微波辐射对雄性大鼠生殖系统的昼夜时间毒性及分子机制
摘要
目的：微波辐射(Microwave Radiation, MWR)是一种重要的环境电磁污染物（EEPs），因无线通讯技术的快速发展，特别是全世界手机用户的急剧增加而备受关注。由于微波辐射可对雄性生殖系统产生不良的影响，明确其作用途径和损伤机制已成为迫切任务。已知哺乳动物的生理功能和行为存在昼夜节律，机体在24小时中不同时相对毒物及微波辐射敏感性不同。本课题采用时间生物学和生殖内分泌毒理学相结合的策略，在建立微波辐射动物模型的基础上，研究微波辐射对雄性生殖系统和褪黑素（Melatonin，MEL）分泌的昼夜时间毒性，以及褪黑素通过GATA-4/SF-1信号通路抑制睾酮合成的作用机制，为微波辐射对生殖功能损害的防治提供新的思路。
方法：(1)微波辐射对雄性大鼠生殖系统的昼夜时间毒性。以褪黑素日节律筛选具有昼夜(L:D,12h:12h)节律的SD大鼠，分别在授时时间（zeitgeber time，ZT,以ZT0为光照开始）ZT0, ZT4, ZT8, ZT12, ZT16和ZT20进行微波辐射（1800MHz，205μw/cm2），每次2h，每天一次，连续32天。对应的假辐射组（Sham）同样处理但不给予微波信号。辐射后24h内每隔4h尾静脉采血一次，ELISA法测定睾酮含量；同时Sham和MWR各时点组在辐射结束时点采集睾丸和附睾组织。测定附睾精子活动度；制作睾丸HE病理切片，测定睾丸每日精子生成量、睾丸标志酶ACP和γ-GT活性，Real-time PCR检测睾酮合成基因StAR和p450cc mRNA表达。利用余弦节律分析软件，根据方程式F(t)=M+Acos(ωt+Φ)将各指标数据拟合为余弦曲线，分析节律参数。(2)微波辐射改变大鼠褪黑素分泌的昼夜节律。微波辐射方法同上，辐射32天后，24h内每隔4h尾静脉采血一次，ELISA法检测血浆褪黑素浓度，同时Sham和MWR各时点组在辐射结束时点采集松果体，Real-time PCR测定褪黑素合成酶NAT mRNA的表达。节律分析同上。(3)褪黑素抑制睾酮分泌的信号通路及微波辐射对睾丸间质细胞睾酮分泌的影响。以小鼠睾丸间质细胞系（TM3）细胞作为研究对象，添加不同浓度(0,10-6,10-8,10-10和10-12mol/L)的褪黑素，或先添加褪黑素受体阻断剂（Luzindole，1μmol/L）再加褪黑素，MTT法检测细胞增殖、流式细胞仪检测线粒体膜电位、ELISA法检测睾酮和cAMP，Real-time PCR和Western blotting测定褪黑素受体和睾酮相关基因GATA-4，SF-1，StAR，P450cc和3β-HSD的mRNA和蛋白的表达。通过睾丸注射褪黑素，利用免疫组化和免疫荧光方法以整体动物实验验证褪黑素抑制睾酮合成的信号通路。采用TM3细胞进行体外培养，在1800MHz微波辐射（205μw/cm2）2h后，流式细胞仪检测线粒体膜电位，ELISA法测定睾酮和cAMP含量，Real-time PCR测定睾酮代谢调节因子相关基因SF-1、StAR和P450cc mRNA表达的改变。
结果：(1)微波辐射可使雄性大鼠睾丸组织发生病理改变，降低睾丸每日精子生成量、精子活动度、睾丸标志酶ACP和γ-GT活性，其中ACP和γ-GT活性以及每日精子生成量的下降在ZT0时辐射的MWR0组最为明显。微波辐射还可改变血浆睾酮的昼夜节律，其中MWR0、MWR8、MWR12和MWR20组的昼夜节律消失，同时MWR0组大鼠血浆中睾酮的日均值水平下降最大。睾酮合成调控因子StAR和P450cc的mRNA表达在微波辐射后失去昼夜节律，且MWR0变化最大，提示大鼠雄性生殖系统对微波辐射最敏感的时点为ZT0:00。(2)微波辐射降低褪黑素的日均分泌量，其中以MWR16组最为明显。微波辐射扰乱褪黑素合成的昼夜节律，其中MWR8，MWR16和MWR20组的血浆褪黑素昼夜节律被破坏，而振幅变化在MWR16组最为明显，表明在ZT16:00时微波辐射对大鼠血浆褪黑素节律的影响最大。MWR后松果体NAT基因表达的昼夜节律改变，以ZT16时下调最为明显，同时表达的中值和振幅明显改变，峰值相位明显滞后。(3)褪黑素在体外可抑制TM3细胞增殖，降低睾酮含量，减少细胞内cAMP浓度，改变线粒体膜电位，下调核转录因子GATA-4及其目标基因SF-1，StAR，Cyp11A，HSD3β的基因和蛋白表达。褪黑素的这些抑制作用可被褪黑素受体阻断剂Luzindole所拮抗，特别是在褪黑素高水平作用时。大鼠睾丸组织注射褪黑素后0.5h、1h、2h，血浆中睾酮含量降低，睾丸间质细胞膜受体Mel1a，GATA-4和SF-1表达减弱，4h后上述效应消失。微波辐射后TM3细胞上清睾酮含量降低，细胞内cAMP浓度和线粒体膜电位水平下降，睾酮合成调节因子SF-1，StAR，P450cc基因表达下调。
结论：
1、建立了微波辐射大鼠的动物模型，发现微波辐射对雄性大鼠的生殖功能和睾酮内分泌具有昼夜时间毒性。
2、微波辐射可改变褪黑素分泌和褪黑素合成酶NAT mRNA的昼夜节律，并通过褪黑素介导对雄性大鼠生殖功能的时间毒性。
3、体内外实验证实褪黑素通过GATA-4/SF-1信号通路抑制睾酮分泌，其中GATA-4因子起着关键性的作用。
Objective: Microwave Radiation (MWR) is an important environmentalelectromagnetic pollutant with the rapid development of wireless communicationtechnology and mobile phone users in the world. It has been reported that MWRexposure may cause damage on male reproduction system, and it is therefore importantto clarify the route and mechanism of the MWR damage. Circadian rhythms of thephysiological and behavioral functions have been widely demonstrated in mammals,which result in different sensitivities of animals to toxicants and MWR at different timesof a day. This project is to study the circadian rhythm of male reproduction system andmelatonin (melatonin, MEL) toxicity induced by MWR with the combination ofchronobiology and reproductive endocrine toxicology on the basis of established animalmodel of microwave radiation, and to ellucidate the mechanism underlyingGATA-4/SF-1signal pathway that inhibits testosterone secretion in TM3Leydig cells,so that to provide with new ways in prevention and treatment of the male reproductionmalfunction caused by MWR.
Methods:(1) Chronotoxicity of reproductive system in male rats exposed to MWR.Animals in circadian rhythm (as indicated by melatonin measurements) were dividedinto several groups and exposed to1800MHz RF at205μw/cm2power density for2h/dfor32days at different zeitgeber time (ZT) points, viz., ZT0, ZT4, ZT8, ZT12, ZT16and ZT20. Sham-exposed animals were used as controls in the study. From each rat,0.1ml blood samples were colleted from the caudal vein every4hours (ZT0, ZT4, ZT8,ZT12, ZT6and ZT20) after MWR exprosure to determine the concentration oftestosterone using the ELISA KIT. Testicular and epididymis tissues were collected forHE pathological section and assessed for testosterone levels, daily sperm productionand sperm motility, testis marker enzymes γ-GT and ACP, cytochrome P450side-chaincleavage (p450cc) mRNA expression, and steroidogenic acute regulatory protein (StAR)mRNA expression. The data obtained were then fitted for cosinor analysis as expressed in Eq.F(t)=M+Acos(w t+j).(2) Circadian alterations of melatonin secretion in male ratsexposed to MWR. The MWR and blood samples celection were the same as the firstsection. The concentration of MEL was determined by the ELISA KIT. Pineals werecollected after MWR from Sham and MWR groups at the end of exposure timepointsrespectively to determine melatonin synthetase NAT mRNA by Real-time PCR.(3)Signal pathway of testosterone secretion inhibition by melatonin and effects of MWRon testosterone secretion in TM3cells. TM3Cells were plated in the presence orabsence of melatonin (0,10-6,10-8,10-10and10-12mol/L) and melatonin receptorantagonist Luzindole (1μmol/L) for3h in multiwell-plates (six wells). Thenintracellular cAMP and testosterone levels in the supernatant were measured by ELISA.Gene and protein expression of the pathway foctors (Mel1a，GATA-4，SF-1，StAR，P450cc and3β-HSD) were determined by Real-qPCR and Western blot.Immunohistochemical (GATA-4) and immunofluorescence (SF-1and Mel1a) analysiswere used to verifiy the signal pathway in vivo model by intra-testicular injection ofmelatonin in C57BL/6J mice. The TM3Cells were exposed to1800MHz MWR (205μw/cm2) for2h to determine mitochondrial membrane potential by flow cytometry. Theintracellular cAMP and testosterone levels in the supernatant were measured by ELISA.Gene and protein expression of SF-1, StAR and P450cc were determined by Real-qPCR.
Results:(1) MWR exposure led to histopathologic changes in testicles, lower dailysperm production and sperm motility, down-regulated activity of γ-GT and ACP, withthe most pronounced change in the MWR0group. Rats exposed to MWR exhibited analteration in circadian rhythms of plasma testosterone, which were absent in MWR0,MWR8, MWR12and MWR20groups. At the same time, the daily average testosteronelevel was most reduced in the MWR0group. Two testosterone synthesis regulatoryfactors of P450cc and StAR mRNA lost their circadian rhythms after MWR exposureand changed most dramatically in the MWR0group. These results suggest that the malereproduction system in rat was most sensitive to MWR exposure at ZT0.(2) MWRexposure decreased daily average testosterone levels, especially in the MWR0group.MWR exposure disturbed the circadian rhythms of plasma melatonin in MWR8, MWR16and MWR20groups, with the greatest amplitude reduction in MWR16group. These findings indicate that the biggest change in plasma melatonin occured at ZT16:00. Thecircadian rhythm of the NAT gene exprsession in pineal changed after MWR exprosure,with the most down-regulation at ZT16:00timepoint. Simultaneously, MWR exposurealtered the mean values and amplitudes of the NAT gene exprsession rhythm, with adelayed peak phase.(3) By measurements in vitro, it was shown that melatonininhibited cell proliferation, lowered the testosterone levels in the supernatant, decreasedintracellular cAMP, and down-regulated mRNA expression of nuclear transcriptionfactor GATA-4and its target genes SF-1(NR5A1), StAR, P450scc (CYP11A1) and3β-HSD, as well as their protein expression. However, the effects of melatonin wereblocked by Luzindole, especially in high melatonin dose level. At0.5h,1h and2h afterintra-testicular injection of melatonin, plasma testosterone level was reduced, Mel1a,GATA-4, SF-1(NR5A1) expression was downregulated, but these effects disappeared at4h. MWR exposure decreased testosterone levels in the culture supernatant of TM3cells, induced reduction of intracellular cAMP and mitochondrial membrane potentiallevels, down-regulated mRNA expression of testosterone synthesis regulatory factor ofSF-1, StAR and P450scc.
Conclusions:
(1) Animal and cell models of microwave radiation were established, andchronotoxicity of reproductive function and testosteron secretion exposed to MWR wasrevealed.
(2) MWR altered circadian rhythms of melatonin secretion and melatoninsynthetase NAT mRNA, and melatonin mediated the reproductive chronotoxicity in ratsby MWR.
(3) Melatonin inhibited testosterone secretion via the GATA-4/SF-1signalingpathway in vitro and vivo, with the GATA-4as a key regulatory factor.
方法：(1)微波辐射对雄性大鼠生殖系统的昼夜时间毒性。以褪黑素日节律筛选具有昼夜(L:D,12h:12h)节律的SD大鼠，分别在授时时间（zeitgeber time，ZT,以ZT0为光照开始）ZT0, ZT4, ZT8, ZT12, ZT16和ZT20进行微波辐射（1800MHz，205μw/cm2），每次2h，每天一次，连续32天。对应的假辐射组（Sham）同样处理但不给予微波信号。辐射后24h内每隔4h尾静脉采血一次，ELISA法测定睾酮含量；同时Sham和MWR各时点组在辐射结束时点采集睾丸和附睾组织。测定附睾精子活动度；制作睾丸HE病理切片，测定睾丸每日精子生成量、睾丸标志酶ACP和γ-GT活性，Real-time PCR检测睾酮合成基因StAR和p450cc mRNA表达。利用余弦节律分析软件，根据方程式F(t)=M+Acos(ωt+Φ)将各指标数据拟合为余弦曲线，分析节律参数。(2)微波辐射改变大鼠褪黑素分泌的昼夜节律。微波辐射方法同上，辐射32天后，24h内每隔4h尾静脉采血一次，ELISA法检测血浆褪黑素浓度，同时Sham和MWR各时点组在辐射结束时点采集松果体，Real-time PCR测定褪黑素合成酶NAT mRNA的表达。节律分析同上。(3)褪黑素抑制睾酮分泌的信号通路及微波辐射对睾丸间质细胞睾酮分泌的影响。以小鼠睾丸间质细胞系（TM3）细胞作为研究对象，添加不同浓度(0,10-6,10-8,10-10和10-12mol/L)的褪黑素，或先添加褪黑素受体阻断剂（Luzindole，1μmol/L）再加褪黑素，MTT法检测细胞增殖、流式细胞仪检测线粒体膜电位、ELISA法检测睾酮和cAMP，Real-time PCR和Western blotting测定褪黑素受体和睾酮相关基因GATA-4，SF-1，StAR，P450cc和3β-HSD的mRNA和蛋白的表达。通过睾丸注射褪黑素，利用免疫组化和免疫荧光方法以整体动物实验验证褪黑素抑制睾酮合成的信号通路。采用TM3细胞进行体外培养，在1800MHz微波辐射（205μw/cm2）2h后，流式细胞仪检测线粒体膜电位，ELISA法测定睾酮和cAMP含量，Real-time PCR测定睾酮代谢调节因子相关基因SF-1、StAR和P450cc mRNA表达的改变。
结果：(1)微波辐射可使雄性大鼠睾丸组织发生病理改变，降低睾丸每日精子生成量、精子活动度、睾丸标志酶ACP和γ-GT活性，其中ACP和γ-GT活性以及每日精子生成量的下降在ZT0时辐射的MWR0组最为明显。微波辐射还可改变血浆睾酮的昼夜节律，其中MWR0、MWR8、MWR12和MWR20组的昼夜节律消失，同时MWR0组大鼠血浆中睾酮的日均值水平下降最大。睾酮合成调控因子StAR和P450cc的mRNA表达在微波辐射后失去昼夜节律，且MWR0变化最大，提示大鼠雄性生殖系统对微波辐射最敏感的时点为ZT0:00。(2)微波辐射降低褪黑素的日均分泌量，其中以MWR16组最为明显。微波辐射扰乱褪黑素合成的昼夜节律，其中MWR8，MWR16和MWR20组的血浆褪黑素昼夜节律被破坏，而振幅变化在MWR16组最为明显，表明在ZT16:00时微波辐射对大鼠血浆褪黑素节律的影响最大。MWR后松果体NAT基因表达的昼夜节律改变，以ZT16时下调最为明显，同时表达的中值和振幅明显改变，峰值相位明显滞后。(3)褪黑素在体外可抑制TM3细胞增殖，降低睾酮含量，减少细胞内cAMP浓度，改变线粒体膜电位，下调核转录因子GATA-4及其目标基因SF-1，StAR，Cyp11A，HSD3β的基因和蛋白表达。褪黑素的这些抑制作用可被褪黑素受体阻断剂Luzindole所拮抗，特别是在褪黑素高水平作用时。大鼠睾丸组织注射褪黑素后0.5h、1h、2h，血浆中睾酮含量降低，睾丸间质细胞膜受体Mel1a，GATA-4和SF-1表达减弱，4h后上述效应消失。微波辐射后TM3细胞上清睾酮含量降低，细胞内cAMP浓度和线粒体膜电位水平下降，睾酮合成调节因子SF-1，StAR，P450cc基因表达下调。
结论：
1、建立了微波辐射大鼠的动物模型，发现微波辐射对雄性大鼠的生殖功能和睾酮内分泌具有昼夜时间毒性。
2、微波辐射可改变褪黑素分泌和褪黑素合成酶NAT mRNA的昼夜节律，并通过褪黑素介导对雄性大鼠生殖功能的时间毒性。
3、体内外实验证实褪黑素通过GATA-4/SF-1信号通路抑制睾酮分泌，其中GATA-4因子起着关键性的作用。
Objective: Microwave Radiation (MWR) is an important environmentalelectromagnetic pollutant with the rapid development of wireless communicationtechnology and mobile phone users in the world. It has been reported that MWRexposure may cause damage on male reproduction system, and it is therefore importantto clarify the route and mechanism of the MWR damage. Circadian rhythms of thephysiological and behavioral functions have been widely demonstrated in mammals,which result in different sensitivities of animals to toxicants and MWR at different timesof a day. This project is to study the circadian rhythm of male reproduction system andmelatonin (melatonin, MEL) toxicity induced by MWR with the combination ofchronobiology and reproductive endocrine toxicology on the basis of established animalmodel of microwave radiation, and to ellucidate the mechanism underlyingGATA-4/SF-1signal pathway that inhibits testosterone secretion in TM3Leydig cells,so that to provide with new ways in prevention and treatment of the male reproductionmalfunction caused by MWR.
Methods:(1) Chronotoxicity of reproductive system in male rats exposed to MWR.Animals in circadian rhythm (as indicated by melatonin measurements) were dividedinto several groups and exposed to1800MHz RF at205μw/cm2power density for2h/dfor32days at different zeitgeber time (ZT) points, viz., ZT0, ZT4, ZT8, ZT12, ZT16and ZT20. Sham-exposed animals were used as controls in the study. From each rat,0.1ml blood samples were colleted from the caudal vein every4hours (ZT0, ZT4, ZT8,ZT12, ZT6and ZT20) after MWR exprosure to determine the concentration oftestosterone using the ELISA KIT. Testicular and epididymis tissues were collected forHE pathological section and assessed for testosterone levels, daily sperm productionand sperm motility, testis marker enzymes γ-GT and ACP, cytochrome P450side-chaincleavage (p450cc) mRNA expression, and steroidogenic acute regulatory protein (StAR)mRNA expression. The data obtained were then fitted for cosinor analysis as expressed in Eq.F(t)=M+Acos(w t+j).(2) Circadian alterations of melatonin secretion in male ratsexposed to MWR. The MWR and blood samples celection were the same as the firstsection. The concentration of MEL was determined by the ELISA KIT. Pineals werecollected after MWR from Sham and MWR groups at the end of exposure timepointsrespectively to determine melatonin synthetase NAT mRNA by Real-time PCR.(3)Signal pathway of testosterone secretion inhibition by melatonin and effects of MWRon testosterone secretion in TM3cells. TM3Cells were plated in the presence orabsence of melatonin (0,10-6,10-8,10-10and10-12mol/L) and melatonin receptorantagonist Luzindole (1μmol/L) for3h in multiwell-plates (six wells). Thenintracellular cAMP and testosterone levels in the supernatant were measured by ELISA.Gene and protein expression of the pathway foctors (Mel1a，GATA-4，SF-1，StAR，P450cc and3β-HSD) were determined by Real-qPCR and Western blot.Immunohistochemical (GATA-4) and immunofluorescence (SF-1and Mel1a) analysiswere used to verifiy the signal pathway in vivo model by intra-testicular injection ofmelatonin in C57BL/6J mice. The TM3Cells were exposed to1800MHz MWR (205μw/cm2) for2h to determine mitochondrial membrane potential by flow cytometry. Theintracellular cAMP and testosterone levels in the supernatant were measured by ELISA.Gene and protein expression of SF-1, StAR and P450cc were determined by Real-qPCR.
Results:(1) MWR exposure led to histopathologic changes in testicles, lower dailysperm production and sperm motility, down-regulated activity of γ-GT and ACP, withthe most pronounced change in the MWR0group. Rats exposed to MWR exhibited analteration in circadian rhythms of plasma testosterone, which were absent in MWR0,MWR8, MWR12and MWR20groups. At the same time, the daily average testosteronelevel was most reduced in the MWR0group. Two testosterone synthesis regulatoryfactors of P450cc and StAR mRNA lost their circadian rhythms after MWR exposureand changed most dramatically in the MWR0group. These results suggest that the malereproduction system in rat was most sensitive to MWR exposure at ZT0.(2) MWRexposure decreased daily average testosterone levels, especially in the MWR0group.MWR exposure disturbed the circadian rhythms of plasma melatonin in MWR8, MWR16and MWR20groups, with the greatest amplitude reduction in MWR16group. These findings indicate that the biggest change in plasma melatonin occured at ZT16:00. Thecircadian rhythm of the NAT gene exprsession in pineal changed after MWR exprosure,with the most down-regulation at ZT16:00timepoint. Simultaneously, MWR exposurealtered the mean values and amplitudes of the NAT gene exprsession rhythm, with adelayed peak phase.(3) By measurements in vitro, it was shown that melatonininhibited cell proliferation, lowered the testosterone levels in the supernatant, decreasedintracellular cAMP, and down-regulated mRNA expression of nuclear transcriptionfactor GATA-4and its target genes SF-1(NR5A1), StAR, P450scc (CYP11A1) and3β-HSD, as well as their protein expression. However, the effects of melatonin wereblocked by Luzindole, especially in high melatonin dose level. At0.5h,1h and2h afterintra-testicular injection of melatonin, plasma testosterone level was reduced, Mel1a,GATA-4, SF-1(NR5A1) expression was downregulated, but these effects disappeared at4h. MWR exposure decreased testosterone levels in the culture supernatant of TM3cells, induced reduction of intracellular cAMP and mitochondrial membrane potentiallevels, down-regulated mRNA expression of testosterone synthesis regulatory factor ofSF-1, StAR and P450scc.
Conclusions:
(1) Animal and cell models of microwave radiation were established, andchronotoxicity of reproductive function and testosteron secretion exposed to MWR wasrevealed.
(2) MWR altered circadian rhythms of melatonin secretion and melatoninsynthetase NAT mRNA, and melatonin mediated the reproductive chronotoxicity in ratsby MWR.
(3) Melatonin inhibited testosterone secretion via the GATA-4/SF-1signalingpathway in vitro and vivo, with the GATA-4as a key regulatory factor.
引文
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