chemicals that affect thyroid metabolism, either through the hypothalamic-pituitary-thyroid axis or directly via nuclear receptors. Studies found that PCB153is the highest content congeners of PCBs in the biological and human tissues; p,p'-DDE, which the most important metabolite of DDT, the most persistent in the environment and the body, the highest concentration of metabolites, is a sign of the residual period of DDT in environment. The study found that the PCBs and p, p'-DDE can disrupt thyroid functions of humans and experimental animals.
In the present study, neonatal Sprague-Dawley (SD) rats were exposed to PCB153and p, p'-DDE at a lower dose, the effects of PCB153and/or p, p'-DDE on rat growth and development, THs, were observed. In addition, The ELISA, Real time-PCR, Western blot and other ways were used to detect possible mechanisms on THs synthesis, secretion, and metabolism, a variety of factors at the level of transcription or translation level. TDCs toxic effects on the thyroid system and its mechanism will provide the knowledge for further study.
Part Ⅰ, the effect of PCB153and/or p, p'-DDE on neonatal rats' thyroid and THs
Objective:To investigate the effects of PCB153and/or p, p'-DDE on neonatal rats' thyroid and THs.
Methods:Neonatal pups from postnatal3day to15day were exposed to PCB153and/or p, p'-DDE every other day at the dose of1ml/kg body weight orally. PCB153exposure experiment:solvent control group,0.025mg/kg PCB153,0.25mg/kg PCB153,2.5mg/kg PCB153. p,p'-DDE single and combibation with PCB153experiment:solvent control,0.1mg/kg p,p'-DDE,1mg/kg p,p'-DDE, lOmg/kg p'-DDE,0.25mg/kg PCB153+1mg/kg p,p'-DDE,2.5mg/kg PCB153+10mg/kg p,p'-DDE. Before every exposure, weight of animals was examed in the lactation period; after the exposure, weight of animals once a week; all animals were sacrificed after the body was weight. The thyroid, cerebrum and liver were sperated from the body, weighted; organ coefficients were calculated. ELISA kits for detection of serum TT4, FT4, TT3, FT3, TSH and TRH were used in the present study. Morris water maze navigation test and space exploration experiments to measure animal spatial memory, working memory, and spatial ability.
Results:Compared with control group, latency and total distance in navigation test in2.5mg/kg PCB153group were increased significantly, and the difference was statistically significant (P<0.05). At postnatal21, Compared with control group, thyroid-body coefficient is lower in0.25mg/kg PCB153,2.5mg/kg PCB153groups, the difference was statistically significant (P<0.05). Thyroid coefficient were increased in p,p'-DDE groups, the difference was statistically significant (P<0.05); liver organ coefficient increases in2.5mg/kg PCB153+10mg/kg p,p'-DDE, the difference was statistically significant (P<0.05). At PND21, compared with control group, serum TT4, FT3, TT3levels were significantly decreased in0.25mg/kg PCB153,2.5mg/kg PCB153groups, the difference was statistically significant (P<0.05); and so do the TRH level in every exposure group. Compared with control group, serum TT4, FT3(except0.1mg/kg p,p'-DDE group) levels were significantly decreased in every exposure group, and the difference was statistically significant (P<0.05), and so FT4levels in2.5mg/kg PCB153+10mg/kg p,p'-DDE group. At PND50, compared with control group, serum TT4, TT3levels were decreased in each exposed group, the difference was statistically significant (P<0.05), serum FT4levels in2.5mg/kg PCB153group, and FT3, TSH level in0.25mg/kg PCB153,2.5mg/kg PCB153group. But serum TRH levels were significantly increased in PCB153group, the difference was statistically significant (P<0.05). Compared with control group, serum TT4levels were significantly decreased in every exposure group, the difference was statistically significant (P<0.05), so does serum FT4levels in10mg/kg p,p'-DDE. Compared with same dose of PCB153single exposure group, serum TT3、FT3level was significantly increased in0.25mg/kg PCB153+lmg/kg p,p'-DDE,2.5mg/kg PCB153+10mg/kg p,p'-DDE group, and the difference was statistically significant (P<0.05). An interaction was found between PCB153and p, p'-DDE combined exposure on serum the FT3level (F=9.49, P<0.05).
Conclusion:PCB153and/or p, p'-DDE exposure could disrupt the growth and development of the thyroids of rats. PCB153and/or p, p'-DDE exposure will disrupt the thyroid hormone homeostasis. PCB153might be harmful to the ability of learning, spatial memory of rats.
Part Ⅱ, potential mechanisms of PCB153and/or p, p'-DDE on rats' thyroid hormone homeostasis
Objective:The present study was designed to investigate potential mechanism of PCB153and/or p, p'-DDE on thyroid hormone homeostasis.
Methods:ELISA kit for detection of serum NIS, TG, TPO, TTR, ROS, MDA, GSH-PX, SOD levels. RT-PCR were used to detect the rat (postnatal day50) hepatic mRNA expression levels of TR (TRal, TRβ1, TRβ2), deiodinase (D1, D2), liver tissue metabolic enzymes (CYP1A1, CYP2B3, UGT1A1, UGT1A9), thyroid hormone transmembrane transport protein (MCT8), retinoid X receptor (RXR alpha), ERK1/2signal pathway (Kras1, KRafl, MEK1, ERK1, ERK2), Western blot to detect the rat hepatic protein expression level of TRβ1, RXRa, total ERK1/2, phosphorylation of ERK1/2protein.
Results:At PND21, compared with control group, serum TPO levels decreased significantly in PCB153group, and the difference was statistically significant (P<0.05), and so does the serum NIS in0.25mg/kg and2.5mg/kg PCB153groups. Gender differences were tested in PCB153groups on serum TG and TTR levels, compared with the control group of the same gender, TG and TTR levels were decreased in0.25mg/kg PCB153and2.5mg/kg PCB153group, the difference was statistically significant (P<0.05). Compared with the control group, serum levels of ROS, MDA were increased in each PCB153group, the difference was statistically significant (P<0.05); but serum GSH-PX, SOD levels were decreased in0.25mg/kg PCB153,2.5mg/kg PCB153group, the difference was statistically significant (P<0.05). Compared with control group, serum ROS levels (except0.1mg/kg p, p'-DDE group) were significantly increased in p,p'-DDE group, the difference was statistically significant (P<0.05). At PND50, compared with control group, serum TPO levels were significantly decreased in PCB153group, serum TG levels in10mg/kg p,p'-DDE group, and the difference was statistically significant (P<0.05). Gender differences were found in serum TTR in PCB153group, compared with control group of the same gender, serum TTR levels were decreased significantly in0.25mg/kg PCB153,2.5mg/kg PCB153female group, and the difference was statistically significant (P<0.05). Compared with control group, serum levels of ROS and MDA levels were increased in PCB153group, the difference was statistically significant (P<0.05); serum GSH-PX, SOD levels were significantly decreased in PCB153group, the difference was statistically significant (P<0.05).
Compared with control group of the same gender, in male rats, the mRNA expression levels of TRα1in each PCB153group, lOmg/kg p,p'-DDE group, TRβ1in PCB153group (except0.25mg/kg group), p,p'-DDE group (except lmg/kg p,p'-DDE group), TRβ2in each p,p'-DDE group and combination groups were significantly increased, difference was statistically significant (P<0.05). In female rats, mRNA expression levels of TRal in2.5mg/kg PCB153group, TRβ1in10mg/kg p,p'-DDE group, TRβ2in2.5mg/kg PCB153, each p,p'-DDE group (except1mg/kg p, p'-DDE exposure group) and combination groups were significantly increased, difference was statistically significant (P<0.05). An interaction was found between PCB153and p,p'-DDE exposure on mRNA expression levels of TRβ1(F=10.00, P<0.05).
Compared with control group of the same gender, in male rats, the mRNA expression levels of D1in each PCB153group, p, p'-DDE group and combination groups, D2in2.5mg/kg PCB153group was significantly increased, the difference was statistically significant (P<0.05). In female rats, the mRNA expression levels of D2in0.25mg/kg PCB153,2.5mg/kg PCB153,1mg/kg p,p'-DDE,10mg/kg p,p'-DDE,2.5mg/kg PCB153+10mg/kg p, p'-DDE group, were significantly increased, the difference was statistically significant (P<0.05).
Compared with control group of the same gender, in male rats, the mRNA expression levels of CYP1A1in each PCB153group, UGT1A1in each PCB153group, p, p'-DDE group, UGT1A9in0.025mg/kg PCB153,2.5mg/kg PCB153group, each p,p'-DDE groups, CYP2B3in0.025mg/kg PCB153,2.5mg/kg PCB153group, each p, p'-DDE group were significantly increased, the difference was statistically significant (P<0.05); In female rats, the mRNA expression levels of CYP1A1in p, p'-DDE group, UGT1A1in2.5mg/kg PCB153, UGT1A9in2.5mg/kg PCB153, lOmg/kg p, p'-DDE group were significantly increased, the difference was statistically significant (P<0.05). An interaction was found between PCB153and p,p'-DDE combination exposure on mRNA expression levels of CYP1A1(F=10.28, P<0.05).
Compared with control group of the same gender, in male rats, the mRNA expression levels of MCT8in each PCB153group,1mg/kg p,p'-DDE,10mg/kg p,p'-DDE group, RXRa in each PCB153group,10mg/kg p,p'-DDE group were significantly increased, the difference was statistically significant (P<0.05); In female rats, the mRNA expression levels of MCT8in lOmg/kg p,p'-DDE group were significantly decreased, the difference was statistically significant (P<0.05), the mRNA expression levels of RXRa in each PCB153group were significantly increased, the difference was statistically significant (P<0.05).
Compared with control group of the same gender, in male rats, the mRNA expression levels of Krasl in lOmg/kg p,p'-DDE group, Krafl in0.25mg/kg PCB153and10mg/kg p, p'-DDE group, ERK1in10mg/kg p,p'-DDE group, ERK2in0.1mg/kg p,p'-DDE, lOmg/kg p,p'-DDE group were significantly increased, and the difference was statistically significant (P<0.05), and the mRNA expression levels of MEK1in each PCB153group were decreased, but in0mg/kg p,p'-DDE group significantly increased, the difference was statistically significant (P<0.05). In female rats, the mRNA expression levels of Krasl in lmg/kg p,p'-DDE group, Krafl in2.5mg/kg PCB153group, MEK1in lmg/kg p,p'-DDE exposure group, were significantly increased, the difference was statistically significant (P<0.05). interactions was found between PCB153and p,p'-DDE combination exposure on mRNA expression levels of Krafl, Krasl, MEK1(F=8.33,6.53,8.19, P<0.05).
Compared with control group of the same gender, in male rats, the protein expression levels of total ERK1/2in0.025mg/kg PCB153,2.5mg/kg PCB153,10mg/kg p,p'-DDE group, p-ERK1/2in2.5mg/kg PCB153,10mg/kg p,p'-DDE group, TRβ1in2.5mg/kg PCB153+10mg/kg p,p'-DDE group, RXRa in2.5mg/kg PCB153+10mg/kg p,p'-DDE were significantly increased, and difference was statistically significant (P<0.05). In female rats, the protein expression levels of RXRa in2.5mg/kg PCB153+10mg/kg p,p'-DDE group were significantly increased, the difference was statistically significant (P<0.05).
Conclusion:
1) PCB153exposure can inhibit the serum levels of TPO, NIS, TG while p, p'-DDE inhibit that of TPO, which could disrupt the synthesis of thyroid hormones.
2) PCB153exposure can inhibit the serum levels of TTR, disrupting the thyroid hormone transporter in the blood.
3) PCB153and p,p'-DDE can upregulate hepatic mRNA expression of MCT8in male rats.
4) PCB153and p,p'-DDE can upregulate hepatic mRNA expression of deiodinase gene and hepatic metabolic enzymes disrupting the thyroid hormone metabolism.
5)PCB153and p,p'-DDE can upregulate hepatic mRNA expression of TR, and the nuclear receptor RXRa to disrupt thyroid hormone homeostasis.
6) PCB153and p, p'-DDE change oxidative stress level of body in the rats, and activated ERK1/2signaling pathways.
本研究以PCB153和p,p'-DDE作为受试物,以新生期SD大鼠作为研究对象,给予不同低剂量的PCB153和p,p'-DDE,建立大鼠暴露模型；本研究主要观察PCB153和p,p'-DDE单独或联合染毒对大鼠甲状腺生长发育,血清THs的影响,并探讨与THs合成、分泌、代谢密切相关的机制,旨在为进一步研究此类TDCs对甲状腺系统的毒性作用及其机制提供科学依据。
第一部分、PCB153和p,p'-DDE单独及联合染毒对大鼠甲状腺及THs的影响
目的：PCB153和p,p'-DDE单独或联合染毒对大鼠甲状腺及THs的影响。
方法：对新生期的仔鼠从出生后第3天至第15天进行染毒,隔天一次,共7次。按照1ml/kg体重的剂量,经口灌胃进行染毒。PCB153单独暴露实验：溶剂对照组,0.025mg/kg PCB153,0.25mg/kg PCB153,2.5mg/kg PCB153。p,p'-DDE单独及与PCB153联合暴露实验：溶剂对照组,0.1mg/kg,p'-DDE,1mg/kg,p'-DDE,10mg/kg p'-DDE,0.25mg/kg PCB153+1mg/kg p,p'-DDE,2.5mg/kg PCB153+10mg/kg p,p'-DDE。每次染毒前,称取动物体重(哺乳期)；染毒结束后,每周称取动物体重一次。所有动物处死后分离甲状腺、大脑、肝等器官,称重后计算脏器系数。采用ELISA试剂盒检测血清中TT4、FT4、TT3、FT3、TSH、TRH。 Morris水迷宫定位航行实验、空间探索实验衡量动物空间学习记忆能力。
结果：与对照组相比,2.5mg/kg PCB153组大鼠定位航行实验的潜伏期和总路程明显增加,差异有统计学意义(P<0.05)。在出生后21天时,与对照组相比：0.25mg/kg PCB153、2.5mg/kg PCB153组甲状腺脏器系数,差异有统计学意义(P<0.05)。与对照组相比:p,p'-DDE单独及与PCB153联合组甲状腺脏器系数、2.5mg/kg PCB153+10mg/kg p,p'-DDE组肝脏脏器系数升高,差异有统计学意义(P<0.05)。对大鼠出生后21天(PND21)血清甲状腺激素影响：与对照组相比,0.25mg/kg PCB153、2.5mg/kg PCB153组大鼠血清TT4、FT3、TT3水平、各染毒组TRH水平明显下降,差异有统计学意义(P<0.05)。与对照组相比,各暴露组大鼠血清TT4,FT3(除0.1mg/kg p,p-DDE暴露组)明显下降,差异有统计学意义(P<0.05)。在出生后50天时,与对照组相比,各暴露组大鼠血清TT4、TT3、FT4(2.5mg/kg PCB153组)、FT3(0.25mg/kg PCB153、2.5mg/kg PCB153)、TSH (0.25mg/kg PCB153、2.5mg/kg PCB153)水平明显下降,差异有统计学意义(P<0.05)。与对照组相比,各PCB153组大鼠血清TRH水平明显上升,差异有统计学意义(P<0.05)；与对照组相比,大鼠血清TT4(各暴露组)、FT4(10mg/kg p,p'-DDE组)水平明显下降,差异有统计学意义(P<0.05)。与PCB153同剂量单独暴露组相比：大鼠血清TT3、FT3水平在0.25mg/kg PCB153+lmg/kg p,p'-DDE、2.5mg/kg PCB153+10mg/kg p,p'-DDE组明显升高,差异有统计学意义(P<0.05)。析因分析表明PCB153与p,p'-DDE联合对大鼠(PND50)血清FT3水平影响存在交互作用(F=9.49,P<0.05)。
结论：PCB153、p,p'-DDE单独和／或联合暴露,会对大鼠甲状腺的生长发育产生影响。PCB153、p,p'-DDE单独和／或联合暴露后,大鼠体内甲状腺激素稳态的遭到破坏。PCB153可能会对大鼠的学习、空间记忆能力产生不良影响。
第二部分、PCB153和p,p'-DDE单独及联合染毒甲状腺干扰机制探讨
目的：研究探讨PCB153和p,p'-DDE单独及联合染毒对甲状腺的干扰机制。
方法：采用ELISA试剂盒检测血清中NIS、TG、TPO、TTR, ROS、MDA、 GSH-PX、SOD水平。用Real time RT-PCR技术检测出生50天后大鼠肝脏组织中TR (TRα1、TRβ1、TRβ2),脱碘酶(D1,D2),肝组织代谢酶(CYP1A1、 CYP2B3、 UGT1A1、UGT1A9)、甲状腺激素跨膜转运蛋白(MCT8)、视黄醇类X受体(RXRα)、ERK1/2信号通路(Kras1、KRaf1、 MEK1、ERK1、ERK2)等基因mRNA表达情况,用Western blot检测出生50天后大鼠肝脏组织中TRβ1、RXRα、总ERK1/2、磷酸化ERK1/2的蛋白表达情况。
结果：21天时,与对照组相比：大鼠血清TPO(各PCB153组)、NIS(0.25mg/kg PCB153、2.5mg/kg PCB153组)水平明显下降,差异有统计学意义(P<0.05)。PCB153染毒对大鼠血清TG、TTR水平有性别差异,与对照组同性别相比,雄与雌性大鼠在0.25mg/kg PCB153、2.5mg/kg PCB153组TG、TTR水平明显下降,差异有统计学意义(P<0.05)。与对照组相比,各PCB153染毒组大鼠血清ROS、MDA水平上升,差异有统计学意义(P<0.05)；0.25mg/kg PCB153、2.5mg/kg PCB153组GSH-PX、SOD水平明显下降,差异有统计学意义(P<0.05)。与对照组相比,各染毒组大鼠血清ROS(除0.1mg/kg p,p'-DDE暴露组)水平明显上升,差异有统计学意义(P<0.05)。50天时,与对照组相比,大鼠血清TPO水平在各PCB153组,TG水平在10mg/kg p,p'-DDE组明显下降,差异有统计学意义(P<0.05)；PCB153染毒TTR水平影响有性别差异,与对照组同性别相比,雌性大鼠在0.25mg/kg PCB153、2.5mg/kg PCB153组大鼠血清TTR水平明显下降,差异有统计学意义(P<0.05)。与对照组相比,各PCB153暴露组大鼠血清ROS、MDA水平上升,差异有统计学意义(P<0.05)；各PCB153暴露组大鼠血清GSH-PX、SOD水平明显下降,差异有统计学意义(P<0.05)。
与对照组同性别相比：雄性大鼠中,肝脏组织TRα1mRNA表达水平在各PCB153、10mg/kg p,p'-DDE, TRβ1mRNA表达水平在各PCB153(除0.25mg/kg PCB153组)、p,p'-DDE组(除1mg/kg p,p'-DDE组),TRβ2mRNA表达水平在各p,p'-DDE组中及联合组明显上升,差异有统计学意义(P<0.05)；雌性大鼠中,TRα1mRNA表达水平在2.5mg/kg PCB153组、TRβ1mRNA表达水平在10mg/kg p,p'-DDE中,TRβ2mRNA表达水平在2.5mg/kg PCB153,各p,p'-DDE(除1mg/kg p,p'-DDE组)组及联合组明显上升,差异有统计学意义(P<0.05)析因分析表明,p,p'-DDE与PCB153联合对雄性大鼠(PND50)肝脏组织TRβ1mRNA表达水平的影响存在交互作用(F=10.00,P<0.05)。
与对照组同性别相比,雄性大鼠肝脏组织D1mRNA表达水平在各PCB153组中、p,p'-DDE单独及与PCB153联合组中,D2mRNA表达水平在2.5mg/kg PCB153组中明显上升,差异有统计学意义(P<0.05)；雌性大鼠肝脏组织,D2mRNA表达水平在0.25mg/kg PCB153、2.5mg/kg PCB153、1mg/kg p,p'-DDE、 lOmg/kg p,p'-DDE、2.5mg/kg PCB153+10mg/kg p,p'-DDE组中明显上升,差异有统计学意义(P<0.05)。
与对照组同性别相比,雄性大鼠肝脏组织CYP1A1mRNA表达水平在各PCB153组、UGT1A1mRNA表达水平在各PCB153组、各p,p'-DDE单独组,UGT1A9mRNA表达水平在0.025mg/kg PCB153、2.5mg/kg PCB153组、各p,p'-DDE组中,CYP2B3mRNA表达水平在0.025mg/kg PCB153、2.5mg/kg PCB153组、各p,p'-DDE单独组中明显上升,差异有统计学意义(P<0.05)。雌性大鼠肝脏,CYP1A1mRNA表达水平在各p,p'-DDE单独组,UGT1A1mRNA表达水平在2.5mg/kg PCB153组中、UGT1A9mRNA表达水平在2.5mg/kg PCB153、10mg/kg p,p'-DDE组中明显上升,差异有统计学意义(P<0.05)。析因分析表明,p,p'-DDE与PCB153联合对雄性大鼠(PND50)肝脏组织CYP1A1mRNA表达水平的影响存在交互作用(F=10.28,P<0.05)。
与对照组同性别相比,雄性大鼠肝脏组织MCT8在各PCB153组中、1mg/kg p,p'-DDE、10mg/kg p,p'-DDE组中,RXRα mRNA表达水平在各PCB153组,10mg/kg p,p'-DDE组中明显上升,差异有统计学意义(P<0.05)；雌性大鼠肝脏组织,MCT8mRNA表达水平在10mg/kg p,p'-DDE组中明显下降,差异有统计学意义(P<0.05),RXRα mRNA表达水平在各个PCB153组中明显上升,差异有统计学意义(P<0.05)。
与对照组同性别相比,雄性大鼠肝脏组织Kras1mRNA表达水平在10mg/kg p,p'-DDE组中、Krafl mRNA表达水平在0.25mg/kg PCB153、10mg/kg p,p'-DDE组,ERK1mRNA表达水平在10mg/kg p,p'-DDE组,ERK2mRNA表达水平在0.1mg/kg p,p'-DDE、10mg/kg p,p'-DDE暴露组中明显上升,差异有统计学意义(P<0.05)；而MEK1mRNA表达水平在各PCB153暴露组中表达水平明显下降,差异有统计学意义(P<0.05),在10mg/kg p,p'-DDE组中表达水平明显上升,差异有统计学意义(P<0.05)。雌性大鼠肝脏组织Kras1mRNA表达水平在lmg/kg p,p'-DDE组中,Krafl mRNA表达水平在2.5mg/kg PCB153组,MEK1mRNA表达水平在1mg/kg p,p'-DDE组中明显上升,差异有统计学意义(P<0.05)。析因分析表明,p,p'-DDE与PCB153联合对雄性大鼠(PND50)肝脏组织Kraf1、 Kras1、MEK1mRNA表达水平的影响存在交互作用(F=8.33、6.53、8.19,P<0.05)。
与对照组同性别相比,雄性大鼠肝脏组织总ERK1/2蛋白表达水平在0.025mg/kg PCB153、2.5mg/kg PCB153、10mg/kg p,p'-DDE组中,p-ERK1/2蛋白表达水平在2.5mg/kg PCB153、10mg/kg p,p'-DDE组中,TRβ1蛋白表达水平在2.5mg/kg PCB153、01mg/kg p,p'-DDE组中,RXRα蛋白表达水平在0.25mg/kg PCB153+lmg/kg p,p'-DDE蛋白表达水平明显上升,差异有统计学意义(P<0.05)。雌性大鼠肝脏组织中RXRa蛋白表达水平在2.5mg/kgPCB153+10mg/kg p,p'-DDE组中明显上升,差异有统计学意义(P<0.05)。
结论：
1) PCB153单独暴露可以抑制TPO、NIS、TG,而p,p'-DDE则对TPO产生抑制作用,对合成THs产生影响。
2) PCB153抑制大鼠体内TTR水平,影响大鼠体内甲状腺激素转运。
3) PCB153和p,p'-DDE能上调雄性大鼠MCT8表达。
4)PCB153和p,p'-DDE能上调脱碘酶和代谢酶的基因表达,干扰THs代谢。
5) PCB153和p,p'-DDE(?)干扰肝脏TR及核受体RXRα,干扰THs稳态。
6) PCB153和p,p'-DDE能改变机体氧化应激状态,并激活ERK1/2信号通路,调节基因表达。
Thyroid disrupting chemicals (TDCs) are chemicals that affect thyroid metabolism, either through the hypothalamic-pituitary-thyroid axis or directly via nuclear receptors. Studies found that PCB153is the highest content congeners of PCBs in the biological and human tissues; p,p'-DDE, which the most important metabolite of DDT, the most persistent in the environment and the body, the highest concentration of metabolites, is a sign of the residual period of DDT in environment. The study found that the PCBs and p, p'-DDE can disrupt thyroid functions of humans and experimental animals.
In the present study, neonatal Sprague-Dawley (SD) rats were exposed to PCB153and p, p'-DDE at a lower dose, the effects of PCB153and/or p, p'-DDE on rat growth and development, THs, were observed. In addition, The ELISA, Real time-PCR, Western blot and other ways were used to detect possible mechanisms on THs synthesis, secretion, and metabolism, a variety of factors at the level of transcription or translation level. TDCs toxic effects on the thyroid system and its mechanism will provide the knowledge for further study.
Part Ⅰ, the effect of PCB153and/or p, p'-DDE on neonatal rats' thyroid and THs
Objective:To investigate the effects of PCB153and/or p, p'-DDE on neonatal rats' thyroid and THs.
Methods:Neonatal pups from postnatal3day to15day were exposed to PCB153and/or p, p'-DDE every other day at the dose of1ml/kg body weight orally. PCB153exposure experiment:solvent control group,0.025mg/kg PCB153,0.25mg/kg PCB153,2.5mg/kg PCB153. p,p'-DDE single and combibation with PCB153experiment:solvent control,0.1mg/kg p,p'-DDE,1mg/kg p,p'-DDE, lOmg/kg p'-DDE,0.25mg/kg PCB153+1mg/kg p,p'-DDE,2.5mg/kg PCB153+10mg/kg p,p'-DDE. Before every exposure, weight of animals was examed in the lactation period; after the exposure, weight of animals once a week; all animals were sacrificed after the body was weight. The thyroid, cerebrum and liver were sperated from the body, weighted; organ coefficients were calculated. ELISA kits for detection of serum TT4, FT4, TT3, FT3, TSH and TRH were used in the present study. Morris water maze navigation test and space exploration experiments to measure animal spatial memory, working memory, and spatial ability.
Results:Compared with control group, latency and total distance in navigation test in2.5mg/kg PCB153group were increased significantly, and the difference was statistically significant (P<0.05). At postnatal21, Compared with control group, thyroid-body coefficient is lower in0.25mg/kg PCB153,2.5mg/kg PCB153groups, the difference was statistically significant (P<0.05). Thyroid coefficient were increased in p,p'-DDE groups, the difference was statistically significant (P<0.05); liver organ coefficient increases in2.5mg/kg PCB153+10mg/kg p,p'-DDE, the difference was statistically significant (P<0.05). At PND21, compared with control group, serum TT4, FT3, TT3levels were significantly decreased in0.25mg/kg PCB153,2.5mg/kg PCB153groups, the difference was statistically significant (P<0.05); and so do the TRH level in every exposure group. Compared with control group, serum TT4, FT3(except0.1mg/kg p,p'-DDE group) levels were significantly decreased in every exposure group, and the difference was statistically significant (P<0.05), and so FT4levels in2.5mg/kg PCB153+10mg/kg p,p'-DDE group. At PND50, compared with control group, serum TT4, TT3levels were decreased in each exposed group, the difference was statistically significant (P<0.05), serum FT4levels in2.5mg/kg PCB153group, and FT3, TSH level in0.25mg/kg PCB153,2.5mg/kg PCB153group. But serum TRH levels were significantly increased in PCB153group, the difference was statistically significant (P<0.05). Compared with control group, serum TT4levels were significantly decreased in every exposure group, the difference was statistically significant (P<0.05), so does serum FT4levels in10mg/kg p,p'-DDE. Compared with same dose of PCB153single exposure group, serum TT3、FT3level was significantly increased in0.25mg/kg PCB153+lmg/kg p,p'-DDE,2.5mg/kg PCB153+10mg/kg p,p'-DDE group, and the difference was statistically significant (P<0.05). An interaction was found between PCB153and p, p'-DDE combined exposure on serum the FT3level (F=9.49, P<0.05).
Conclusion:PCB153and/or p, p'-DDE exposure could disrupt the growth and development of the thyroids of rats. PCB153and/or p, p'-DDE exposure will disrupt the thyroid hormone homeostasis. PCB153might be harmful to the ability of learning, spatial memory of rats.
Part Ⅱ, potential mechanisms of PCB153and/or p, p'-DDE on rats' thyroid hormone homeostasis
Objective:The present study was designed to investigate potential mechanism of PCB153and/or p, p'-DDE on thyroid hormone homeostasis.
Methods:ELISA kit for detection of serum NIS, TG, TPO, TTR, ROS, MDA, GSH-PX, SOD levels. RT-PCR were used to detect the rat (postnatal day50) hepatic mRNA expression levels of TR (TRal, TRβ1, TRβ2), deiodinase (D1, D2), liver tissue metabolic enzymes (CYP1A1, CYP2B3, UGT1A1, UGT1A9), thyroid hormone transmembrane transport protein (MCT8), retinoid X receptor (RXR alpha), ERK1/2signal pathway (Kras1, KRafl, MEK1, ERK1, ERK2), Western blot to detect the rat hepatic protein expression level of TRβ1, RXRa, total ERK1/2, phosphorylation of ERK1/2protein.
Results:At PND21, compared with control group, serum TPO levels decreased significantly in PCB153group, and the difference was statistically significant (P<0.05), and so does the serum NIS in0.25mg/kg and2.5mg/kg PCB153groups. Gender differences were tested in PCB153groups on serum TG and TTR levels, compared with the control group of the same gender, TG and TTR levels were decreased in0.25mg/kg PCB153and2.5mg/kg PCB153group, the difference was statistically significant (P<0.05). Compared with the control group, serum levels of ROS, MDA were increased in each PCB153group, the difference was statistically significant (P<0.05); but serum GSH-PX, SOD levels were decreased in0.25mg/kg PCB153,2.5mg/kg PCB153group, the difference was statistically significant (P<0.05). Compared with control group, serum ROS levels (except0.1mg/kg p, p'-DDE group) were significantly increased in p,p'-DDE group, the difference was statistically significant (P<0.05). At PND50, compared with control group, serum TPO levels were significantly decreased in PCB153group, serum TG levels in10mg/kg p,p'-DDE group, and the difference was statistically significant (P<0.05). Gender differences were found in serum TTR in PCB153group, compared with control group of the same gender, serum TTR levels were decreased significantly in0.25mg/kg PCB153,2.5mg/kg PCB153female group, and the difference was statistically significant (P<0.05). Compared with control group, serum levels of ROS and MDA levels were increased in PCB153group, the difference was statistically significant (P<0.05); serum GSH-PX, SOD levels were significantly decreased in PCB153group, the difference was statistically significant (P<0.05).
Compared with control group of the same gender, in male rats, the mRNA expression levels of TRα1in each PCB153group, lOmg/kg p,p'-DDE group, TRβ1in PCB153group (except0.25mg/kg group), p,p'-DDE group (except lmg/kg p,p'-DDE group), TRβ2in each p,p'-DDE group and combination groups were significantly increased, difference was statistically significant (P<0.05). In female rats, mRNA expression levels of TRal in2.5mg/kg PCB153group, TRβ1in10mg/kg p,p'-DDE group, TRβ2in2.5mg/kg PCB153, each p,p'-DDE group (except1mg/kg p, p'-DDE exposure group) and combination groups were significantly increased, difference was statistically significant (P<0.05). An interaction was found between PCB153and p,p'-DDE exposure on mRNA expression levels of TRβ1(F=10.00, P<0.05).
Compared with control group of the same gender, in male rats, the mRNA expression levels of D1in each PCB153group, p, p'-DDE group and combination groups, D2in2.5mg/kg PCB153group was significantly increased, the difference was statistically significant (P<0.05). In female rats, the mRNA expression levels of D2in0.25mg/kg PCB153,2.5mg/kg PCB153,1mg/kg p,p'-DDE,10mg/kg p,p'-DDE,2.5mg/kg PCB153+10mg/kg p, p'-DDE group, were significantly increased, the difference was statistically significant (P<0.05).
Compared with control group of the same gender, in male rats, the mRNA expression levels of CYP1A1in each PCB153group, UGT1A1in each PCB153group, p, p'-DDE group, UGT1A9in0.025mg/kg PCB153,2.5mg/kg PCB153group, each p,p'-DDE groups, CYP2B3in0.025mg/kg PCB153,2.5mg/kg PCB153group, each p, p'-DDE group were significantly increased, the difference was statistically significant (P<0.05); In female rats, the mRNA expression levels of CYP1A1in p, p'-DDE group, UGT1A1in2.5mg/kg PCB153, UGT1A9in2.5mg/kg PCB153, lOmg/kg p, p'-DDE group were significantly increased, the difference was statistically significant (P<0.05). An interaction was found between PCB153and p,p'-DDE combination exposure on mRNA expression levels of CYP1A1(F=10.28, P<0.05).
Compared with control group of the same gender, in male rats, the mRNA expression levels of MCT8in each PCB153group,1mg/kg p,p'-DDE,10mg/kg p,p'-DDE group, RXRa in each PCB153group,10mg/kg p,p'-DDE group were significantly increased, the difference was statistically significant (P<0.05); In female rats, the mRNA expression levels of MCT8in lOmg/kg p,p'-DDE group were significantly decreased, the difference was statistically significant (P<0.05), the mRNA expression levels of RXRa in each PCB153group were significantly increased, the difference was statistically significant (P<0.05).
Compared with control group of the same gender, in male rats, the mRNA expression levels of Krasl in lOmg/kg p,p'-DDE group, Krafl in0.25mg/kg PCB153and10mg/kg p, p'-DDE group, ERK1in10mg/kg p,p'-DDE group, ERK2in0.1mg/kg p,p'-DDE, lOmg/kg p,p'-DDE group were significantly increased, and the difference was statistically significant (P<0.05), and the mRNA expression levels of MEK1in each PCB153group were decreased, but in0mg/kg p,p'-DDE group significantly increased, the difference was statistically significant (P<0.05). In female rats, the mRNA expression levels of Krasl in lmg/kg p,p'-DDE group, Krafl in2.5mg/kg PCB153group, MEK1in lmg/kg p,p'-DDE exposure group, were significantly increased, the difference was statistically significant (P<0.05). interactions was found between PCB153and p,p'-DDE combination exposure on mRNA expression levels of Krafl, Krasl, MEK1(F=8.33,6.53,8.19, P<0.05).
Compared with control group of the same gender, in male rats, the protein expression levels of total ERK1/2in0.025mg/kg PCB153,2.5mg/kg PCB153,10mg/kg p,p'-DDE group, p-ERK1/2in2.5mg/kg PCB153,10mg/kg p,p'-DDE group, TRβ1in2.5mg/kg PCB153+10mg/kg p,p'-DDE group, RXRa in2.5mg/kg PCB153+10mg/kg p,p'-DDE were significantly increased, and difference was statistically significant (P<0.05). In female rats, the protein expression levels of RXRa in2.5mg/kg PCB153+10mg/kg p,p'-DDE group were significantly increased, the difference was statistically significant (P<0.05).
Conclusion:
1) PCB153exposure can inhibit the serum levels of TPO, NIS, TG while p, p'-DDE inhibit that of TPO, which could disrupt the synthesis of thyroid hormones.
2) PCB153exposure can inhibit the serum levels of TTR, disrupting the thyroid hormone transporter in the blood.
3) PCB153and p,p'-DDE can upregulate hepatic mRNA expression of MCT8in male rats.
4) PCB153and p,p'-DDE can upregulate hepatic mRNA expression of deiodinase gene and hepatic metabolic enzymes disrupting the thyroid hormone metabolism.
5)PCB153and p,p'-DDE can upregulate hepatic mRNA expression of TR, and the nuclear receptor RXRa to disrupt thyroid hormone homeostasis.
6) PCB153and p, p'-DDE change oxidative stress level of body in the rats, and activated ERK1/2signaling pathways.
引文
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