氯化汞对小鼠睾丸间质瘤细胞类固醇激素合成的影响及机制研究
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摘要
近年来全球范围的人类生育能力明显下降,不孕症发病率尤其是男性不孕症发病率呈逐年增长趋势,这已成为影响人类发展与健康的一个全球性医学和社会学问题。这种现象的发生主要归因于近年来的社会竞争、就业压力以及环境的恶化等等。其中日益加剧的环境污染是导致该现象的主要原因。能引起生殖障碍的环境污染物种类繁多,重金属汞是其中的一种。汞是人体非必需的元素。金属汞常温下呈液态。金属汞及其化合物广泛存在于自然界中,用途极为广泛。目前国内外学者对甲基汞的研究较多,而对无机汞的毒性虽已有大量研究,但主要集中在神经毒性和肾脏毒性的作用机制研究,而对生殖毒性方面的研究较少。人群流行病学研究发现汞能蓄积在睾丸组织中,影响精子数量、质量以及生精过程,并能透过血-睾屏障,诱发男性不孕症的发生。急性毒性试验也显示,小鼠在未出现明显的神经系统中毒症状之前,睾丸组织中汞的含量已明显增高,并出现明显的病理学改变,说明汞损伤睾丸生理功能的阈剂量比引起神经毒性的阈剂量低,睾丸对汞的毒性更为敏感。此外,汞还能引起动物内分泌激素的改变,HgCl_2染毒的家兔,其血清睾酮水平明显低于染毒前,且接触汞作业男性工人血清睾酮水平也明显下降,同时伴有性功能障碍:醋酸汞能使经HCG刺激的Leydig细胞睾酮含量显著性下降并出现明显的剂量-反应关系,但其作用机制目前还未见报道。本研究利用MA-10小鼠睾丸间质瘤细胞(MA-10 mouse Leydig tumor cells,mLTC-1)作为模型,观察HgCl_2对睾丸间质细胞类固醇激素合成的影响,并初步探讨其作用机制,为进一步研究其生殖和发育毒性机制提供理论依据。
方法
1.HgCl_2对mLTC-1细胞活性的影响:采用MTT比色法将对数生长期的mLTC-1细胞以4×10~4/ml接种于96孔板上,分别加入不同浓度HgCl_2(0、10~(-10)、10~(-9)、10~(-8)、10~(-7)、10~(-6)、10~(-5)和10~(-4) mol/L)对细胞染毒,每个浓度设6个复孔,在酶标仪上测各孔OD值,确定染毒剂量。
2.mLTC-1细胞培养基上清中孕酮的分泌量:对数生长期的mLTC-1细胞以4x10~4/ml接种于24孔板,分别作如下操作:(1)加入不同浓度的HCG(0.0 IU/ml、0.1IU/ml、1.0IU/ml、10.0IU/ml、100.0IU/ml),培养4h后,RIA测各孔培养上清液中孕酮的含量;(2)加入10.0 IU/ml HCG和10~(-7) mol/L HgCl_2混合染毒,以10.0 IU/ml HCG作为对照,分别在1h、2h、3h、6h、12h、24h提取培养上清液,RIA测定培养上清液中孕酮的含量;(3)分别加入含HgCl_2浓度为0、10~(-8)、10~(-7)、10~(-6)和10~(-5) mol/L,含HCG浓度为10 IU/ml的无FBS的培养基,染毒2h后,RIA测定培养上清中孕酮的含量。
3.mLTC-1细胞中StAR和P450scc mRNA表达水平:将铺满瓶底的80%左右的mLTC-1细胞分别加入含不同浓度HgCl_2(0、10~(-8)、10~(-7)、10~(-6)和10~(-5) mol/L)的无FBS的培养基,对细胞染毒2h后,提取RNA,以β-actin基因为内参照,运用半定量RT-PCR技术检测各个剂量组HgCl_2对mLTC-1细胞StAR和P450sccmRNA的表达。
结果
1.MTT结果显示:不同浓度的HgCl_2作用于mLTC-1细胞后的OD值不同,10~(-5) mol/L HgCl_2能明显促进细胞的增值,与对照组相比,差异有统计学意义(P＜0.05);10~(-4) mol/L HgCl_2能明显抑制细胞的增值,且与对照组相比,差异有统计学意义(P＜0.05);而10~(-6)～10~(-8) mol/L的HgCl_2虽能轻微刺激mLTC-1细胞增长,但与对照组比较,差异无统计学意义(P＞0.05),即在该剂量下HgCl_2对mLTC-1细胞活性没有明显影响。
2.RIA结果显示:(1)给予HCG刺激后,mLTC-1细胞分泌孕酮量随HCG浓度的增加而增加,在10IU/ml剂量时,其分泌量进入平台期,故选择该剂量作为HCG最佳刺激浓度;(2)10 IU/ml HCG与10~(-7) mol/L HgCl_2染毒组和10 IU/mlHCG对照组的mLTC-1细胞分泌孕酮量在6h达到最高峰,6h前随时间的增加而增加,6h后出现下降趋势,到24h孕酮量基本接近零。HgCl_2染毒组在2h和12h时分泌孕酮量比同时间HCG对照组孕酮分泌量下降,且二者差异有统计学意义(P＜0.05),而HgCl_2染毒组在1h、3h、6h和24h分泌孕酮量比同时间HCG对照组孕酮分泌量虽有所下降,但均无统计学差异(P＞0.05);(3)mLTC-1细胞经过含有10 IU/ml的HCG和0 mol/L、10~(-8) mol/L、10~(-7) mol/L、10~(-6) mol/L和10~(-5) mol/L的HgCl_2的混合染毒后,各染毒组mLTC-1细胞分泌孕酮量均比对照组下降,但仅10~(-7) mol/L和10~(-6) mol/L HgCl_2染毒组与对照组比较,差异有统计学意义(P＜0.05),而10~(-5) mol/L和10~(-8) mol/L HgCl_2染毒组与对照组比较,差异无统计学意义(P＞0.05)。
3.半定量RT-PCR结果显示:10~(-5)～10~(-7) mol/L HgCl_2剂量组StAR和P450sccmRNA的表达量比对照组该两个基因表达量低,且差异有统计学意义(P＜0.05)。而10~(-8) mol/L HgCl_2剂量组的StAR和P450scc的mRNA的达量虽比对照组低,但差异无统计学意义(P＞0.05)。
结论
本实验条件下,HgCl_2对mLTC-1细胞分泌孕酮存在时间.效应关系和剂量-效应关系;并且HgCl_2可能是通过抑制StAR和P450sc表达而降低mLTC-1细胞分泌孕酮的。
In recent years,the capacity of the human reproductive in global scope decreased significantly,the incidence of infertility patients especially with male infertility is growing year by year.It has become a global medical and sociological issue that impact human development and health.This phenomenon mainly attributed to the social competition,the employment pressure and the deterioration of the environment and so on.The growing environmental pollution is the main reason leading to the phenomenon.A wide range of environmental pollutants can lead to reproductive disorders,Heavy metals is one of the environmental pollutants.Mercury is non-essential for humanbody,it is liquid at room temperature.Mercury and its compounds are widespread in nature,its usage is extremely broad.In recent years, scholars at home and abroad study methylmercury much more than inorganic mercury, and the study of inorganic mercury is concentration in nerve toxicity and kidney toxicity,but the study of reproductive toxicity is less.Epidemiological study on the crowd showed that the accumulation of mercury found in the testes,it also affected the quantity and quality of sperm and the spermatogenic process,and it can through the blood-testis barrier,which can induce male infertility.Acute toxicity tests also showed that the level of mercury in the mice testicular tissue has increased significantly and appeared a clear and pathological change before the symptoms of nervous toxicity,it showed that the threshold dose of mercury injuded testicular physiological function lower than the threshold dose caused nerve toxicity,so mercury is more sensitive to the testicular.In addition,mercury can also cause the changes of animal endocrine secretion.Testosterone levels in serum of the rabbits exposed to mercuric chloride were significantly lower than that before the exposure, and the testosterone levels in serum of male workers exposed to mercury also declined, accompanied with sexual dysfunction.Testosterone levels of Leydig cells exposed mercury acetate were significantly decreased and it had a dose-response relationship. But its mechanism is not reported.This study will use MA-10 mouse Leydig tumor cells(mLTC-1) as a model,and observation the effect of HgCl_2 on the steroidgenesis in mouse Leydig tumor cells and its mechanism,it will provide a theoretical basis for the mechanisms of reproductive and developmental toxicity in the furture.
Methods
1.The cell viability of mLTC-1 affected by HgCl_2:The mLTC-1 cells of logarithmic phase were plated in 96-well plates,added culture medium containing different concentrations of HgCl_2(0,10~(-10),10~(-9),10~(-8),10~(-7),10~(-6),10~(-5) and 10~(-4) mol/L) respectively.Each concentration for six parallel ways,the OD value was measured by MTT.
2.The secretion of progesterone of mLTC-1 cells:The mLTC-1 cells of logarithmic phase were plated in 96-well plates,each concentration for six parallel way,did the following step,respectively:(1)added diffenrent concentrations of HCG(0.0 IU/ml,0.1 IU/ml,1.0 IU/ml,10.0 IU/ml,100.0 IU/ml),after 4h,progester -one of supernatant was measured by the RIA;(2) Exposed on the mixture of 10.0 IU/ml HCG and 10~(-7) mol/L HgCl_2,10.0 IU/ml HCG as the control,after 1h,2h,3h, 6h,12h,24h,progesterone of supernatant was measured by the RIA;(3) added FBS -free mudium containing the different concentration of HgCl_2(0,10~(-8),10~(-7),10~(-6)and 10~(-5)mol/L) and 10IU/ml HCG,after 2h,progesterone of supernatant was measured by the RIA.
3.The level of mRNA expression of StAR and P450scc in mLTC-1 cells was determined by semi-quantitative RT-PCR:FBS-free medium containing different concentrations HgCl_2(0,10~(-8),10~(-7),10~(-6)and 10~(-5)mol/L) were added to mLTC-1 cells, after 2h,extracted RNA,the level of mRNA expression of StAR and P450scc in mLTC-1 cells was determined by semi-quantitative RT-PCR.
Results
1.The results of MTT assay showed that exposure of mLTC-1 cells to different concentrations of mercury chloride can promote cells growth in the dose of 10~(-5) mol/L and inhibit cells growth in the dose of 10~(-4) mol/L,they had significant statistically differences compared with the control group.Also it had no remarked effect on the viability of mLTC-1 in the other dose.
2.The RIA results showed that:(1) given HCG stimulation,the secretion function of mLTC-1 cells incesased with the concentration of HCG,but when the concentration of HCG reached 10.0 IU/ml,the secretion function of mLTC-1 cells enter the platform,so10.0 IU/ml was the best concentration;(2) the progesterone secretion of mLTC-1 exposed on HCG and the mixture of HCG and mercury chloride reached its peak after 6h,followed by the downward trend,it is close to zero after 24h. The secretion of mLTC-1 cells in mixed stimulation group decreased than that of the HCG control group at all time points,and it had statistically differences compared with the control at 2h and 12h(P＜0.05),but there was no statistically difference at other time points(P＞0.05);(3) after stimulationg,the progesterone secretion of mLTC-1 in all dose group is lower than that of the control groups,just the 10~(-5) mol/L and 10~(-8) mol/L dose groups had statistically differences compared with the control(P＜0.05).
3.The level of mRNA express of StAR and P450scc:Semi-quantitative RT-PCR showed that the level of mRNA express of StAR and p450scc in the mLTC-1 cells had statistically differences compared with the control in the dose of 10~(-5)～10~(-7) mol/L mercury chloride and had no statistically differences compared with the control in the dose of 10~(-8) mol/L mercury chloride.
Conclusions
This study demonstrated that it has the dose-effect relationgship and the time-effect relationship of HgCl_2 on the steroidgenesis in mLTC-1,and it may reduce secretion of progesterone by inhibiting the expression of StAR and P450scc.
方法
1.HgCl_2对mLTC-1细胞活性的影响:采用MTT比色法将对数生长期的mLTC-1细胞以4×10~4/ml接种于96孔板上,分别加入不同浓度HgCl_2(0、10~(-10)、10~(-9)、10~(-8)、10~(-7)、10~(-6)、10~(-5)和10~(-4) mol/L)对细胞染毒,每个浓度设6个复孔,在酶标仪上测各孔OD值,确定染毒剂量。
2.mLTC-1细胞培养基上清中孕酮的分泌量:对数生长期的mLTC-1细胞以4x10~4/ml接种于24孔板,分别作如下操作:(1)加入不同浓度的HCG(0.0 IU/ml、0.1IU/ml、1.0IU/ml、10.0IU/ml、100.0IU/ml),培养4h后,RIA测各孔培养上清液中孕酮的含量;(2)加入10.0 IU/ml HCG和10~(-7) mol/L HgCl_2混合染毒,以10.0 IU/ml HCG作为对照,分别在1h、2h、3h、6h、12h、24h提取培养上清液,RIA测定培养上清液中孕酮的含量;(3)分别加入含HgCl_2浓度为0、10~(-8)、10~(-7)、10~(-6)和10~(-5) mol/L,含HCG浓度为10 IU/ml的无FBS的培养基,染毒2h后,RIA测定培养上清中孕酮的含量。
3.mLTC-1细胞中StAR和P450scc mRNA表达水平:将铺满瓶底的80%左右的mLTC-1细胞分别加入含不同浓度HgCl_2(0、10~(-8)、10~(-7)、10~(-6)和10~(-5) mol/L)的无FBS的培养基,对细胞染毒2h后,提取RNA,以β-actin基因为内参照,运用半定量RT-PCR技术检测各个剂量组HgCl_2对mLTC-1细胞StAR和P450sccmRNA的表达。
结果
1.MTT结果显示:不同浓度的HgCl_2作用于mLTC-1细胞后的OD值不同,10~(-5) mol/L HgCl_2能明显促进细胞的增值,与对照组相比,差异有统计学意义(P＜0.05);10~(-4) mol/L HgCl_2能明显抑制细胞的增值,且与对照组相比,差异有统计学意义(P＜0.05);而10~(-6)～10~(-8) mol/L的HgCl_2虽能轻微刺激mLTC-1细胞增长,但与对照组比较,差异无统计学意义(P＞0.05),即在该剂量下HgCl_2对mLTC-1细胞活性没有明显影响。
2.RIA结果显示:(1)给予HCG刺激后,mLTC-1细胞分泌孕酮量随HCG浓度的增加而增加,在10IU/ml剂量时,其分泌量进入平台期,故选择该剂量作为HCG最佳刺激浓度;(2)10 IU/ml HCG与10~(-7) mol/L HgCl_2染毒组和10 IU/mlHCG对照组的mLTC-1细胞分泌孕酮量在6h达到最高峰,6h前随时间的增加而增加,6h后出现下降趋势,到24h孕酮量基本接近零。HgCl_2染毒组在2h和12h时分泌孕酮量比同时间HCG对照组孕酮分泌量下降,且二者差异有统计学意义(P＜0.05),而HgCl_2染毒组在1h、3h、6h和24h分泌孕酮量比同时间HCG对照组孕酮分泌量虽有所下降,但均无统计学差异(P＞0.05);(3)mLTC-1细胞经过含有10 IU/ml的HCG和0 mol/L、10~(-8) mol/L、10~(-7) mol/L、10~(-6) mol/L和10~(-5) mol/L的HgCl_2的混合染毒后,各染毒组mLTC-1细胞分泌孕酮量均比对照组下降,但仅10~(-7) mol/L和10~(-6) mol/L HgCl_2染毒组与对照组比较,差异有统计学意义(P＜0.05),而10~(-5) mol/L和10~(-8) mol/L HgCl_2染毒组与对照组比较,差异无统计学意义(P＞0.05)。
3.半定量RT-PCR结果显示:10~(-5)～10~(-7) mol/L HgCl_2剂量组StAR和P450sccmRNA的表达量比对照组该两个基因表达量低,且差异有统计学意义(P＜0.05)。而10~(-8) mol/L HgCl_2剂量组的StAR和P450scc的mRNA的达量虽比对照组低,但差异无统计学意义(P＞0.05)。
结论
本实验条件下,HgCl_2对mLTC-1细胞分泌孕酮存在时间.效应关系和剂量-效应关系;并且HgCl_2可能是通过抑制StAR和P450sc表达而降低mLTC-1细胞分泌孕酮的。
In recent years,the capacity of the human reproductive in global scope decreased significantly,the incidence of infertility patients especially with male infertility is growing year by year.It has become a global medical and sociological issue that impact human development and health.This phenomenon mainly attributed to the social competition,the employment pressure and the deterioration of the environment and so on.The growing environmental pollution is the main reason leading to the phenomenon.A wide range of environmental pollutants can lead to reproductive disorders,Heavy metals is one of the environmental pollutants.Mercury is non-essential for humanbody,it is liquid at room temperature.Mercury and its compounds are widespread in nature,its usage is extremely broad.In recent years, scholars at home and abroad study methylmercury much more than inorganic mercury, and the study of inorganic mercury is concentration in nerve toxicity and kidney toxicity,but the study of reproductive toxicity is less.Epidemiological study on the crowd showed that the accumulation of mercury found in the testes,it also affected the quantity and quality of sperm and the spermatogenic process,and it can through the blood-testis barrier,which can induce male infertility.Acute toxicity tests also showed that the level of mercury in the mice testicular tissue has increased significantly and appeared a clear and pathological change before the symptoms of nervous toxicity,it showed that the threshold dose of mercury injuded testicular physiological function lower than the threshold dose caused nerve toxicity,so mercury is more sensitive to the testicular.In addition,mercury can also cause the changes of animal endocrine secretion.Testosterone levels in serum of the rabbits exposed to mercuric chloride were significantly lower than that before the exposure, and the testosterone levels in serum of male workers exposed to mercury also declined, accompanied with sexual dysfunction.Testosterone levels of Leydig cells exposed mercury acetate were significantly decreased and it had a dose-response relationship. But its mechanism is not reported.This study will use MA-10 mouse Leydig tumor cells(mLTC-1) as a model,and observation the effect of HgCl_2 on the steroidgenesis in mouse Leydig tumor cells and its mechanism,it will provide a theoretical basis for the mechanisms of reproductive and developmental toxicity in the furture.
Methods
1.The cell viability of mLTC-1 affected by HgCl_2:The mLTC-1 cells of logarithmic phase were plated in 96-well plates,added culture medium containing different concentrations of HgCl_2(0,10~(-10),10~(-9),10~(-8),10~(-7),10~(-6),10~(-5) and 10~(-4) mol/L) respectively.Each concentration for six parallel ways,the OD value was measured by MTT.
2.The secretion of progesterone of mLTC-1 cells:The mLTC-1 cells of logarithmic phase were plated in 96-well plates,each concentration for six parallel way,did the following step,respectively:(1)added diffenrent concentrations of HCG(0.0 IU/ml,0.1 IU/ml,1.0 IU/ml,10.0 IU/ml,100.0 IU/ml),after 4h,progester -one of supernatant was measured by the RIA;(2) Exposed on the mixture of 10.0 IU/ml HCG and 10~(-7) mol/L HgCl_2,10.0 IU/ml HCG as the control,after 1h,2h,3h, 6h,12h,24h,progesterone of supernatant was measured by the RIA;(3) added FBS -free mudium containing the different concentration of HgCl_2(0,10~(-8),10~(-7),10~(-6)and 10~(-5)mol/L) and 10IU/ml HCG,after 2h,progesterone of supernatant was measured by the RIA.
3.The level of mRNA expression of StAR and P450scc in mLTC-1 cells was determined by semi-quantitative RT-PCR:FBS-free medium containing different concentrations HgCl_2(0,10~(-8),10~(-7),10~(-6)and 10~(-5)mol/L) were added to mLTC-1 cells, after 2h,extracted RNA,the level of mRNA expression of StAR and P450scc in mLTC-1 cells was determined by semi-quantitative RT-PCR.
Results
1.The results of MTT assay showed that exposure of mLTC-1 cells to different concentrations of mercury chloride can promote cells growth in the dose of 10~(-5) mol/L and inhibit cells growth in the dose of 10~(-4) mol/L,they had significant statistically differences compared with the control group.Also it had no remarked effect on the viability of mLTC-1 in the other dose.
2.The RIA results showed that:(1) given HCG stimulation,the secretion function of mLTC-1 cells incesased with the concentration of HCG,but when the concentration of HCG reached 10.0 IU/ml,the secretion function of mLTC-1 cells enter the platform,so10.0 IU/ml was the best concentration;(2) the progesterone secretion of mLTC-1 exposed on HCG and the mixture of HCG and mercury chloride reached its peak after 6h,followed by the downward trend,it is close to zero after 24h. The secretion of mLTC-1 cells in mixed stimulation group decreased than that of the HCG control group at all time points,and it had statistically differences compared with the control at 2h and 12h(P＜0.05),but there was no statistically difference at other time points(P＞0.05);(3) after stimulationg,the progesterone secretion of mLTC-1 in all dose group is lower than that of the control groups,just the 10~(-5) mol/L and 10~(-8) mol/L dose groups had statistically differences compared with the control(P＜0.05).
3.The level of mRNA express of StAR and P450scc:Semi-quantitative RT-PCR showed that the level of mRNA express of StAR and p450scc in the mLTC-1 cells had statistically differences compared with the control in the dose of 10~(-5)～10~(-7) mol/L mercury chloride and had no statistically differences compared with the control in the dose of 10~(-8) mol/L mercury chloride.
Conclusions
This study demonstrated that it has the dose-effect relationgship and the time-effect relationship of HgCl_2 on the steroidgenesis in mLTC-1,and it may reduce secretion of progesterone by inhibiting the expression of StAR and P450scc.
引文
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