环境内分泌干扰物对垂体—性腺轴相关基因调控网络的不良影响及其中药治疗的拮抗作用机制
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摘要
目的:(1)通过染毒动物实验,观察环境内分泌干扰物(environmentalendocrine disruptor,EEDs)的拟雌激素作用及中药对其拟雌激素活性的拮抗作用,以验证既往的临床研究结果。(2)采用功能基因组学方法,研究EEDs对垂体—性腺轴功能相关的基因调控网络的不良影响及其中药治疗干预的拮抗作用,以阐明中药拮抗作用的机制。
方法:(1)以三周龄的雌性SD大鼠为实验对象,选取具有代表性的EEDs—壬基酚(4-nonylphenol,NP)、双酚A(bisphenol A,BPA)作为染毒物质,复制NP单独染毒及NP+BPA联合染毒的动物模型,治疗组同时喂饲中药,进行治疗干预,疗程15天。以子宫湿重、子宫脏器系数、子宫内膜上皮细胞高度、子宫内膜腺体数及腺上皮高度,环形平滑肌厚度、子宫内膜及肌层的细胞增殖核抗原(proliferating cell nuclear antigen,PCNA)蛋白表达水平及雌激素受体蛋白(estrogen receptor,ER)表达水平(免疫组织化学方法)作为检测指标,采用单因素方差分析进行统计分析,观察EEDs的拟雌激素作用及中药对其拟雌激素活性的拮抗作用。(2)采用illumina大鼠全基因组表达谱芯片(ratref-12),在与垂体—性腺轴功能相关的系列基因中大规模筛选其表达谱受EEDs染毒后产生显著变化而中药治疗干预可产生显著拮抗作用的基因。对筛选出的系列基因再采用实时荧光定量聚合酶链式反应(real-time FQ-PCR)及免疫印迹方法(westernblot)分别从基因表达及蛋白表达的水平进一步加以验证。结果采用单因素方差分析。(3)对芯片关注及验证确定的所有相关基因,按三个功能系列加以分类:①垂体促性腺激素释放激素受体(GnRHR)及受体后信号转导通路相关的系列基因。②卵巢雌激素受体及受体后信号转导通路相关的系列基因。③卵巢上与雌激素合成代谢相关的系列酶基因。
结果:(1)染毒组与对照组比较,子宫湿重、子宫脏器系数、子宫内膜上皮细胞高度、子宫内膜腺体数及腺上皮高度、环形平滑肌厚度显著增加(p＜0.05),子宫内膜及肌层的PCNA蛋白表达、ER蛋白表达显著增高(p＜0.05)。治疗组与染毒组相比,上述各指标均明显降低(p＜0.05)。(2)Illumina Beadchip基因芯片(ratref-12)分析结果显示,垂体GnRHR及受体后信号转导通路相关的系列基因中,在染毒及中药干预治疗8天时,LHβ、FSHβ的mRNA均表现为染毒组表达上调、治疗组表达下调。GnRH受体后信号转导通路中的磷脂酶C(PLCd1、PLC11、PLCb2、PLCg2)、二酰甘油DG(DGat2、DGkq)、蛋白激酶CPKC(PrKCb1)、脂氧合酶(Atox15、Alox5、Alox3、Alox12)、白细胞三烯(1tb4r2、1te4s、1tb4dh)在染毒组表达水平上调,治疗组表达水平下调。脂氧合酶Alox15在芯片中表现为差异基因;卵巢雌激素受体及受体后信号转导通路相关的系列基因中,ERα、ERβmRNA在染毒后8、15天均表达上调、治疗后表达下调。ER的共激活因子Sra1、交叉对话的EGF、EGFR、IGFb2、IGFr2 mRNA表达染毒后上调、治疗后下调。其中EGFR在芯片上表现为差异基因,变化趋势与ER相一致;卵巢上与雌激素合成代谢相关的系列酶基因中,染毒组与对照组比较,表达上调的差异基因有stAR、CYP19a1。而治疗组与染毒组比较,表达水平下调的差异基因有stAR、CYP11A1。(3)经real-time PCR及westernblot进一步验证结果显示,NP及BPA染毒可使卵巢ERα、ERβ、EGFR、StAR、CYP19a1的mRNA水平显著上调(p＜0.05),ERα、ERβ、stAR、CYP19a1、Cyp11A1蛋白表达明显增加(p＜0.05);中药干预则可使ERα、ERβ、EGFR、stAR、Cyp11a1的mRNA水平显著下调(p＜0.05),ERα、ERβ、stAR、Cyp11A1蛋白表达显著减少(p＜0.05)。
结论:(1)通过染毒动物实验,证实了EEDs的拟雌激素活性及中药治疗干预对其拟雌激素活性具有显著的拮抗作用,验证了我们既往的临床研究结果。(2)EEDs可显著促进与垂体-性腺轴功能相关的系列基因的表达水平上调,从而发挥其拟雌激素活性。(3)中药治疗干预可明显抑制EEDs对垂体-性腺轴功能相关的系列基因表达的不良影响,从而有效地拮抗EEDs的拟雌激素活性。
Objective:(1)To investigate the estrognic effects of environmental endocrine disruptors(EEDs) and to test the antagonistic effects of traditional Chinese medicine on the estrogenic animal model induced by EEDs.(2) To investigate the adverse effects of EEDs on the gene regulative network related to pituitary-gonadal axis in rats using the functionally genomic analysis.Furthermore,the mechanisms of estrogen antagonistic action of traditional Chinese medicine on the estrogenic rats were also explored.
Methods:(1) The estrogenic animal models were induced by the administration of the representative EEDs such as 4-nonylphenol(NP) alone,or by the co-administration of NP and bisphenol A(BPA) in the female SD rat at the age of three-week-old.For testing the preventive action of traditional Chinese medicine on the estrogenic rat induced by the abovementioned EEDs,traditional Chinese medicine was also i.g.administered to the rat when the animal model was producing.After 15-day course of treatment with or without traditional Chinese medicine,the uterine wet weight,uterus organ coefficient,height of endometrium epithelium,endometrial glands,myometrium thickness,protein level of proliferating cell nuclear antigen (PCNA) in the endometrium and myometrium and the estrogen receptor(ER) expression in the rat uterine were measured and analyzed by one-way ANOVA.(2) The gene expression profiles in pituitary—ovarian axis of rats which were fed with NP+BPA or co-treatment with traditional Chinese medicine respectively were detected by Illumina Beadchip(ratref-12).The expression of genes which could be influenced significantly by EEDs and reversely affected by traditional Chinese medicine was analyzed.Moreover,the screened genes which are closely related to sexual development were further verified by real-time polymerase chain reaction (real-time PCR)and western blotting.Significance was analyzed by one-way ANOVA. (3)All the screened and verified genes were categorized into three groups according to their functions,i.e.1) Genes related to GnRHR and GnRHR receptor-mediated signal transduction pathway;2) Genes related to ER and ER-mediated signal transduction pathway and 3) Enzymes involved in the estrogen metabolism in ovary.
Results:(1) The uterine wet weight,uterus organ coefficient,the height of endometrium epithelium,myometrium thickness,endometrial glands significantly increased in the NP or NP+BPA groups as compared with those of control group.In addition,PCNA and ER expression in endometrium and myometrium were also significantly up-regulated in the EEDs groups.However,all the increased or up-regulated indicators abovementioned were notably decreased in the animals which were co-treated with traditional Chinese medicine(p＜0.05).(2) The data of gene expression profiles screened and analyzed by Illumina Beadchip(ratref-12) demonstrated that the mRNA levels of LHβand FSHβ,which involve in the functional group of GnRHR and GnRHR receptor-mediated signal transduction pathway significantly up-regulated in the EEDs exposure animals.With traditional Chinese medicine treatment,the up-regulated mRNA expressions of LHβand FSHβby EEDs were significantly inhibited.Moreover,the mRNA expression profile of genes related to the GnRHR receptor-medicated signal pathway,including phospholipase family(PLCd1,PLC 11,PLCb2,PLCg2),diacylglycerol(DG)family (DGat2,DGkq),lipoxygenase family(Alox15,Alox5,Alox3,Alox12)and leukotriene family(ltb4r2,ltc4s,ltb4dh) also showed the similar patterns as those of LHβand FSHβ,which significantly increased in the EEDs exposure groups and reduced in the traditional Chinese medicine treatment groups.Among them, lipoxygenase Alox15 was the differential gene displayed by the ratref-12 analysis.In the group of genes related to ER and ER-receptor mediated signal pathway,the mRNA expression of ERαand ERβwas significantly increased in rats exposure to the EEDs for 8 and 15 days and decreased in the rat with traditional Chinese medicine treatment.Furthermore,the increases in ER coactivator Sral,cross-talker EGF, EFGR,IGFβ2,IGFr2 mRNA expression induced by EEDs decreased with 15 days-treatment with traditional Chinese medicine.Among them,EGFR was the differential gene,which showed the similar trend as that of ER.Our data also showed that among the enzymes participate in the estrogen metabolism,the gene expression of stAR and CYP19al was significantly increased in the EEDs exposure groups as compared to the control group.However,traditional Chinese medicine treatment significantly down-regulated stAR and CYP11A1 expression when compared to the animals with the EEDs exposure alone.(3) The expression levels,including mRNA and protein of ERα,ERβ,EGFR,stAR,CYP19al and Cyp11A1 were further validated by real-time PCR and western blot.The results indicated that the mRNA levels of ERα,ERβ,EGFR,stAR,CYP19al on ovary were significantly raised(p＜0.05) after exposed to NP+BPA.The protein expressions of ERα,ERβ,stAR, CYP19al,Cyp11A1 were significantly increased(p＜0.05) as well.After treatment with traditional Chinese medicine the upregulated-mRNA levels of ERα,ERβ,EGFR, stAR and Cyp11al were significantly down-regulated(p＜0.05) and the protein expression of ERα,ERβ,stAR,Cyp11A1 significantly reduced(p＜0.05).
Conclusions:(1) The estrogenic effects of EEDs were tested and validated by uterotrophie assays in immature female SD rats.Our data demonstrated that treatment with the traditional Chinese medicine could inhibit the estrogenic effects induced by EEDs,which was consistent with our previous studies.(2) With the analysis of gene expression profiles,EEDs could up-regulate the mRNA levels of genes which promote pituitary-gonadal axis function and therefore elicited estrogenic activity.(3) Traditional Chinese medicine could significantly inhibit the adversely estrogenic effect of EEDs by intervening the gene expression related to pituitary-gonadal axis function.
方法:(1)以三周龄的雌性SD大鼠为实验对象,选取具有代表性的EEDs—壬基酚(4-nonylphenol,NP)、双酚A(bisphenol A,BPA)作为染毒物质,复制NP单独染毒及NP+BPA联合染毒的动物模型,治疗组同时喂饲中药,进行治疗干预,疗程15天。以子宫湿重、子宫脏器系数、子宫内膜上皮细胞高度、子宫内膜腺体数及腺上皮高度,环形平滑肌厚度、子宫内膜及肌层的细胞增殖核抗原(proliferating cell nuclear antigen,PCNA)蛋白表达水平及雌激素受体蛋白(estrogen receptor,ER)表达水平(免疫组织化学方法)作为检测指标,采用单因素方差分析进行统计分析,观察EEDs的拟雌激素作用及中药对其拟雌激素活性的拮抗作用。(2)采用illumina大鼠全基因组表达谱芯片(ratref-12),在与垂体—性腺轴功能相关的系列基因中大规模筛选其表达谱受EEDs染毒后产生显著变化而中药治疗干预可产生显著拮抗作用的基因。对筛选出的系列基因再采用实时荧光定量聚合酶链式反应(real-time FQ-PCR)及免疫印迹方法(westernblot)分别从基因表达及蛋白表达的水平进一步加以验证。结果采用单因素方差分析。(3)对芯片关注及验证确定的所有相关基因,按三个功能系列加以分类:①垂体促性腺激素释放激素受体(GnRHR)及受体后信号转导通路相关的系列基因。②卵巢雌激素受体及受体后信号转导通路相关的系列基因。③卵巢上与雌激素合成代谢相关的系列酶基因。
结果:(1)染毒组与对照组比较,子宫湿重、子宫脏器系数、子宫内膜上皮细胞高度、子宫内膜腺体数及腺上皮高度、环形平滑肌厚度显著增加(p＜0.05),子宫内膜及肌层的PCNA蛋白表达、ER蛋白表达显著增高(p＜0.05)。治疗组与染毒组相比,上述各指标均明显降低(p＜0.05)。(2)Illumina Beadchip基因芯片(ratref-12)分析结果显示,垂体GnRHR及受体后信号转导通路相关的系列基因中,在染毒及中药干预治疗8天时,LHβ、FSHβ的mRNA均表现为染毒组表达上调、治疗组表达下调。GnRH受体后信号转导通路中的磷脂酶C(PLCd1、PLC11、PLCb2、PLCg2)、二酰甘油DG(DGat2、DGkq)、蛋白激酶CPKC(PrKCb1)、脂氧合酶(Atox15、Alox5、Alox3、Alox12)、白细胞三烯(1tb4r2、1te4s、1tb4dh)在染毒组表达水平上调,治疗组表达水平下调。脂氧合酶Alox15在芯片中表现为差异基因;卵巢雌激素受体及受体后信号转导通路相关的系列基因中,ERα、ERβmRNA在染毒后8、15天均表达上调、治疗后表达下调。ER的共激活因子Sra1、交叉对话的EGF、EGFR、IGFb2、IGFr2 mRNA表达染毒后上调、治疗后下调。其中EGFR在芯片上表现为差异基因,变化趋势与ER相一致;卵巢上与雌激素合成代谢相关的系列酶基因中,染毒组与对照组比较,表达上调的差异基因有stAR、CYP19a1。而治疗组与染毒组比较,表达水平下调的差异基因有stAR、CYP11A1。(3)经real-time PCR及westernblot进一步验证结果显示,NP及BPA染毒可使卵巢ERα、ERβ、EGFR、StAR、CYP19a1的mRNA水平显著上调(p＜0.05),ERα、ERβ、stAR、CYP19a1、Cyp11A1蛋白表达明显增加(p＜0.05);中药干预则可使ERα、ERβ、EGFR、stAR、Cyp11a1的mRNA水平显著下调(p＜0.05),ERα、ERβ、stAR、Cyp11A1蛋白表达显著减少(p＜0.05)。
结论:(1)通过染毒动物实验,证实了EEDs的拟雌激素活性及中药治疗干预对其拟雌激素活性具有显著的拮抗作用,验证了我们既往的临床研究结果。(2)EEDs可显著促进与垂体-性腺轴功能相关的系列基因的表达水平上调,从而发挥其拟雌激素活性。(3)中药治疗干预可明显抑制EEDs对垂体-性腺轴功能相关的系列基因表达的不良影响,从而有效地拮抗EEDs的拟雌激素活性。
Objective:(1)To investigate the estrognic effects of environmental endocrine disruptors(EEDs) and to test the antagonistic effects of traditional Chinese medicine on the estrogenic animal model induced by EEDs.(2) To investigate the adverse effects of EEDs on the gene regulative network related to pituitary-gonadal axis in rats using the functionally genomic analysis.Furthermore,the mechanisms of estrogen antagonistic action of traditional Chinese medicine on the estrogenic rats were also explored.
Methods:(1) The estrogenic animal models were induced by the administration of the representative EEDs such as 4-nonylphenol(NP) alone,or by the co-administration of NP and bisphenol A(BPA) in the female SD rat at the age of three-week-old.For testing the preventive action of traditional Chinese medicine on the estrogenic rat induced by the abovementioned EEDs,traditional Chinese medicine was also i.g.administered to the rat when the animal model was producing.After 15-day course of treatment with or without traditional Chinese medicine,the uterine wet weight,uterus organ coefficient,height of endometrium epithelium,endometrial glands,myometrium thickness,protein level of proliferating cell nuclear antigen (PCNA) in the endometrium and myometrium and the estrogen receptor(ER) expression in the rat uterine were measured and analyzed by one-way ANOVA.(2) The gene expression profiles in pituitary—ovarian axis of rats which were fed with NP+BPA or co-treatment with traditional Chinese medicine respectively were detected by Illumina Beadchip(ratref-12).The expression of genes which could be influenced significantly by EEDs and reversely affected by traditional Chinese medicine was analyzed.Moreover,the screened genes which are closely related to sexual development were further verified by real-time polymerase chain reaction (real-time PCR)and western blotting.Significance was analyzed by one-way ANOVA. (3)All the screened and verified genes were categorized into three groups according to their functions,i.e.1) Genes related to GnRHR and GnRHR receptor-mediated signal transduction pathway;2) Genes related to ER and ER-mediated signal transduction pathway and 3) Enzymes involved in the estrogen metabolism in ovary.
Results:(1) The uterine wet weight,uterus organ coefficient,the height of endometrium epithelium,myometrium thickness,endometrial glands significantly increased in the NP or NP+BPA groups as compared with those of control group.In addition,PCNA and ER expression in endometrium and myometrium were also significantly up-regulated in the EEDs groups.However,all the increased or up-regulated indicators abovementioned were notably decreased in the animals which were co-treated with traditional Chinese medicine(p＜0.05).(2) The data of gene expression profiles screened and analyzed by Illumina Beadchip(ratref-12) demonstrated that the mRNA levels of LHβand FSHβ,which involve in the functional group of GnRHR and GnRHR receptor-mediated signal transduction pathway significantly up-regulated in the EEDs exposure animals.With traditional Chinese medicine treatment,the up-regulated mRNA expressions of LHβand FSHβby EEDs were significantly inhibited.Moreover,the mRNA expression profile of genes related to the GnRHR receptor-medicated signal pathway,including phospholipase family(PLCd1,PLC 11,PLCb2,PLCg2),diacylglycerol(DG)family (DGat2,DGkq),lipoxygenase family(Alox15,Alox5,Alox3,Alox12)and leukotriene family(ltb4r2,ltc4s,ltb4dh) also showed the similar patterns as those of LHβand FSHβ,which significantly increased in the EEDs exposure groups and reduced in the traditional Chinese medicine treatment groups.Among them, lipoxygenase Alox15 was the differential gene displayed by the ratref-12 analysis.In the group of genes related to ER and ER-receptor mediated signal pathway,the mRNA expression of ERαand ERβwas significantly increased in rats exposure to the EEDs for 8 and 15 days and decreased in the rat with traditional Chinese medicine treatment.Furthermore,the increases in ER coactivator Sral,cross-talker EGF, EFGR,IGFβ2,IGFr2 mRNA expression induced by EEDs decreased with 15 days-treatment with traditional Chinese medicine.Among them,EGFR was the differential gene,which showed the similar trend as that of ER.Our data also showed that among the enzymes participate in the estrogen metabolism,the gene expression of stAR and CYP19al was significantly increased in the EEDs exposure groups as compared to the control group.However,traditional Chinese medicine treatment significantly down-regulated stAR and CYP11A1 expression when compared to the animals with the EEDs exposure alone.(3) The expression levels,including mRNA and protein of ERα,ERβ,EGFR,stAR,CYP19al and Cyp11A1 were further validated by real-time PCR and western blot.The results indicated that the mRNA levels of ERα,ERβ,EGFR,stAR,CYP19al on ovary were significantly raised(p＜0.05) after exposed to NP+BPA.The protein expressions of ERα,ERβ,stAR, CYP19al,Cyp11A1 were significantly increased(p＜0.05) as well.After treatment with traditional Chinese medicine the upregulated-mRNA levels of ERα,ERβ,EGFR, stAR and Cyp11al were significantly down-regulated(p＜0.05) and the protein expression of ERα,ERβ,stAR,Cyp11A1 significantly reduced(p＜0.05).
Conclusions:(1) The estrogenic effects of EEDs were tested and validated by uterotrophie assays in immature female SD rats.Our data demonstrated that treatment with the traditional Chinese medicine could inhibit the estrogenic effects induced by EEDs,which was consistent with our previous studies.(2) With the analysis of gene expression profiles,EEDs could up-regulate the mRNA levels of genes which promote pituitary-gonadal axis function and therefore elicited estrogenic activity.(3) Traditional Chinese medicine could significantly inhibit the adversely estrogenic effect of EEDs by intervening the gene expression related to pituitary-gonadal axis function.
引文
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