海带多糖对慢性电离辐射致雄性大鼠生殖功能损伤干预机制的探讨
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摘要
随着人类社会的发展,人类面临着比过去更多天然本底辐射的危险；近半个多世纪来世界各国男性生殖能力出现了明显下降；睾丸组织作为电离辐射的敏感靶器官,电离辐射已成为导致人类男性性功能障碍和不育的最常见原因之一；男性生殖健康面临着十分严峻的形势,改善和维护男性的生殖健康日益受到关注。
海带多糖(Laminaria japonica polysaccharides, LJP)是存在于海带细胞间和细胞内的一类天然大分子物质,由褐藻酸钠(Algin)、褐藻淀粉(Laminarin)和褐藻糖胶(Fucoidan)三种成分组成；研究表明,海带多糖不仅具有抗凝血、抗动脉硬化、抗肿瘤、抗病毒等生物学活性,还具有抗辐射作用；但在慢性局部电离辐射和生殖功能防护领域的研究报道甚少。
因此本研究旨在通过对慢性局部辐射致雄性大鼠性功能、生精功能、睾丸细胞等损伤后的自身恢复及其相关分子异常表达调控的研究,比较海带多糖干预后对其辐射损伤恢复及相关分子调控效果的影响；从动物整体、细胞以及分子水平上探讨海带多糖对慢性局部辐射致大鼠生殖功能损伤后恢复影响的可能机制。为进一步研究海带多糖抗辐射机理提供科学依据；并为海带多糖的深加工和开发安全有效的生殖保健产品提供理论支持。
第一部分海带多糖对慢性电离辐射致雄性大鼠性功能损伤恢复的干预机制探讨
目的：观察慢性局部辐射导致雄性大鼠性功能损伤后自身恢复的情况以及海带多糖干预后其损伤恢复的效果,探讨海带多糖对其辐射损伤恢复影响的可能作用机理,为下一步研究提供依据。方法：56只Wistar雄性大鼠适应性饲养7d后随机分为对照组、模型3个组和LJP 3个组；LJP 3个组给予LJP100mg.kg-1.d-1灌胃,其余各组以等量生理盐水灌胃；除对照组外,各组进行60Coγ射线局部照射,每天1次,每周连续5次,共20次,总剂量2.3 Gy.只-1；分别在停止照射后1、7和14 d进行勃起、交配试验,1天后处死,收集血液,分离睾丸、附睾等组织；检测大鼠交配及阴茎勃起,机体、性腺器官质量及其脏器系数,血清性激素(LH、FSH、Ts和E2)等各项指标。结果：慢性局部电离辐射后随着1、7、14d恢复时间的延长,模型1、7、14d组除睾丸质量显著减轻外(P<0.01),大鼠体质量、附睾、精囊腺与前列腺的质量逐步增加,均低于对照组；而LJP各组的体质量、睾丸、附睾、精囊腺与前列腺质量均随时间延长逐步增加,各组质量均大于对应模型组,且LJP7、14d组的睾丸质量比对应模型组显著增加(P<0.05)；模型各组的睾丸、附睾、精囊腺与前列腺的脏器系数均随时间的延长逐步减少,且其睾丸脏器系数与对照组相比差异极其显著(P<0.01)；而LJP各组的睾丸脏器系数与对照组和对应模型组相比同样存在显著差异(P<0.01),更接近对照组。模型各组勃起、骑跨潜伏期显著延长(P<0.01),骑跨、射精次数明显减少(P<0.01)；LJP各组随恢复时间的延长而勃起、骑跨潜伏期缩短,骑跨、射精次数增加；LJP14d组的各指标与对照组更接近(P>0.05)。模型1、7、14d组与对照组相比,血清LH、FSH、Ts含量减少,停止辐射14d后下降明显(P<0.01)；血清E2含量持续升高,但仍低于对照组;LJP1、7、14d组在辐射后,血清Ts由低到高,血清LH和FSH的含量均呈现下降趋势,血清E2由高到低变化,14d后血清LH、FSH、Ts和E2含量值趋于对照组(P>0.05)。结论：海带多糖促进了辐射损伤后在停止辐射恢复期间大鼠机体和睾丸质量的增加以及睾丸脏器系数的提高,进而改善了损伤后大鼠血清性激素LH、FSH、Ts、E2的水平；通过下丘脑-垂体-睾丸性腺轴系的调控,缩短了阴茎勃起和骑跨潜伏期,提高骑跨和射精次数；对慢性局部电离辐射致雄性大鼠性功能损伤后的恢复改善产生了显著作用。
第二部分海带多糖对慢性电离辐射致大鼠生精功能损伤恢复的干预机制探讨
目的：观察慢性局部辐射造成雄性大鼠睾丸生精功能损伤后自身恢复的情况以及海带多糖干预后其损伤恢复的效果,探讨海带多糖对其损伤恢复的可能作用机理,为下一步研究提供依据。方法：56只Wistar雄性大鼠适应性饲养7d后随机分为对照组、模型3个组和LJP3个组；LJP3个组给予LJP100mg.kg-1.d-1灌胃,其余各组以等量生理盐水灌胃；除对照组外,各组进行60Coγ射线局部照射,每天1次,每周连续5次,共20次,总剂量2.3 Gy.只-1；分别在停止照射1、7和14d后处死大鼠,分离大鼠睾丸组织；制作光镜和电镜切片观察睾丸组织形态,测定大鼠精子数量及其存活率,睾丸组织MDA、GSH含量及SOD、GSH-PX、LDH活力等指标。结果：大鼠在受到慢性局部电离辐射后,在14d恢复期间,与对照组相比,LJPld组(P<0.05)与模型和LJP各组精子数量及存活率持续显著降低(P<0.01)；但LJP各组精子数量降低趋势减缓,精子存活率增加,与对应模型组相比差异均有显著性(P<0.01)。光镜观察睾丸组织形态表明,辐射后曲细精管的损伤随恢复时间延长而加重,睾丸自身修复不明显；虽然LJP各组的睾丸曲细精管损伤也随时间延长加重,但各组损伤均小于对应模型组。电镜观察其超微结构发现,模型组精原细胞和初级精母细胞内细胞核膜及胞质中细胞器均发生损伤,脂质颗粒增多；精子的顶体、精核等损伤明显；虽支持细胞和精子细胞损伤较轻,但其胞质内依然可见脂质颗粒和变形的细胞器；LJP组睾丸各类细胞损伤趋势与模型组一致,但胞质内脂质颗粒却远少于模型组,细胞器与精子损伤小于模型组,视野内精子数量多于模型组。停止辐射后,与对照组相比,模型各组大鼠睾丸组织内抗氧化酶SOD及GSH-PX活力明显减弱(P<0.01),MDA和GSH含量差异均有显著性(P<0.01)；而LJP各组随停止辐射时间的延长,MDA含量下降,LJP14d组MDA含量与对照组相比差异不显著(P>0.05),GSH含量及SOD、GSH-PX活力与模型14d组相比开始回升差异显著(P<0.05)；模型各组LDH活力持续降低,与对照组差异显著(P<0.01),而LJP各组睾丸组织中LDH活力接近对照组水平(P>0.05)。结论：海带多糖可使受慢性局部电离辐射损伤的睾丸组织中的MDA含量降低、GSH含量增加,增强睾丸组织SOD、GSH-PX和LDH的活力,促进睾丸组织中抗氧化体系的恢复；从而减轻了睾丸曲细精管的损伤,维持睾丸各生精细胞及其细胞器较好的组织形态,使的精子数量及其存活率增加,明显促进了受损大鼠的生精功能恢复。
第三部分海带多糖对慢性电离辐射致大鼠睾丸细胞损伤恢复的干预机制探讨
目的：观察慢性局部辐射造成大鼠睾丸细胞损伤凋亡后自身恢复的情况以及海带多糖干预后其损伤后恢复的效果,探讨海带多糖对其损伤修复的可能机制,为下一步研究提供依据。方法：56只Wistar雄性大鼠适应性饲养7d后随机分为对照组、模型3个组和LJP 3个组；LJP 3个组给予LJP100mg.kg-1.d-1灌胃,其余各组以等量生理盐水灌胃；除对照组外,各组进行60Coγ射线局部照射,每天1次,每周连续5次,共20次,总剂量2.3 Gy.只-1；分别在停止照射1、7和14 d后处死大鼠,分离大鼠睾丸组织；制作大鼠睾丸细胞悬液、睾丸组织电镜与冰冻切片,观察睾丸细胞内线粒体超微结构,测定大鼠睾丸各细胞含量、睾丸细胞内线粒体膜电位及钙离子浓度等指标。结果：停止辐射后,模型各组的凋亡细胞数量显著增加(P<0.01),精子细胞和精子明显减少(P<0.01),LJP1、7、14d组HC峰内细胞占睾丸细胞百分比均明显低于对应模型组(P<0.01),LJP14d组1C、2C、4C峰内细胞占睾丸细胞百分比明显高于模型14d组(P<0.01)。慢性电离辐射对睾丸生精细胞及精子内的线粒体大小和结构造成的损伤,在恢复14d后修复不明显；而海带多糖干预后其线粒体结构相对模型组损伤修复明显,状态好于模型组。辐射损伤后模型各组的线粒体△Ψm比对照组明显持续降低(P<0.01)；海带多糖干预后,LJP各组线粒体△Ψm均比对应模型组明显升高(P<0.01)。模型各组睾丸细胞内Ca2+浓度比对照组明显升高(P<0.01);而LJP7、14d组的Ca2+浓度明显比对应模型组降低(P<0.01)。结论：海带多糖通过提高线粒体膜电位△Ψm,降低睾丸细胞内Ca2+浓度；改善了睾丸细胞线粒体及精子尾部线粒体的超微结构；促进了受损睾丸细胞的自身修复,.从而减少了睾丸细胞的损伤；对慢性局部电离辐射致雄性大鼠睾丸细胞损伤凋亡具有较好的抑制。
第四部分海带多糖对慢性电离辐射致雄性大鼠生殖功能损伤恢复分子干预机制的探讨
目的：观察慢性局部辐射造成雄性大鼠生殖功能损伤后睾丸细胞中分子异常表达的调控作用以及海带多糖干预后其分子表达调控的效果,探讨海带多糖对大鼠生殖功能损伤恢复的分子机制。方法：56只Wistar雄性大鼠适应性饲养7d后随机分为对照组、模型3个组和LJP 3个组；LJP 3个组给予LJP100mg.kg-1.d-1灌胃,其余各组以等量生理盐水灌胃；除对照组外,各组进行60Coγ射线局部照射,每天1次,每周连续5次,共20次,总剂量2.3 Gy.只-1；分别在停止照射1、7和14d后处死大鼠,分离大鼠睾丸组织；测定睾丸细胞的DNA损伤,P53、Hsp70蛋白、基因在睾丸细胞中的差异表达以及Bcl-2/Bax、Fas、Caspase-3蛋白在睾丸组织中表达等指标。结果：模型1、7、14d组的睾丸细胞彗星拖尾率及彗星尾长均随辐射后恢复时间的增加而逐步加剧,与对照组相比差异显著(P<0.01)；虽LJP各组睾丸细胞彗星拖尾率及彗星尾长也随时间延长加重,但均比对应模型组指标显著减少(P<0.01)。与对照组相比,模型各组中Bcl-2表达显著降低(P<0.05),而Bax则显著增高(P<0.01),Bcl-2/Bax比值呈下降趋势；在恢复14d后,Fas、Caspase3和P53均明显升高(P<0.01),Hsp70显著降低(P<0.01)。LJP各组的P53变化趋势与模型组相同,LJP14d组虽比对照组显著增加(P<0.01),但与对应模型14d组相比则显著降低(P<0.01)。LJP各组Bcl-2含量比对照组显著降低(P<0.05),但呈现升高趋势,LJP14d组比对应模型组显著增加(P<0.05)；Bax含量虽呈升高趋势,但LJP各组均明显低于对应模型组(P<0.01)；Bcl-2/Bax的比值呈下降趋势,大于模型组。LJP各组Fas表达量虽也呈升高趋势,但均明显低于对应模型组(P<0.01)。LJP各组Caspase-3含量呈持续升高,显著高于对照组(P<0.01)；与对应的模型组间相比则明显降低(P<0.01)。LJPld组的Hsp 70表达量与对照组相比显著增高(P<0.01),但LJP14d组与对照组相比却显著降低(P<0.05),LJP14d组HSP 70含量与模型14d组相比明显增高(P<0.05)。结论：海带多糖对慢性局部电离辐射致雄性大鼠睾丸细胞分子表达具有明显的调控作用,在恢复14天后诱导大鼠睾丸细胞中P53表达降低,引起Bax表达降低,Bcl-2表达升高,Bcl-2/Bax比值增加；Hsp70表达升高,Fas表达减少,从而使得Caspase-3降低,促进睾丸细胞DNA损伤的修复,减少了凋亡,保护了大鼠的生殖细胞,改善了大鼠的生殖功能。
With the development of human society, mankind is faced with more than the risk of natural background radiation; nearly half a century to the world male fertility declined significantly; testicular tissue as a target organ sensitivity to ionizing radiation, ionizing radiation has been become a cause of human male sexual dysfunction and infertility is one of the most common cause; male reproductive health is facing a very serious situation, improvement and maintenance of male reproductive health have become an increasing concern.
Laminaria japonica polysaccharides is a kind of natural macromolecular substances whitch exists in Intercellular and Intracellular of laminaria japonica, and include three kinds of elements:Algin, Laminarin and Fucoidan.Studies have shown that Laminaria japonica polysaccharides is not only anti-coagulation, anti-arteriosclerosis, anti-tumor, anti-virus and other biological activity, also has anti-radiation; but in several small doses of local radiation and the field of reproductive function protection system has rarely been reported.
Therefore, this research was to study the affects of repeated small doses of local radiation to the o sexual function, spermatogenic function, testicular cell apoptosis and related molecules of male rats; to study the potential mechanisms of the Interfere with recovery of reproductive dysfunction repeated small doses of laminarin on the local radiation-induced reproductive injury may interfere with recovery mechanisms, and from the overall level of cells and animals many small doses of laminarin on the local radiation-induced damage of testicular cells and its molecular mechanism. To provide a scientific basis for the mechanisms of anti-radiation by UP, and to provide theoretical support for the deep processing of LJP and the development of safe and effective eproductive health products.
Part I The investigation of mechanism of laminaria japonica polysaccharides interfere the damage of sexual function lead bychronic ionizing radiation
Objective:To set up foundation for further study by observing the self recovery and the recovery after interfered by LJP of the sexual function of male rat from damage of chronic ionizing radiation and discussing the potential mechanism. Method:56 Wistar male rats are divided at random into control group,3 model groups and 3 LJP groups after 7d adaptable feeding.3 LJP groups are lavaged with LJP100mg·kg-1·d-1 and other groups with saline. Each group is partly irradiated by 60Coγradial once per day but control group, which last for five continuous times per week and total 20 times with total dose 2.3 Gy for each rat. Erection and mate experiments are performed at 1,7 and 14 day from ceasing irradiation. One day later the rats are executed to collect blood, separate testicle and test indicator of rats'organization, sex gland quality and organ coefficient, mating and erection and LH,FSH, Ts and E2. Result:after chronic ionizing radiation, the model group 1,7, 14d rat's weight and its gland weight gradually increase but testicles weight along with recovery time prolonging. Yet model group rats'weight and gland weight is under control group while LJP group is above model group including testicles weight. Moreover, LJP7, 14d group rats'testicle weight is obviously increased compared to corresponding mode group. Coefficient of model group rats'organs is reduced along with time prolonging, especially testicle. While LJP group coefficient is closer to control group. Model group erection latent period is obviously prolonged and ejaculation frequency is obviously reduced while LJP groups' erection latent period is shortened and ejaculation frequency is increased along with recover time prolonging. Indicator of LJP14d group is closer to control group. Compare with control group, model group 1,7,14d serum LH, FSH, Ts content reduced and declined obviously after ceasing radiation 14d later. Serum E2 is continuously increased yet still under control group. While LJP 1,7,14d serum Ts increased and LH, FSH, E2 declined to be closed to control group. Conclusion:LJP has favorable effect on protection of male rats sexual function which is damaged by chronic ionizing radiation to promote rats weight and its testicle weight that is damaged by radiation, to elevate the coefficient of testicle, to shorten erection latent period, to enhance ejection and to restore serum sex hormone LH, FSH, Ts, and E2; to shorten erection and riding latent period by the regulation of hypothalamus-pituitary gland-goand shafting. LJP can improve sex function obviously.
Part II The investigation of mechanism of laminaria japonica polysaccharides interfere the damage of spermatogenous function of testis on rat lead by chronic ionizing radiation
Objective:To set up foundation for further study by observing the self recovery and the recovery after interfered by LJP of the sexual function of male rat from damage of chronic ionizing radiation and discussing the potential mechanism. Method:56 Wistar male rats are divided at random into control group, 3 model groups and 3 LJP groups after 7d adaptable feeding. 3 LJP groups are lavaged with LJP100mg·kg-1·d-1 and other groups with saline. Each group is partly irradiated by 60Coγradial once per day but control group, which last for five continuous times per week and total 20 times with total dose 2.3 Gy for each rat. Erection and mate experiments are performed at 1,7 and 14 day from ceasing irradiation. One day later the rats are executed to collect blood, separate testicle and test germ cell and indictor of MDA, GSH, SOD, GSH-PX and LDH. Result:After multiple mini-doses ionizing radiation, the number of spermatozoa and its survival rate are decreased obviously in LJP1d group, modle group and LJP groups compared to control group; but the drcrease trend of spermatozoa in LJP groups is slow down, the survival rate of spermatozoa is increased, there is significiant difference compared with modle group. Observation by optical microscope shows that the damage of sperm tube aggravates along with recovery time prolonging and testicle self repair unobviously. Although LJP groups have the same result, the damage of LJP groups is comparatively mild. Observation it s ultra-structure by electron microscope, we can find that damages are existed in nucleus membrane and Organelles of spermatogenous cell and spermiocytes in modle group, lipid granule increased, the damage is obviously in acrosome and arrhenokaryon of spermatozoa, although the gamage of sertoli cell and spermatid is mild, but there are deformed organelles and lipid granule in cytoplasm. The damage trend of all kinds of testis cells is the same in LJP group to modle group, but the lipid granule in in cytoplasm is more fewer than that of in modle group, the damage degree of organelles and spermatozoa is less than that of in modle group, and the number of spermatozoa is more than in modle group. After cessation of radiation, the vitality of SOD and GSH-PX in testis tissue of rat is obviously decreased in modle group, and there is significant difference between the content of MDA and GSH compared with control group, But in LJP groups, the content of MDA is decreased, there is no significant difference of the content of MDA in LJP 14d group, the content of GSH and the vitality of SOD、GSH-PX are increased compared with modle 14d group with the arrest of radiation time prolonging. The vitality of LDH is continuing decreasing in modle groups, and the difference is significant compared with control group, but it is almost the same with control group in testis tissue of LJP groups. Conclusion:LJP has satisfactory promotive effect to spermatogenic dysfunction of testis tissue on male rat after chronic ionizing radiation, the mechanism is likely to decresses the content of MDA, increases GSH in testis tissue, improves the vitality of SOD、GSH-PX and LDH in testis tissue, promote the recovery of anti-oxidant system in testis, improves it's spermatozoa count and survival rate,relieve the damage of convoluted tubule, maintains the better morphous of androgone and it's organelles in testis, and promotrs the recovery of spermatogenic dysfunction of testis on male rat obviously.
Part III The investigation of mechanism of laminaria japonica polysaccharides interfere the recovery of testicle cells injury on rat lead by chronic ionizing radiation
Objective:To set up foundation for further study by observing the self recovery of apoptosis in testicular cells and the recovery after interfered by LJP of male rat from damage of chronic ionizing radiation and discussing the potential mechanism. Method:56 Wistar male rats are divided at random into control group, 3 model groups and 3 LJP groups after 7d adaptable feeding.3 LJP groups are lavaged with LJP100mg·kg-1·d-1 and other groups with saline. Each group is partly irradiated by Coy radial once per day but control group, which last for five continuous times per week and total 20 times with total dose 2.3 Gy for each rat. the rats are executed at 1,7 and 14 day from ceasing irradiation to separate testicle tissue, make testicle cell suspension, electron microscopic and frozen section of testicle tissue, observe ultra-structure of Mitochondrion in testicle cell, measure the content of testicle cell、membrane potentials of Mitochondrion and density of Ca2+ etal in testicle cell of rat. Result:After cessation of radiation, the apoptosis count of modle group is increasing significantly,spermatozoa and spermatozoa cells are decreasing obviously, in LJP1,7,14d groups, the Percentage of cells in testicular cells in HC peak is obviously lower than that of corresponding modle group; in LJP14d group, the Percentage of cells in testicular cells in 1C、2C、4C peak is much higher than that of in modle14d group. After recovery for 14 days, chronic ionizing radiation to the repair of the mitochondrion s size and structure damage in androgone and spermatozoa of testicle is unobviously; after interfere with LJP, the restoration of mitochondrion is obvious than that of in modle groupand the condition is better. TheΔΨm of mitochondrion in modle groups is continuely decreases than that of in control groups after radiation damage; therefore, after interfere with LJP, theΔΨm of mitochondrion is obviously higher than that of in modle groups. The density of Ca2+ in testicle cell of modle groups is significantly higher than that of in control groups; but it is obviously lower in LJP 7 and LJP 14 groups than that of in corresponding modle groups. Conclusion:LJP has depressant effect to apoptosis of testicle cell on male rat which lead by multiple chronic ionizing radiation, the mechanism is likely to cuts down the count of apoptosis in testis, improves the ultra-structure of sperm tail and mitochondrion of testicle cell, elevates the membrane potentials of mitochondrion, reduces the density of Ca2+ in testicle cell, promotes self recovery of damaged testicle cell, avoides abundant generation of apoptosis cells.
Part IV The investigation of mechanism of laminaria japonica polysaccharides interfere the molecule of testicle cell on rat lead by chronic ionizing radiation
Objective:To observe the regulation of abnormality expression of molecular in testicular cells damaged by chronic ionizing radiation to the injury of reproductive function on male rat and the regulation effect after interfered with LJP, to discuss the molecular mechanism of LJP to the recovery of reproductive function injury on rat. Method:56 Wistar male rats are divided at random into control group,3 model groups and 3 LJP groups after 7d adaptable feeding. 3 LJP groups are lavaged with LJP100mg·kg-1·d-1 and other groups with saline. Each group is partly irradiated by 60Coγradial once per day but control group, which last for five continuous times per week and total 20 times with total dose 2.3 Gy for each rat. the rats are executed at 1,7 and 14 day from ceasing irradiation,separates the tisticke tissue of rat, determines the damage of DNA in testicle cell, the differential expression of P53 and Hsp70 protein and gene in testicle cell and the expression of Bcl-2/Bax, Fas and casapse3 in testicle tissue. Result:The comets tailing rate and the tail length of testicle cell in modleld, modle 7d and modle 14d group is aggravate with the recovery time prolonging after radiation, and there is significant difference compared to the control group; although the comets tailing rate and the tail length of testicle cell in LJP groups is also aggravate with the recovery time prolonging, but is obviously palliate than that of in corresponding modle groups. Bcl-2 decreasing but Bax increasing significantly in modle groups compared to control groups, the ratio of Bcl-2 and Bax is depressed; after recovery for 14 days, Fas, caspase3 and P53 are increasing but Hsp70 is decreasing obviously. The change tendency of P53 in LJP groups is the same to modle groups,although P53 in LJP14d group is notable increasing compared to control group, but is decreased obviously than that of in corresponding modle14d group. Bcl-2 in LJP groups is notable lower than that of in control groups, but the tendency is rosen; and in LJP14d group, Bcl-2 is increasing than that of in corresponding modle group; Bax is also shows a set-up tendency, but in LJP groups is notable lower than that of in corresponding modle groups; Bcl-2/Bax is downtrend, but the ratio is greater than modle groups. Alougth the expression of Fas in LJP groups is also shows a set-up tendency, but are all obviously lower than those of in corresponding modle groups. The Caspase3 in LJP groups is increasing continuely, higher than that of in control groups significantly, but is decreasing compared to corresponding modle groups. The expression of Hsp70 in LJP 1d group is notable higher than that of in control group, but is decreasing significantly in LJP 14d group compared to control group, and the content of Hsp70 in LJP 14d group is increasing obviously than that of in modle 14d group. Conclusion:LJP has apparent regulation effect to the molecular expression of testicle cell on male rat lead by chronic ionizing radiation, induces depression of the expression of P53 in testicle tissue on rat after 14 days recovery, lead to the reduction of Bax s expression, elevation of Bcl-2, aubmentation of Bcl-2/Bax; the expression of Hsp70 is elevated, the expression of Fas is reduced, so the Caspase-3 is decreased, and it promotes the damage repair of DNA in testicle cell, abates the cell apoptosis, protects the germ cell of rat, and improves it s reproductive function.
海带多糖(Laminaria japonica polysaccharides, LJP)是存在于海带细胞间和细胞内的一类天然大分子物质,由褐藻酸钠(Algin)、褐藻淀粉(Laminarin)和褐藻糖胶(Fucoidan)三种成分组成；研究表明,海带多糖不仅具有抗凝血、抗动脉硬化、抗肿瘤、抗病毒等生物学活性,还具有抗辐射作用；但在慢性局部电离辐射和生殖功能防护领域的研究报道甚少。
因此本研究旨在通过对慢性局部辐射致雄性大鼠性功能、生精功能、睾丸细胞等损伤后的自身恢复及其相关分子异常表达调控的研究,比较海带多糖干预后对其辐射损伤恢复及相关分子调控效果的影响；从动物整体、细胞以及分子水平上探讨海带多糖对慢性局部辐射致大鼠生殖功能损伤后恢复影响的可能机制。为进一步研究海带多糖抗辐射机理提供科学依据；并为海带多糖的深加工和开发安全有效的生殖保健产品提供理论支持。
第一部分海带多糖对慢性电离辐射致雄性大鼠性功能损伤恢复的干预机制探讨
目的：观察慢性局部辐射导致雄性大鼠性功能损伤后自身恢复的情况以及海带多糖干预后其损伤恢复的效果,探讨海带多糖对其辐射损伤恢复影响的可能作用机理,为下一步研究提供依据。方法：56只Wistar雄性大鼠适应性饲养7d后随机分为对照组、模型3个组和LJP 3个组；LJP 3个组给予LJP100mg.kg-1.d-1灌胃,其余各组以等量生理盐水灌胃；除对照组外,各组进行60Coγ射线局部照射,每天1次,每周连续5次,共20次,总剂量2.3 Gy.只-1；分别在停止照射后1、7和14 d进行勃起、交配试验,1天后处死,收集血液,分离睾丸、附睾等组织；检测大鼠交配及阴茎勃起,机体、性腺器官质量及其脏器系数,血清性激素(LH、FSH、Ts和E2)等各项指标。结果：慢性局部电离辐射后随着1、7、14d恢复时间的延长,模型1、7、14d组除睾丸质量显著减轻外(P<0.01),大鼠体质量、附睾、精囊腺与前列腺的质量逐步增加,均低于对照组；而LJP各组的体质量、睾丸、附睾、精囊腺与前列腺质量均随时间延长逐步增加,各组质量均大于对应模型组,且LJP7、14d组的睾丸质量比对应模型组显著增加(P<0.05)；模型各组的睾丸、附睾、精囊腺与前列腺的脏器系数均随时间的延长逐步减少,且其睾丸脏器系数与对照组相比差异极其显著(P<0.01)；而LJP各组的睾丸脏器系数与对照组和对应模型组相比同样存在显著差异(P<0.01),更接近对照组。模型各组勃起、骑跨潜伏期显著延长(P<0.01),骑跨、射精次数明显减少(P<0.01)；LJP各组随恢复时间的延长而勃起、骑跨潜伏期缩短,骑跨、射精次数增加；LJP14d组的各指标与对照组更接近(P>0.05)。模型1、7、14d组与对照组相比,血清LH、FSH、Ts含量减少,停止辐射14d后下降明显(P<0.01)；血清E2含量持续升高,但仍低于对照组;LJP1、7、14d组在辐射后,血清Ts由低到高,血清LH和FSH的含量均呈现下降趋势,血清E2由高到低变化,14d后血清LH、FSH、Ts和E2含量值趋于对照组(P>0.05)。结论：海带多糖促进了辐射损伤后在停止辐射恢复期间大鼠机体和睾丸质量的增加以及睾丸脏器系数的提高,进而改善了损伤后大鼠血清性激素LH、FSH、Ts、E2的水平；通过下丘脑-垂体-睾丸性腺轴系的调控,缩短了阴茎勃起和骑跨潜伏期,提高骑跨和射精次数；对慢性局部电离辐射致雄性大鼠性功能损伤后的恢复改善产生了显著作用。
第二部分海带多糖对慢性电离辐射致大鼠生精功能损伤恢复的干预机制探讨
目的：观察慢性局部辐射造成雄性大鼠睾丸生精功能损伤后自身恢复的情况以及海带多糖干预后其损伤恢复的效果,探讨海带多糖对其损伤恢复的可能作用机理,为下一步研究提供依据。方法：56只Wistar雄性大鼠适应性饲养7d后随机分为对照组、模型3个组和LJP3个组；LJP3个组给予LJP100mg.kg-1.d-1灌胃,其余各组以等量生理盐水灌胃；除对照组外,各组进行60Coγ射线局部照射,每天1次,每周连续5次,共20次,总剂量2.3 Gy.只-1；分别在停止照射1、7和14d后处死大鼠,分离大鼠睾丸组织；制作光镜和电镜切片观察睾丸组织形态,测定大鼠精子数量及其存活率,睾丸组织MDA、GSH含量及SOD、GSH-PX、LDH活力等指标。结果：大鼠在受到慢性局部电离辐射后,在14d恢复期间,与对照组相比,LJPld组(P<0.05)与模型和LJP各组精子数量及存活率持续显著降低(P<0.01)；但LJP各组精子数量降低趋势减缓,精子存活率增加,与对应模型组相比差异均有显著性(P<0.01)。光镜观察睾丸组织形态表明,辐射后曲细精管的损伤随恢复时间延长而加重,睾丸自身修复不明显；虽然LJP各组的睾丸曲细精管损伤也随时间延长加重,但各组损伤均小于对应模型组。电镜观察其超微结构发现,模型组精原细胞和初级精母细胞内细胞核膜及胞质中细胞器均发生损伤,脂质颗粒增多；精子的顶体、精核等损伤明显；虽支持细胞和精子细胞损伤较轻,但其胞质内依然可见脂质颗粒和变形的细胞器；LJP组睾丸各类细胞损伤趋势与模型组一致,但胞质内脂质颗粒却远少于模型组,细胞器与精子损伤小于模型组,视野内精子数量多于模型组。停止辐射后,与对照组相比,模型各组大鼠睾丸组织内抗氧化酶SOD及GSH-PX活力明显减弱(P<0.01),MDA和GSH含量差异均有显著性(P<0.01)；而LJP各组随停止辐射时间的延长,MDA含量下降,LJP14d组MDA含量与对照组相比差异不显著(P>0.05),GSH含量及SOD、GSH-PX活力与模型14d组相比开始回升差异显著(P<0.05)；模型各组LDH活力持续降低,与对照组差异显著(P<0.01),而LJP各组睾丸组织中LDH活力接近对照组水平(P>0.05)。结论：海带多糖可使受慢性局部电离辐射损伤的睾丸组织中的MDA含量降低、GSH含量增加,增强睾丸组织SOD、GSH-PX和LDH的活力,促进睾丸组织中抗氧化体系的恢复；从而减轻了睾丸曲细精管的损伤,维持睾丸各生精细胞及其细胞器较好的组织形态,使的精子数量及其存活率增加,明显促进了受损大鼠的生精功能恢复。
第三部分海带多糖对慢性电离辐射致大鼠睾丸细胞损伤恢复的干预机制探讨
目的：观察慢性局部辐射造成大鼠睾丸细胞损伤凋亡后自身恢复的情况以及海带多糖干预后其损伤后恢复的效果,探讨海带多糖对其损伤修复的可能机制,为下一步研究提供依据。方法：56只Wistar雄性大鼠适应性饲养7d后随机分为对照组、模型3个组和LJP 3个组；LJP 3个组给予LJP100mg.kg-1.d-1灌胃,其余各组以等量生理盐水灌胃；除对照组外,各组进行60Coγ射线局部照射,每天1次,每周连续5次,共20次,总剂量2.3 Gy.只-1；分别在停止照射1、7和14 d后处死大鼠,分离大鼠睾丸组织；制作大鼠睾丸细胞悬液、睾丸组织电镜与冰冻切片,观察睾丸细胞内线粒体超微结构,测定大鼠睾丸各细胞含量、睾丸细胞内线粒体膜电位及钙离子浓度等指标。结果：停止辐射后,模型各组的凋亡细胞数量显著增加(P<0.01),精子细胞和精子明显减少(P<0.01),LJP1、7、14d组HC峰内细胞占睾丸细胞百分比均明显低于对应模型组(P<0.01),LJP14d组1C、2C、4C峰内细胞占睾丸细胞百分比明显高于模型14d组(P<0.01)。慢性电离辐射对睾丸生精细胞及精子内的线粒体大小和结构造成的损伤,在恢复14d后修复不明显；而海带多糖干预后其线粒体结构相对模型组损伤修复明显,状态好于模型组。辐射损伤后模型各组的线粒体△Ψm比对照组明显持续降低(P<0.01)；海带多糖干预后,LJP各组线粒体△Ψm均比对应模型组明显升高(P<0.01)。模型各组睾丸细胞内Ca2+浓度比对照组明显升高(P<0.01);而LJP7、14d组的Ca2+浓度明显比对应模型组降低(P<0.01)。结论：海带多糖通过提高线粒体膜电位△Ψm,降低睾丸细胞内Ca2+浓度；改善了睾丸细胞线粒体及精子尾部线粒体的超微结构；促进了受损睾丸细胞的自身修复,.从而减少了睾丸细胞的损伤；对慢性局部电离辐射致雄性大鼠睾丸细胞损伤凋亡具有较好的抑制。
第四部分海带多糖对慢性电离辐射致雄性大鼠生殖功能损伤恢复分子干预机制的探讨
目的：观察慢性局部辐射造成雄性大鼠生殖功能损伤后睾丸细胞中分子异常表达的调控作用以及海带多糖干预后其分子表达调控的效果,探讨海带多糖对大鼠生殖功能损伤恢复的分子机制。方法：56只Wistar雄性大鼠适应性饲养7d后随机分为对照组、模型3个组和LJP 3个组；LJP 3个组给予LJP100mg.kg-1.d-1灌胃,其余各组以等量生理盐水灌胃；除对照组外,各组进行60Coγ射线局部照射,每天1次,每周连续5次,共20次,总剂量2.3 Gy.只-1；分别在停止照射1、7和14d后处死大鼠,分离大鼠睾丸组织；测定睾丸细胞的DNA损伤,P53、Hsp70蛋白、基因在睾丸细胞中的差异表达以及Bcl-2/Bax、Fas、Caspase-3蛋白在睾丸组织中表达等指标。结果：模型1、7、14d组的睾丸细胞彗星拖尾率及彗星尾长均随辐射后恢复时间的增加而逐步加剧,与对照组相比差异显著(P<0.01)；虽LJP各组睾丸细胞彗星拖尾率及彗星尾长也随时间延长加重,但均比对应模型组指标显著减少(P<0.01)。与对照组相比,模型各组中Bcl-2表达显著降低(P<0.05),而Bax则显著增高(P<0.01),Bcl-2/Bax比值呈下降趋势；在恢复14d后,Fas、Caspase3和P53均明显升高(P<0.01),Hsp70显著降低(P<0.01)。LJP各组的P53变化趋势与模型组相同,LJP14d组虽比对照组显著增加(P<0.01),但与对应模型14d组相比则显著降低(P<0.01)。LJP各组Bcl-2含量比对照组显著降低(P<0.05),但呈现升高趋势,LJP14d组比对应模型组显著增加(P<0.05)；Bax含量虽呈升高趋势,但LJP各组均明显低于对应模型组(P<0.01)；Bcl-2/Bax的比值呈下降趋势,大于模型组。LJP各组Fas表达量虽也呈升高趋势,但均明显低于对应模型组(P<0.01)。LJP各组Caspase-3含量呈持续升高,显著高于对照组(P<0.01)；与对应的模型组间相比则明显降低(P<0.01)。LJPld组的Hsp 70表达量与对照组相比显著增高(P<0.01),但LJP14d组与对照组相比却显著降低(P<0.05),LJP14d组HSP 70含量与模型14d组相比明显增高(P<0.05)。结论：海带多糖对慢性局部电离辐射致雄性大鼠睾丸细胞分子表达具有明显的调控作用,在恢复14天后诱导大鼠睾丸细胞中P53表达降低,引起Bax表达降低,Bcl-2表达升高,Bcl-2/Bax比值增加；Hsp70表达升高,Fas表达减少,从而使得Caspase-3降低,促进睾丸细胞DNA损伤的修复,减少了凋亡,保护了大鼠的生殖细胞,改善了大鼠的生殖功能。
With the development of human society, mankind is faced with more than the risk of natural background radiation; nearly half a century to the world male fertility declined significantly; testicular tissue as a target organ sensitivity to ionizing radiation, ionizing radiation has been become a cause of human male sexual dysfunction and infertility is one of the most common cause; male reproductive health is facing a very serious situation, improvement and maintenance of male reproductive health have become an increasing concern.
Laminaria japonica polysaccharides is a kind of natural macromolecular substances whitch exists in Intercellular and Intracellular of laminaria japonica, and include three kinds of elements:Algin, Laminarin and Fucoidan.Studies have shown that Laminaria japonica polysaccharides is not only anti-coagulation, anti-arteriosclerosis, anti-tumor, anti-virus and other biological activity, also has anti-radiation; but in several small doses of local radiation and the field of reproductive function protection system has rarely been reported.
Therefore, this research was to study the affects of repeated small doses of local radiation to the o sexual function, spermatogenic function, testicular cell apoptosis and related molecules of male rats; to study the potential mechanisms of the Interfere with recovery of reproductive dysfunction repeated small doses of laminarin on the local radiation-induced reproductive injury may interfere with recovery mechanisms, and from the overall level of cells and animals many small doses of laminarin on the local radiation-induced damage of testicular cells and its molecular mechanism. To provide a scientific basis for the mechanisms of anti-radiation by UP, and to provide theoretical support for the deep processing of LJP and the development of safe and effective eproductive health products.
Part I The investigation of mechanism of laminaria japonica polysaccharides interfere the damage of sexual function lead bychronic ionizing radiation
Objective:To set up foundation for further study by observing the self recovery and the recovery after interfered by LJP of the sexual function of male rat from damage of chronic ionizing radiation and discussing the potential mechanism. Method:56 Wistar male rats are divided at random into control group,3 model groups and 3 LJP groups after 7d adaptable feeding.3 LJP groups are lavaged with LJP100mg·kg-1·d-1 and other groups with saline. Each group is partly irradiated by 60Coγradial once per day but control group, which last for five continuous times per week and total 20 times with total dose 2.3 Gy for each rat. Erection and mate experiments are performed at 1,7 and 14 day from ceasing irradiation. One day later the rats are executed to collect blood, separate testicle and test indicator of rats'organization, sex gland quality and organ coefficient, mating and erection and LH,FSH, Ts and E2. Result:after chronic ionizing radiation, the model group 1,7, 14d rat's weight and its gland weight gradually increase but testicles weight along with recovery time prolonging. Yet model group rats'weight and gland weight is under control group while LJP group is above model group including testicles weight. Moreover, LJP7, 14d group rats'testicle weight is obviously increased compared to corresponding mode group. Coefficient of model group rats'organs is reduced along with time prolonging, especially testicle. While LJP group coefficient is closer to control group. Model group erection latent period is obviously prolonged and ejaculation frequency is obviously reduced while LJP groups' erection latent period is shortened and ejaculation frequency is increased along with recover time prolonging. Indicator of LJP14d group is closer to control group. Compare with control group, model group 1,7,14d serum LH, FSH, Ts content reduced and declined obviously after ceasing radiation 14d later. Serum E2 is continuously increased yet still under control group. While LJP 1,7,14d serum Ts increased and LH, FSH, E2 declined to be closed to control group. Conclusion:LJP has favorable effect on protection of male rats sexual function which is damaged by chronic ionizing radiation to promote rats weight and its testicle weight that is damaged by radiation, to elevate the coefficient of testicle, to shorten erection latent period, to enhance ejection and to restore serum sex hormone LH, FSH, Ts, and E2; to shorten erection and riding latent period by the regulation of hypothalamus-pituitary gland-goand shafting. LJP can improve sex function obviously.
Part II The investigation of mechanism of laminaria japonica polysaccharides interfere the damage of spermatogenous function of testis on rat lead by chronic ionizing radiation
Objective:To set up foundation for further study by observing the self recovery and the recovery after interfered by LJP of the sexual function of male rat from damage of chronic ionizing radiation and discussing the potential mechanism. Method:56 Wistar male rats are divided at random into control group, 3 model groups and 3 LJP groups after 7d adaptable feeding. 3 LJP groups are lavaged with LJP100mg·kg-1·d-1 and other groups with saline. Each group is partly irradiated by 60Coγradial once per day but control group, which last for five continuous times per week and total 20 times with total dose 2.3 Gy for each rat. Erection and mate experiments are performed at 1,7 and 14 day from ceasing irradiation. One day later the rats are executed to collect blood, separate testicle and test germ cell and indictor of MDA, GSH, SOD, GSH-PX and LDH. Result:After multiple mini-doses ionizing radiation, the number of spermatozoa and its survival rate are decreased obviously in LJP1d group, modle group and LJP groups compared to control group; but the drcrease trend of spermatozoa in LJP groups is slow down, the survival rate of spermatozoa is increased, there is significiant difference compared with modle group. Observation by optical microscope shows that the damage of sperm tube aggravates along with recovery time prolonging and testicle self repair unobviously. Although LJP groups have the same result, the damage of LJP groups is comparatively mild. Observation it s ultra-structure by electron microscope, we can find that damages are existed in nucleus membrane and Organelles of spermatogenous cell and spermiocytes in modle group, lipid granule increased, the damage is obviously in acrosome and arrhenokaryon of spermatozoa, although the gamage of sertoli cell and spermatid is mild, but there are deformed organelles and lipid granule in cytoplasm. The damage trend of all kinds of testis cells is the same in LJP group to modle group, but the lipid granule in in cytoplasm is more fewer than that of in modle group, the damage degree of organelles and spermatozoa is less than that of in modle group, and the number of spermatozoa is more than in modle group. After cessation of radiation, the vitality of SOD and GSH-PX in testis tissue of rat is obviously decreased in modle group, and there is significant difference between the content of MDA and GSH compared with control group, But in LJP groups, the content of MDA is decreased, there is no significant difference of the content of MDA in LJP 14d group, the content of GSH and the vitality of SOD、GSH-PX are increased compared with modle 14d group with the arrest of radiation time prolonging. The vitality of LDH is continuing decreasing in modle groups, and the difference is significant compared with control group, but it is almost the same with control group in testis tissue of LJP groups. Conclusion:LJP has satisfactory promotive effect to spermatogenic dysfunction of testis tissue on male rat after chronic ionizing radiation, the mechanism is likely to decresses the content of MDA, increases GSH in testis tissue, improves the vitality of SOD、GSH-PX and LDH in testis tissue, promote the recovery of anti-oxidant system in testis, improves it's spermatozoa count and survival rate,relieve the damage of convoluted tubule, maintains the better morphous of androgone and it's organelles in testis, and promotrs the recovery of spermatogenic dysfunction of testis on male rat obviously.
Part III The investigation of mechanism of laminaria japonica polysaccharides interfere the recovery of testicle cells injury on rat lead by chronic ionizing radiation
Objective:To set up foundation for further study by observing the self recovery of apoptosis in testicular cells and the recovery after interfered by LJP of male rat from damage of chronic ionizing radiation and discussing the potential mechanism. Method:56 Wistar male rats are divided at random into control group, 3 model groups and 3 LJP groups after 7d adaptable feeding.3 LJP groups are lavaged with LJP100mg·kg-1·d-1 and other groups with saline. Each group is partly irradiated by Coy radial once per day but control group, which last for five continuous times per week and total 20 times with total dose 2.3 Gy for each rat. the rats are executed at 1,7 and 14 day from ceasing irradiation to separate testicle tissue, make testicle cell suspension, electron microscopic and frozen section of testicle tissue, observe ultra-structure of Mitochondrion in testicle cell, measure the content of testicle cell、membrane potentials of Mitochondrion and density of Ca2+ etal in testicle cell of rat. Result:After cessation of radiation, the apoptosis count of modle group is increasing significantly,spermatozoa and spermatozoa cells are decreasing obviously, in LJP1,7,14d groups, the Percentage of cells in testicular cells in HC peak is obviously lower than that of corresponding modle group; in LJP14d group, the Percentage of cells in testicular cells in 1C、2C、4C peak is much higher than that of in modle14d group. After recovery for 14 days, chronic ionizing radiation to the repair of the mitochondrion s size and structure damage in androgone and spermatozoa of testicle is unobviously; after interfere with LJP, the restoration of mitochondrion is obvious than that of in modle groupand the condition is better. TheΔΨm of mitochondrion in modle groups is continuely decreases than that of in control groups after radiation damage; therefore, after interfere with LJP, theΔΨm of mitochondrion is obviously higher than that of in modle groups. The density of Ca2+ in testicle cell of modle groups is significantly higher than that of in control groups; but it is obviously lower in LJP 7 and LJP 14 groups than that of in corresponding modle groups. Conclusion:LJP has depressant effect to apoptosis of testicle cell on male rat which lead by multiple chronic ionizing radiation, the mechanism is likely to cuts down the count of apoptosis in testis, improves the ultra-structure of sperm tail and mitochondrion of testicle cell, elevates the membrane potentials of mitochondrion, reduces the density of Ca2+ in testicle cell, promotes self recovery of damaged testicle cell, avoides abundant generation of apoptosis cells.
Part IV The investigation of mechanism of laminaria japonica polysaccharides interfere the molecule of testicle cell on rat lead by chronic ionizing radiation
Objective:To observe the regulation of abnormality expression of molecular in testicular cells damaged by chronic ionizing radiation to the injury of reproductive function on male rat and the regulation effect after interfered with LJP, to discuss the molecular mechanism of LJP to the recovery of reproductive function injury on rat. Method:56 Wistar male rats are divided at random into control group,3 model groups and 3 LJP groups after 7d adaptable feeding. 3 LJP groups are lavaged with LJP100mg·kg-1·d-1 and other groups with saline. Each group is partly irradiated by 60Coγradial once per day but control group, which last for five continuous times per week and total 20 times with total dose 2.3 Gy for each rat. the rats are executed at 1,7 and 14 day from ceasing irradiation,separates the tisticke tissue of rat, determines the damage of DNA in testicle cell, the differential expression of P53 and Hsp70 protein and gene in testicle cell and the expression of Bcl-2/Bax, Fas and casapse3 in testicle tissue. Result:The comets tailing rate and the tail length of testicle cell in modleld, modle 7d and modle 14d group is aggravate with the recovery time prolonging after radiation, and there is significant difference compared to the control group; although the comets tailing rate and the tail length of testicle cell in LJP groups is also aggravate with the recovery time prolonging, but is obviously palliate than that of in corresponding modle groups. Bcl-2 decreasing but Bax increasing significantly in modle groups compared to control groups, the ratio of Bcl-2 and Bax is depressed; after recovery for 14 days, Fas, caspase3 and P53 are increasing but Hsp70 is decreasing obviously. The change tendency of P53 in LJP groups is the same to modle groups,although P53 in LJP14d group is notable increasing compared to control group, but is decreased obviously than that of in corresponding modle14d group. Bcl-2 in LJP groups is notable lower than that of in control groups, but the tendency is rosen; and in LJP14d group, Bcl-2 is increasing than that of in corresponding modle group; Bax is also shows a set-up tendency, but in LJP groups is notable lower than that of in corresponding modle groups; Bcl-2/Bax is downtrend, but the ratio is greater than modle groups. Alougth the expression of Fas in LJP groups is also shows a set-up tendency, but are all obviously lower than those of in corresponding modle groups. The Caspase3 in LJP groups is increasing continuely, higher than that of in control groups significantly, but is decreasing compared to corresponding modle groups. The expression of Hsp70 in LJP 1d group is notable higher than that of in control group, but is decreasing significantly in LJP 14d group compared to control group, and the content of Hsp70 in LJP 14d group is increasing obviously than that of in modle 14d group. Conclusion:LJP has apparent regulation effect to the molecular expression of testicle cell on male rat lead by chronic ionizing radiation, induces depression of the expression of P53 in testicle tissue on rat after 14 days recovery, lead to the reduction of Bax s expression, elevation of Bcl-2, aubmentation of Bcl-2/Bax; the expression of Hsp70 is elevated, the expression of Fas is reduced, so the Caspase-3 is decreased, and it promotes the damage repair of DNA in testicle cell, abates the cell apoptosis, protects the germ cell of rat, and improves it s reproductive function.
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