邻苯二甲酸单丁酯影响类固醇激素合成的机制研究
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摘要
邻苯二甲酸酯(phthalate acid esters，PAEs)是一类结构相似的化学物质，广泛应用于工农业生产中，环境污染非常普遍。邻苯二甲酸二丁酯(dibutyl phthalate，DBP)是使用量最大、污染最为严重的PAEs之一。尿液PAEs代谢产物检测显示，DBP代谢产物邻苯二甲酸单丁酯(mono-butyl phthalate，MBP)含量最高，说明DBP的人体内暴露水平最高。研究表明DBP和MBP对雄激素与其受体结合无干扰作用，但是动物实验却显示出明显的抗雄激素效应，此效应主要由MBP引起，可能与影响雄激素的生物合成有关。DBP和MBP影响雄激素合成的具体机制目前尚不清楚。本研究以小鼠间质细胞瘤细胞(mouse Leydig tumor cells，MLTC-1)为模型探讨MBP影响类固醇激素合成的机制。
第一部分MBP对MLTC-1细胞类固醇激素合成的影响
目的：探讨MLTC-1细胞对hCG等刺激剂的反应性以及MBP对MLTC-1细胞类固醇激素合成的影响。方法：细胞预培养24h贴壁后改为无血清培养液并用hCG、CT或forskolin刺激，刺激结束后收集培养液待测孕酮。在另一实验中，预培养24h后用MBP染毒24、48、72h，染毒结束后再用hCG刺激4h，收集培养液待测孕酮。孕酮测定用放射免疫法。细胞活性试验使用MTT法和~3H-TDR法。
结果：hCG、CT或forskolin刺激MLTC-1细胞孕酮合成表现为剂量-关系性上升。MBP浓度在低于10~(-3)mol／L时对细胞活性未产生显著性影响。此外，MBP对孕酮合成的作用表现为双向调节趋势，低剂量(10~(-7)-10~(-6)mol／L)时表现为兴奋效应、高剂量时表现为抑制效应。
结论：MLTC-1细胞对hCG、CT或forskolin等具有良好的刺激反应性。低剂量MBP对类固醇激素合成的影响具有“低剂量兴奋效应”。下列剂量可以用于研究MBP生殖内分泌干扰作用，即：10~(-9)，10~(-8)，10~(-7),10~(-6)，10~(-5)，mol／L和50，100，200，400 and 800μmol／L。
第二部分hCG-cAMP-PKA通路在MBP影响MLTC-1细胞类固醇激素合成中的作用
目的：探讨hCG-cAMP-PKA通路及胆固醇转运在MBP影响类固醇激素合成中的作用。方法：细胞预培养24h贴壁，用MBP处理细胞24h。处理结束后分别用hCG、CT、8-Br-cAMP、22R-HC或孕烯醇酮刺激4h。处理结束后，收集上清测定孕酮或者收集细胞提取蛋白和mRNA。放射免疫法测定孕酮和细胞内cAMP水平、western blot测定蛋白表达、实时定量PCR分析mRNA表达水平。结果：MBP在10~(-7)和10~(-6)mol／L时对hCG、CT和8-Br-cAMP刺激的孕酮合成具有明显的刺激作用。相反，MBP在大于或等于200μmol／L则具有抑制效应。此外，MBP对hCG、CT和forskolin刺激的细胞内cAMP水平未见有明显的影响。当培养液中有22R-HC或孕烯醇酮存在时，MBP对孕酮合成的影响被抵消，说明MBP对P450scc和3β-HSD的活性未产生明显的作用，可能作用位点是胆固醇转运过程。StARmRNA、StAR蛋白及PBR mRNA测定的结果证明了这一假设，因为StAR和PBR是调节胆固醇转运的关键蛋白。结论：MBP对类固醇激素合成的影响表现为双向调节效应，主要通过调节胆固醇转运影响类固醇激素合成。胆固醇转运既是高剂量MBP抑制效应的作用位点，也是低剂量刺激效应的作用位点。
第三部分PKC信号通路及钙离子在MBP影响MLTC-1细胞类固醇激素合成中的作用
目的：探讨蛋白激酶C(PKC)和钙信号系统在MBP影响类固醇激素合成中的作用。方法：细胞预培养24h贴壁，用MBP处理细胞24h。处理结束后分别用hCG和佛波酯(PMA)、蛋白激酶A抑制剂(PKI)、花生四烯酸(AA)、钙离子螯合剂(EGTA)、钙通道阻滞剂(VER)、钙离子载体(A23187)和Ca~(2+)-ATP抑制剂(TG)处理4h。收集上清放射免疫法测定孕酮。细胞内钙离子浓度([Ca~(2+)]i)以fluo3／AM为探针用激光共聚焦系统测定。结果：PMA和PKI能显著抑制hCG诱导的孕酮合成。MBP在10~(-5)和10~(-6)mol／L以下剂量对孕酮合成的刺激作用分别被PMA和PKI完全抵消。用AA与hCG联合刺激后，MBP≤10~(-4)mol／L时的刺激效应消失，染毒组的孕酮合成水平与对照组相比无显著性差异。当培养液中无Ca~(2+)或Ca~(2+)被EGTA螯合后，MBP对孕酮合成的影响完全消失。虽然Ca~(2+)载体A23187可显著增加hCG刺激的孕酮合成，但是对MBP诱导的孕酮合成变化趋势没有改变。同样地，钙通道阻滞剂VER虽然可显著降低hCG刺激的孕酮合成，但是影响MBP诱导的孕酮合成变化趋势也没有改变。当培养中同时存在hCG和Ca~(2+)-ATPase抑制剂TG时，MBP对孕酮合成的影响在200μmol／L以下剂量时消失。[Ca~(2+)]i检测结果显示，胞外无Ca~(2+)时10~(-6)mol／L MBP可使[Ca~(2+)]i快速上升，而10~(-3)mol／L MBP则对[Ca~(2+)]i产生抑制效应。结论：MBP在较低剂量影响类固醇激素合成的机制可能与PKC、AA及钙信号系统有关，钙信号系统可能主要参与较高剂量MBP的作用。
Phthalate acid esters (PAEs), a large group of industrial andpharmaceutical chemicals distributed diffusely in the environment, caninterfere with reproduction and development in an endocrine-mediatedprocess. Dibutyl phthalate (DBP), one of the most dominant PAEs, isused mainly as a plasticizer in PVC products as well as in cosmetics andother personal care products. Examination of urinary PAEs metabolitesrevealed that the general people appeared to be exposed todisproportionately higher amounts of DBP than other PAEs. DBP and itsactive metabolite, mono-butyl phthalate (MBP), display no bindingaffinity for the androgen receptor, yet exert anti-androgenic effects byaltering steroid biosynthesis. However, the mechanisms underlying thisobserved effect are not known. The purpose of this study was todetermine the site of MBP action on steroidogenesis in vitro in mouseLeydig tumor cells (MLTC-1).
PartⅠEffect of MBP on Steroidogenesis in MLTC-1 Cells
Objective: To examine the response of MLTC-1 cells to somestimulators and the effects of MBP on steroidogenesis in intro. Methods:MLTC-1 cells were employed as a cellular model. Cell viability wasevaluated by measuring the level of ~3H-thymidine incorporation(~3H-TDR) and MTT assay. To assess the response of MLTC-1 cell tosome stimulators, the cells were stimulated by human chorionicgonadotrophin (hCG), cholera toxin (CT) and forsklin for 4h afterpreincubation for 24h. Then the medium was collected for progesteronemeasurement. In another experiment, various concentrations of MBPdetermined by cell viability test and the solvent DMSO were added tothe medium for 24, 48 and 72h followed by 4h-stimulation by hCG toexplore the time-and dose-effect of MBP on stroidogenesis. Results:Data showed that progesterone synthesis stimulated by hCG, CT andforskolin was in a dose-response manner. Furthermore, the MBPdosages below 10~(-3) mol/L did not have any effects on cell viability. Theprogesterone levels induced by MBP exhibited biphasic model. Therewere rapid increases in progesterone production under MBP treatment at10~(-7) to 10~(-6) mol/L. Conclusion: This cell line displayed an excellentresponse to hCG, CT and forskolin. There was a stimulatory effect ofMBP on steroid hormone synthesis at relative low concentratin. MBPdosages used in this part, i.e. 10~(-9), 10~(-8), 10~(-7), 10~(-6), 10~(-5), 10~(-4) mol/L and 50,100, 200, 400 and 800μmol/L, could be used in the followingexperiments.
Objective: To investigate the role of hCG-cAMP-PKA pathway andtransport of cholesterol in steroidogenesis induced by MBP. Methods:Various concentrations of MBP determined by partⅠwere added to themedium for 24h followed by stimulation of some compounds such ashCG, CT, cAMP analog 8-Br-cAMP, 22R-HC and pregnenolone.Progesterone levels in the medium and amounts of intracellular cAMPwere measured by RIA. Expression of steroidogenic acute regulatoryprotein (StAR) was monitored by real-time PCR and Western blot.
Results: The increases in progesterone production in the presence ofhCG, CT and 8-Br-cAMP were augmented by MBP at 10~(-7) and 10~(-6)mol/L while suppressed at 200μmol/L and higher. In contrast, the levelsof intracellular cAMP exhibited no statistical significance under MBPtreatment. Moreover, 22R-HC and pregnenolone resulted in no alterationin progesterone production, making clear that MBP did not influence theP450scc and 3β-HSD activity but on the rate-limiting step insteroidogenesis pathway, cholesterol transportation into mitochondria. Infact, these results were confirmed by StAR expression in MBP-treatedcells as StAR is a key protein in the process of cholesterol transportation.
Conclusion: Effect of this chemical on steroidogenesis shows aninvert-U dose-response curve. Furthermore, MBP promotes steroidhormone production by facilitating StAR expression while MBP inhibitssteroid hormone production by down-regulating StAR expression inMLTC-1 cells.
PartⅢRole of Protein kinase C (PKC) and Ca~(2+) signalin Steroidogenesis Induced by MBP
Objective: To explore the role of PKC and Ca~(2+) in steroidogenesisinduced by MBP. Methods: Various concentrations of MBP determinedby partⅠwere added to the medium for 24h followed by co-treatmentwith hCG and PMA, PKI, AA, EGTA, VER, A23187 and TGrespectively. Progesterone levels were measured by RIA andintracellular Ca~(2+) concentration ([Ca~(2+)]i) was monitored with fluorescentprobe for Ca~(2+), fluo3/AM. Results: Progesterone production in thepresence of hCG was seriously inhibited in the presence of PMA andPKI. Moreover, effect of MBP at the doses lower than 10~(-5) mol/L on theprogesterone synthesis stimulated by hCG disappeared when the cellswere co-treated with PMA and hCG. Similar results could be seen withPKI in the medium at the doses of 10~(-6) mol/L MBP and below. AAcould offset MBP effect at 10~(-4) mol/L and lower. On the other hand,progesterone synthesis was thoroughly counteracted in the Ca~(2+)-fleemedium or in the medium supplemented with Ca~(2+) chelator EGTA.Opposite result was obtained in the presence of A23187 which allowsextracellular Ca~(2+) entry. VER, a Ca~(2+) channel blocker, dramaticallydiminished MBP-induced progesterone biosynthesis in the presence ofhCG, but these two trends were similar. On the contrary, TG, aCa~(2+)-ATPase inhibitor which increases [Ca~(2+)]i, prevented the MBPeffects at doses of 200μmol/L and lower. Results from [Ca~(2+)]imeasurement showed that 10~(-6) mol/L MBP could markedly augmented[Ca~(2+)]i under hCG treatment in Ca~(2+)-free buffers. But, this dose didn't increase [Ca~(2+)]i in Ca~(2+)-supplemented buffers. In addition, [Ca~(2+)]i wassuppressed by 10~(-3) mol/L MBP in both Ca~(2+)-free and Ca~(2+)-supplemented buffers. Conclusion: Data from this part support thatPKC, AA and Ca~(2+) signal was involved in the changes of steroidhormone production affected by low concentrations of MBP in MLTC-1cells. Ca~(2+) signal is a key factor implicated in adjusting steroidogenesisaffected by MBP at relative high doses.
第一部分MBP对MLTC-1细胞类固醇激素合成的影响
目的：探讨MLTC-1细胞对hCG等刺激剂的反应性以及MBP对MLTC-1细胞类固醇激素合成的影响。方法：细胞预培养24h贴壁后改为无血清培养液并用hCG、CT或forskolin刺激，刺激结束后收集培养液待测孕酮。在另一实验中，预培养24h后用MBP染毒24、48、72h，染毒结束后再用hCG刺激4h，收集培养液待测孕酮。孕酮测定用放射免疫法。细胞活性试验使用MTT法和~3H-TDR法。
结果：hCG、CT或forskolin刺激MLTC-1细胞孕酮合成表现为剂量-关系性上升。MBP浓度在低于10~(-3)mol／L时对细胞活性未产生显著性影响。此外，MBP对孕酮合成的作用表现为双向调节趋势，低剂量(10~(-7)-10~(-6)mol／L)时表现为兴奋效应、高剂量时表现为抑制效应。
结论：MLTC-1细胞对hCG、CT或forskolin等具有良好的刺激反应性。低剂量MBP对类固醇激素合成的影响具有“低剂量兴奋效应”。下列剂量可以用于研究MBP生殖内分泌干扰作用，即：10~(-9)，10~(-8)，10~(-7),10~(-6)，10~(-5)，mol／L和50，100，200，400 and 800μmol／L。
第二部分hCG-cAMP-PKA通路在MBP影响MLTC-1细胞类固醇激素合成中的作用
目的：探讨hCG-cAMP-PKA通路及胆固醇转运在MBP影响类固醇激素合成中的作用。方法：细胞预培养24h贴壁，用MBP处理细胞24h。处理结束后分别用hCG、CT、8-Br-cAMP、22R-HC或孕烯醇酮刺激4h。处理结束后，收集上清测定孕酮或者收集细胞提取蛋白和mRNA。放射免疫法测定孕酮和细胞内cAMP水平、western blot测定蛋白表达、实时定量PCR分析mRNA表达水平。结果：MBP在10~(-7)和10~(-6)mol／L时对hCG、CT和8-Br-cAMP刺激的孕酮合成具有明显的刺激作用。相反，MBP在大于或等于200μmol／L则具有抑制效应。此外，MBP对hCG、CT和forskolin刺激的细胞内cAMP水平未见有明显的影响。当培养液中有22R-HC或孕烯醇酮存在时，MBP对孕酮合成的影响被抵消，说明MBP对P450scc和3β-HSD的活性未产生明显的作用，可能作用位点是胆固醇转运过程。StARmRNA、StAR蛋白及PBR mRNA测定的结果证明了这一假设，因为StAR和PBR是调节胆固醇转运的关键蛋白。结论：MBP对类固醇激素合成的影响表现为双向调节效应，主要通过调节胆固醇转运影响类固醇激素合成。胆固醇转运既是高剂量MBP抑制效应的作用位点，也是低剂量刺激效应的作用位点。
第三部分PKC信号通路及钙离子在MBP影响MLTC-1细胞类固醇激素合成中的作用
目的：探讨蛋白激酶C(PKC)和钙信号系统在MBP影响类固醇激素合成中的作用。方法：细胞预培养24h贴壁，用MBP处理细胞24h。处理结束后分别用hCG和佛波酯(PMA)、蛋白激酶A抑制剂(PKI)、花生四烯酸(AA)、钙离子螯合剂(EGTA)、钙通道阻滞剂(VER)、钙离子载体(A23187)和Ca~(2+)-ATP抑制剂(TG)处理4h。收集上清放射免疫法测定孕酮。细胞内钙离子浓度([Ca~(2+)]i)以fluo3／AM为探针用激光共聚焦系统测定。结果：PMA和PKI能显著抑制hCG诱导的孕酮合成。MBP在10~(-5)和10~(-6)mol／L以下剂量对孕酮合成的刺激作用分别被PMA和PKI完全抵消。用AA与hCG联合刺激后，MBP≤10~(-4)mol／L时的刺激效应消失，染毒组的孕酮合成水平与对照组相比无显著性差异。当培养液中无Ca~(2+)或Ca~(2+)被EGTA螯合后，MBP对孕酮合成的影响完全消失。虽然Ca~(2+)载体A23187可显著增加hCG刺激的孕酮合成，但是对MBP诱导的孕酮合成变化趋势没有改变。同样地，钙通道阻滞剂VER虽然可显著降低hCG刺激的孕酮合成，但是影响MBP诱导的孕酮合成变化趋势也没有改变。当培养中同时存在hCG和Ca~(2+)-ATPase抑制剂TG时，MBP对孕酮合成的影响在200μmol／L以下剂量时消失。[Ca~(2+)]i检测结果显示，胞外无Ca~(2+)时10~(-6)mol／L MBP可使[Ca~(2+)]i快速上升，而10~(-3)mol／L MBP则对[Ca~(2+)]i产生抑制效应。结论：MBP在较低剂量影响类固醇激素合成的机制可能与PKC、AA及钙信号系统有关，钙信号系统可能主要参与较高剂量MBP的作用。
Phthalate acid esters (PAEs), a large group of industrial andpharmaceutical chemicals distributed diffusely in the environment, caninterfere with reproduction and development in an endocrine-mediatedprocess. Dibutyl phthalate (DBP), one of the most dominant PAEs, isused mainly as a plasticizer in PVC products as well as in cosmetics andother personal care products. Examination of urinary PAEs metabolitesrevealed that the general people appeared to be exposed todisproportionately higher amounts of DBP than other PAEs. DBP and itsactive metabolite, mono-butyl phthalate (MBP), display no bindingaffinity for the androgen receptor, yet exert anti-androgenic effects byaltering steroid biosynthesis. However, the mechanisms underlying thisobserved effect are not known. The purpose of this study was todetermine the site of MBP action on steroidogenesis in vitro in mouseLeydig tumor cells (MLTC-1).
PartⅠEffect of MBP on Steroidogenesis in MLTC-1 Cells
Objective: To examine the response of MLTC-1 cells to somestimulators and the effects of MBP on steroidogenesis in intro. Methods:MLTC-1 cells were employed as a cellular model. Cell viability wasevaluated by measuring the level of ~3H-thymidine incorporation(~3H-TDR) and MTT assay. To assess the response of MLTC-1 cell tosome stimulators, the cells were stimulated by human chorionicgonadotrophin (hCG), cholera toxin (CT) and forsklin for 4h afterpreincubation for 24h. Then the medium was collected for progesteronemeasurement. In another experiment, various concentrations of MBPdetermined by cell viability test and the solvent DMSO were added tothe medium for 24, 48 and 72h followed by 4h-stimulation by hCG toexplore the time-and dose-effect of MBP on stroidogenesis. Results:Data showed that progesterone synthesis stimulated by hCG, CT andforskolin was in a dose-response manner. Furthermore, the MBPdosages below 10~(-3) mol/L did not have any effects on cell viability. Theprogesterone levels induced by MBP exhibited biphasic model. Therewere rapid increases in progesterone production under MBP treatment at10~(-7) to 10~(-6) mol/L. Conclusion: This cell line displayed an excellentresponse to hCG, CT and forskolin. There was a stimulatory effect ofMBP on steroid hormone synthesis at relative low concentratin. MBPdosages used in this part, i.e. 10~(-9), 10~(-8), 10~(-7), 10~(-6), 10~(-5), 10~(-4) mol/L and 50,100, 200, 400 and 800μmol/L, could be used in the followingexperiments.
Objective: To investigate the role of hCG-cAMP-PKA pathway andtransport of cholesterol in steroidogenesis induced by MBP. Methods:Various concentrations of MBP determined by partⅠwere added to themedium for 24h followed by stimulation of some compounds such ashCG, CT, cAMP analog 8-Br-cAMP, 22R-HC and pregnenolone.Progesterone levels in the medium and amounts of intracellular cAMPwere measured by RIA. Expression of steroidogenic acute regulatoryprotein (StAR) was monitored by real-time PCR and Western blot.
Results: The increases in progesterone production in the presence ofhCG, CT and 8-Br-cAMP were augmented by MBP at 10~(-7) and 10~(-6)mol/L while suppressed at 200μmol/L and higher. In contrast, the levelsof intracellular cAMP exhibited no statistical significance under MBPtreatment. Moreover, 22R-HC and pregnenolone resulted in no alterationin progesterone production, making clear that MBP did not influence theP450scc and 3β-HSD activity but on the rate-limiting step insteroidogenesis pathway, cholesterol transportation into mitochondria. Infact, these results were confirmed by StAR expression in MBP-treatedcells as StAR is a key protein in the process of cholesterol transportation.
Conclusion: Effect of this chemical on steroidogenesis shows aninvert-U dose-response curve. Furthermore, MBP promotes steroidhormone production by facilitating StAR expression while MBP inhibitssteroid hormone production by down-regulating StAR expression inMLTC-1 cells.
PartⅢRole of Protein kinase C (PKC) and Ca~(2+) signalin Steroidogenesis Induced by MBP
Objective: To explore the role of PKC and Ca~(2+) in steroidogenesisinduced by MBP. Methods: Various concentrations of MBP determinedby partⅠwere added to the medium for 24h followed by co-treatmentwith hCG and PMA, PKI, AA, EGTA, VER, A23187 and TGrespectively. Progesterone levels were measured by RIA andintracellular Ca~(2+) concentration ([Ca~(2+)]i) was monitored with fluorescentprobe for Ca~(2+), fluo3/AM. Results: Progesterone production in thepresence of hCG was seriously inhibited in the presence of PMA andPKI. Moreover, effect of MBP at the doses lower than 10~(-5) mol/L on theprogesterone synthesis stimulated by hCG disappeared when the cellswere co-treated with PMA and hCG. Similar results could be seen withPKI in the medium at the doses of 10~(-6) mol/L MBP and below. AAcould offset MBP effect at 10~(-4) mol/L and lower. On the other hand,progesterone synthesis was thoroughly counteracted in the Ca~(2+)-fleemedium or in the medium supplemented with Ca~(2+) chelator EGTA.Opposite result was obtained in the presence of A23187 which allowsextracellular Ca~(2+) entry. VER, a Ca~(2+) channel blocker, dramaticallydiminished MBP-induced progesterone biosynthesis in the presence ofhCG, but these two trends were similar. On the contrary, TG, aCa~(2+)-ATPase inhibitor which increases [Ca~(2+)]i, prevented the MBPeffects at doses of 200μmol/L and lower. Results from [Ca~(2+)]imeasurement showed that 10~(-6) mol/L MBP could markedly augmented[Ca~(2+)]i under hCG treatment in Ca~(2+)-free buffers. But, this dose didn't increase [Ca~(2+)]i in Ca~(2+)-supplemented buffers. In addition, [Ca~(2+)]i wassuppressed by 10~(-3) mol/L MBP in both Ca~(2+)-free and Ca~(2+)-supplemented buffers. Conclusion: Data from this part support thatPKC, AA and Ca~(2+) signal was involved in the changes of steroidhormone production affected by low concentrations of MBP in MLTC-1cells. Ca~(2+) signal is a key factor implicated in adjusting steroidogenesisaffected by MBP at relative high doses.
引文
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