贫铀暴露对肾脏和免疫系统的影响及锌的解毒作用研究
摘要
研究背景和目的
贫铀(depleted uranium，DU)是天然铀经过提炼浓缩铀(~(235)U)之后的剩余产物，其~(235)U含量低于0.712％。由于DU具有良好的穿透性和原料的廉价性，被广泛地用于核电站、平衡锤、辐射防护及军事活动中(如作为装甲材料及弹药成分)。在DU的生产和使用过程中，可能会不规范地释放到环境中，经呼吸道、消化道或皮肤进入体内，对周围居民的健康造成严重地威胁。
DU可发射高线性能量转移的α、β粒子，既具有放射毒性，又具有重金属毒性，其生物学影响与接触剂量、持续时间、接触途径等多种因素有关。在大剂量急性暴露的条件下，肾脏是铀急性化学毒性的主要靶器官，可造成严重的肾近曲小管坏死，然而，DU引起肾脏毒性的准确机制还不清楚。在低剂量慢性暴露的情况下，可能会引起一系列有害的效应，如神经行为的异常、生殖毒性、遗传毒性和癌症等，然而，普遍关注的问题——长期摄入DU污染的食物对免疫系统的影响，目前还没有报道。因此，本研究分别建立DU急性暴露模型和经过食入途径的慢性暴露模型，分别评价急性DU暴露对肾脏的影响和慢性DU暴露对免疫系统的影响，深入探索急慢性DU暴露的作用机制，为DU生物学效应的研究打下基础。
此外，针对DU中毒的救治，仍是国内外研究的重点和难点。现有的DU促排药在促排效果或安全性方面都或多或少存在问题。金属硫蛋白(metallothinein, MT)是一类广泛存在于哺乳动物器官和组织中的低分子量非酶蛋白，富含半胱氨酸，对重金属离子有很高的亲和力，并能清除多种自由基，可实现对金属的解毒，但其解毒机制仍不完全清楚。MT基因的表达，需要二价锌离子的参与，锌属于高效且安全的MT诱导剂。因此，可试图通过锌诱导机体产生MT来实现DU的解毒治疗，为临床上开发高效低毒的DU解毒药物提供新的思路，具有重要的实用价值和现实意义。
研究方法
首先分别利用人肾脏近曲小管上皮HK-2细胞和成年Sprague Dawley大鼠，暴露于不同剂量的DU，造成DU急性染毒模型，分别观察暴露于DU后24h对细胞存活率、凋亡及相关酶活力的影响，以及暴露于DU后4d对大鼠肾脏铀含量、肾功能、组织病理学及肾脏组织抗氧化水平的影响。
其次，3周龄昆明系小鼠，按照喂食饲料(含DU)剂量的不同分为4组：0(对照组)，3(DU3组)，30(DU_(30)组)，和300(DU_(300)组)mg/kg，喂食长达4个月，造成DU慢性染毒模型，评价小鼠天然免疫和获得性免疫功能的变化。
最后，分别利用HK-2细胞、Sprague Dawley大鼠和MT基因敲除小鼠，进行锌对DU中毒的解毒作用及机制的研究，通过组织形态学、细胞超微病理学、流式细胞术、激光共聚焦显微镜技术、酶联免疫吸附试验(ELISA)、分子生物学及蛋白组学等技术方法多角度评价锌对DU的解毒作用，深入探索锌对DU的解毒机制。
研究结果及结论
1.高于125μM的DU(硝酸铀酰)暴露后24h，均可引起HK-2细胞质膜和溶酶体膜的破坏，而导致乳酸脱氢酶(LDH)和N-乙酰-β-葡萄糖苷酶(NAG)从细胞内释放到培养液中，最终导致细胞的凋亡。另外，将Sprague Dawley大鼠急性暴露于不同剂量的DU(2.5、5、10mg/kg)，4d后观察发现，大于2.5mg/kg的DU暴露剂量均可引起明显的肾脏毒性，导致肾脏组织铀含量、血清尿素(BUN)和肌酐(Cr)均明显增高，组织病理学损伤严重，且随着DU暴露剂量的增高损伤逐渐加重。进一步研究发现，DU引起了肾脏组织氧化应激，导致抗氧化能力下降，脂质过氧化水平增高，可能是导致DU肾脏毒性的机制之一。
2.3周龄小鼠喂食不同剂量的含DU饲料4个月后，各组血生化检查均无明显异常。在中剂量组(30mg/kg)和低剂量组(3mg/kg)，免疫学影响并不明显或影响相对轻微。但在高剂量组(300mg/kg)，小鼠的天然免疫功能下降，表现为腹腔巨噬细胞分泌的NO、IL-1、IL-18、TNF-α水平降低，脾脏自然杀伤细胞(natural killer cells，NK cells)的细胞毒性作用降低；小鼠的细胞免疫和体液免疫功能异常，表现为脾脏T细胞增殖能力下降而B细胞的增殖能力提高，血清总IgG、IgE的含量增高，迟发性超敏反应实验显示足跖增厚程度下降；流式细胞术实验发现脾脏mIgM+mIgD+双阳性细胞比例增高，CD3+细胞比例降低，CD4+/CD8+脾脏T细胞的比值降低；ELISA检测发现，脾细胞经过刺激后，释放IFN-γ和TNF-α的水平降低，而释放IL-4和IL-10的水平却增高。以上结果提示，造成高剂量组小鼠免疫功能障碍的原因主要与体内辅助T细胞(Th)1/Th2细胞因子平衡紊乱，引起机体各项免疫功能的调节失常有关。
3.线粒体调节的凋亡途径和FasR调节的凋亡途径共同参与了DU引起的HK-2细胞的凋亡过程。而100μM锌预处理可明显抑制DU(500μM)引起的HK-2凋亡，通过降低细胞内活性氧的生成，增加过氧化氢酶(CAT)和还原型谷胱甘肽(GSH)的含量，抑制DU引起的sFasR和sFasL的过表达，抑制线粒体中的细胞色素c和凋亡诱导因子(AIF)释放到胞浆，抑制Caspases-9、Caspases-8和Caspases-3的激活以及促进了金属硫蛋白的表达。进一步观察发现，外源性金属硫蛋白也具有很好的抗DU引起的凋亡的作用。本研究结果证实了，锌通过一些独立的机制抑制了DU引起的凋亡，包括抗氧化效应、抑制Caspases-9、Caspases-8和Caspases-3的激活，并且金属硫蛋白可能参与了锌抗DU引起的凋亡过程。
4.锌预处理(10mg/kg)对急性DU中毒(10mg/kg)具有明显的解毒作用，明显提高了大鼠暴露于DU后30d的存活率，使暴露于DU4d后的尿铀含量增加，肝、脾、肾铀含量降低，血清BUN、Cr及尿液NAG显著降低，并使血清IL-6和TNF-α、肾脏组织金属硫蛋白MT-1、MT-2的基因表达水平明显增高，CAT含量增高，丙二醛(MDA)含量降低，病理学损伤减轻。进一步使用锌预处理MT-/-小鼠和MT+/+小鼠，发现MT+/+小鼠的铀含量明显降低，且肾脏损伤明显减轻，抗氧化能力增强；但锌预处理对MT-/-小鼠却没有明显的DU解毒效果。外源性MT的不同基因型(MT1和MT2)对DU解毒效果的研究发现，MT1和MT2均可降低MT-/-小鼠肾脏的铀含量，且MT-1可使肾脏的病理损伤明显减轻，抗氧化能力增强，而MT2的保护效果却并不明显。因此，锌的解毒作用与诱导MT的合成有关，一方面，MT可促进DU的排出；另一方面，MT可增强体内的抗氧化能力，拮抗DU对组织的损伤，并且MT1的作用更加明显。
5. MT-/-小鼠和MT+/+小鼠暴露于DU后，利用蛋白组学方法对小鼠肾脏组织蛋白的改变进行研究，发现有13个差异表达蛋白，它们的主要功能集中在糖和脂肪酸的代谢、电子传递呼吸链以及抗氧化防御系统等方面。进一步分析发现，超氧化物歧化酶(SOD)、氨基酰化酶-3(ACY-3)在暴露于DU后明显降低，且MT-/-小鼠降低更为明显，提示了这些蛋白可能参与了DU引起的肾脏中毒过程。采用免疫印迹技术对典型的差异蛋白SOD和ACY-3的表达量进行验证，所得结果与蛋白组学研究结果相吻合，再次验证了贫铀肾毒性的机制之一是引起氧化应激，并且ACY-3可能是DU发挥肾毒性的新的靶点，而MT可通过调节它们的含量在一定程度上减轻肾脏损伤。
Background and Objectives
Depleted uranium (DU) is the by-product of uranium (235U) enrichment from naturaluranium, as having235U content lower than0.712%. Due to its efficient penetration andaffordability, DU has recently been widely used in nuclear power plants, counterweights,radiation protection and military activities (such as armour material and ammunitioncomponents). However, during its production and use, DU may be released into theenvironment due to failure to follow standard procedures, thus causing environmentalpollution. DU may eventually enter the human body through the respiratory tract, digestivetract or skin, leading to contamination of local residents.
DU emits α and β particles with high linear energy transfer, and DU has the dualeffects of radioactive toxicity and heavy metal toxicity. The biological effects of DU areaffected by the exposure dose, exposure duration, the exposure pathway and many otherfactors. During acute high-dose exposures, the kidney is the main target organ of thechemical toxicity of DU, which may cause severe tubular necrosis. However, themechanism of DU-induced nephrotoxicity is not clear. Low-dose chronic exposure maycause a series of harmful effects, such as neurobehavioral abnormalities, genetic toxicity,reproductive toxicity, and cancer. However, few published studies exist on the impact ofDU on immune function in live animals. There is still no report on the effects of ingestingDU-contaminated food on the immune system, which continues to be a worldwide concern.Therefore, the present study created an acute toxicity model and a chronic toxicity modelthrough long-term ingestion of DU-containing feed. We evaluated the effect of DU on thekidney after acute exposure and the immune system after chronic exposure. We alsoexplored in depth the mechanism of DU-induced toxicity. This study was a basic for thestudy of the biological effects of DU.
In addition, the prevention and treatment of DU intoxication is still a worldwide keyand difficult point. However, at present, most of chelating agents for DU still have someinsufficiencies more or less in removal effect or security. MT is a low-molecular weight, thiol-containing protein that is found throughout the body and that participates inscavenging free radical and heavy metal detoxification. However, the mechanism involvedin the protective role of MT remains an enigma. The gene expression of MT is dependenton the zinc ions. Zinc is an efficient and safe inductor of MT. Therefore, we used zinc todetoxify the DU intoxication by inducing MT. This study provided a new idea for thedevelopment of the high-performance and low-toxicity drugs against DU in clinicapplications, and might have an important practical value.
Methods
First, human kidney cells (HK-2) and Sprague Dawley rats were used to expose to thedifferent doses of DU for creating an acute toxicity model, respectively. After24h exposureto DU, the cell viability, apoptosis and related enzyme activity were assessed in HK-2cells,and after4d exposure to DU, kidney uranium content, renal function, histopathology andantioxidant levels in tissue were measured in rats.
Second, three-week-old Kunming mice were divided into the following4groups basedon the various feeding doses (containing DU):0(control group),3(DU3group),30(DU30group), and300mg/kg feed (DU300group). After4months of exposure, the innate immunefunction and acquired immune function were evaluated.
Third, HK-2cells, Sprague Dawley rats and MT knockout mice were used to study theprotective role of zinc against DU, respectively. The methods including histomorphology,ultrastructural pathology, flow cytometry, laser scanning confocal microscope, enzymelinked immunosorbent assay (ELISA), molecular biology and proteomics were used toevaluated the detoxification of zinc against DU. The mechanism of protective role of zincagainst DU was explored in depth.
Results and Conclusion
1. After24h exposure to uranyl nitrate (more than125μM), cytoplasmic membranesand lysosomal membranes of HK-2cells damaged, and lactate dehydrogenase (LDH) andN-acethyl-β-D-glucosaminidase (NAG) were released from cell to culture medium, leadingto cell apoptosis at last. In addition, Sprague Dawley rats were exposed to different doses ofDU (2.5、5、10mg/kg). After4d exposure, DU (more than2.5mg/kg) led to obviousnephrotoxicity, including increasing kidney uranium content, blood urea nitrogen (BUN)and creatinine (Cr) levels, and serious pathological damage. The nephrotoxicity becamemore severe with higher DU dose. Further studies showed that the antioxidant function decreased and lipid peroxidation level increased in the kidney tissue after exposure to DU,which may be one of the mechanisms of DU-induced nephrotoxicity.
2. Three-week-old mice were fed with various doses of DU for4months. After4months of exposure, the biochemical parameters in blood serum of each group were all innormal level. In the DU30and DU3groups, immunological changes were either minor orindiscernible. However, in the DU300group, the innate immune function decreased,manifesting as decreased secretion of nitric oxide, interleukin (IL)-1, IL-18, and tumournecrosis factor (TNF)-α in the peritoneal macrophages, as well as reduced cytotoxicity ofthe splenic natural killer cells. Moreover, the cellular and humoral immune functions wereabnormal, as manifested by decreased proliferation of the splenic T cells, proportion of thecluster of differentiation (CD)3+cells, ratio of CD4+/CD8+cells and delayed-typehypersensitivity, and increased proliferation of the splenic B cells, total serumimmunoglobin (Ig) G and IgE, and proportion of splenic mIgM+mIgD+cells. Throughstimulation, the secretion levels of interferon (IFN)-and TNF-α in the splenic cellsreduced, and the levels of IL-4and IL-10increased. In conclusions, chronic intake ofhigher doses of DU (300mg/kg) had a significant impact on the immune function, mostlikely due to an imbalance in T helper (Th)1and Th2cytokines.
3. Mitochondrial and FasR-mediated apoptosis pathways contribute to DU-inducedapoptosis in HK-2cells. Pre-treatment with zinc (100μM) significantly inhibited DU(500μM)-induced HK-2cells apoptosis. It reduced the formation of reactive oxygen speciesin the cells, increased the catalase (CAT) and glutathione (GSH) concentrations, suppressedthe DU-induced soluble Fas receptor (sFasR) and soluble Fas ligand (sFasL)overexpression, suppressed the release of cytochrome c and apoptosis inhibitor factor (AIF)form mitochondria to cytoplasm, inhibited the activation of caspase-9, caspase-8, andcaspase-3, and induced MT expression. Furthermore, exogenous MT effectively inhibitedDU-induced cell apoptosis. In conclusions, through independent mechanisms, such asantioxidant effects, inhibition of the activation of caspase-9, caspase-8, and caspase-3, andinduction of MT expression, zinc inhibits DU-induced apoptosis.
4. Pre-treatment with zinc (10mg/kg) had significantly higher survival rates than ratswithout zinc pre-treatment at30d post depleted uranium administration. At4d postadministration, the former had higher urine uranium content but lower liver and kidneyuranium content. Meanwhile, serum BUN and Cr levels and urine NAG concentrations significantly decreased; Gene expression levels of MT-1and MT-2in kidney tissuessignificantly increased; and CAT levels increased and malonaldehyde (MDA) levelsdecreased, both significantly. Compared to rats exposed only to DU, rats with zincpre-treatment had insignificant renal tubular epithelial cell necrosis and less transparenttubes. With regard to mice, after DU injection, both MT+/+and MT-/-mice showedsignificantly increased uranium content of the renal tissues and serum Cr and BUN.Meanwhile, renal tissues displayed severe renal pathological damage. However, thesechanges were more evident in MT-/-mice. Zinc pre-treatment significantly decreaseduranium content in renal tissues with increasing MT content, and alleviated renal damage inMT+/+mice, which was not observed in MT-/-mice. Furthermore, exogenous MT1andMT2all could significantly decrease the kidney uranium content at4d post DUadministration in MT-/-mice. MT1also alleviated renal damage, and increased theantioxidant activity, while MT2could not. In conclusion, MT, not zinc, plays a crucial rolein antagonising the nephrotoxicity of DU. The underlying mechanism includes DUexcretion, which is facilitated by the stable binding of MT to DU in the kidney, and theantioxidant activity of MT, which cleans excess reactive oxygen species and preventssuperoxide generation from the renal tissue, especially MT1.
5. An expression proteomic analysis involving two-dimensional electrophoresis andmatrix-assisted laser desorption ionization time-of-flight mass spectrometry was used toidentify proteins changes between MT+/+and MT-/-mice after exposure to DU. Thirteenproteins were identified, whose functions were focus on glycometabolism, fatty acidmetabolism, electron transport respiratory chain and antioxidant defense system. Furtherstudies showed that, the levels of superoxide dismutase (SOD) and amino-acylase3(ACY-3) decreased after exposure to DU. They decreased more significant in MT-/-mice,which suggested these proteins might participate in DU-induced toxicity. Western blot wasused to assess the expression of SOD and ACY-3, and the results were in accord with theproteomic analysis. The results also verified that one of the mechanisms of DU-inducednephrotoxicity was oxidative stress. In addition, ACY-3might be a new target ofDU-induced nephrotoxicity, and MT could alleviate the DU-induced kidney damagethrough modifying SOD and ACY-3expressions.
贫铀(depleted uranium，DU)是天然铀经过提炼浓缩铀(~(235)U)之后的剩余产物，其~(235)U含量低于0.712％。由于DU具有良好的穿透性和原料的廉价性，被广泛地用于核电站、平衡锤、辐射防护及军事活动中(如作为装甲材料及弹药成分)。在DU的生产和使用过程中，可能会不规范地释放到环境中，经呼吸道、消化道或皮肤进入体内，对周围居民的健康造成严重地威胁。
DU可发射高线性能量转移的α、β粒子，既具有放射毒性，又具有重金属毒性，其生物学影响与接触剂量、持续时间、接触途径等多种因素有关。在大剂量急性暴露的条件下，肾脏是铀急性化学毒性的主要靶器官，可造成严重的肾近曲小管坏死，然而，DU引起肾脏毒性的准确机制还不清楚。在低剂量慢性暴露的情况下，可能会引起一系列有害的效应，如神经行为的异常、生殖毒性、遗传毒性和癌症等，然而，普遍关注的问题——长期摄入DU污染的食物对免疫系统的影响，目前还没有报道。因此，本研究分别建立DU急性暴露模型和经过食入途径的慢性暴露模型，分别评价急性DU暴露对肾脏的影响和慢性DU暴露对免疫系统的影响，深入探索急慢性DU暴露的作用机制，为DU生物学效应的研究打下基础。
此外，针对DU中毒的救治，仍是国内外研究的重点和难点。现有的DU促排药在促排效果或安全性方面都或多或少存在问题。金属硫蛋白(metallothinein, MT)是一类广泛存在于哺乳动物器官和组织中的低分子量非酶蛋白，富含半胱氨酸，对重金属离子有很高的亲和力，并能清除多种自由基，可实现对金属的解毒，但其解毒机制仍不完全清楚。MT基因的表达，需要二价锌离子的参与，锌属于高效且安全的MT诱导剂。因此，可试图通过锌诱导机体产生MT来实现DU的解毒治疗，为临床上开发高效低毒的DU解毒药物提供新的思路，具有重要的实用价值和现实意义。
研究方法
首先分别利用人肾脏近曲小管上皮HK-2细胞和成年Sprague Dawley大鼠，暴露于不同剂量的DU，造成DU急性染毒模型，分别观察暴露于DU后24h对细胞存活率、凋亡及相关酶活力的影响，以及暴露于DU后4d对大鼠肾脏铀含量、肾功能、组织病理学及肾脏组织抗氧化水平的影响。
其次，3周龄昆明系小鼠，按照喂食饲料(含DU)剂量的不同分为4组：0(对照组)，3(DU3组)，30(DU_(30)组)，和300(DU_(300)组)mg/kg，喂食长达4个月，造成DU慢性染毒模型，评价小鼠天然免疫和获得性免疫功能的变化。
最后，分别利用HK-2细胞、Sprague Dawley大鼠和MT基因敲除小鼠，进行锌对DU中毒的解毒作用及机制的研究，通过组织形态学、细胞超微病理学、流式细胞术、激光共聚焦显微镜技术、酶联免疫吸附试验(ELISA)、分子生物学及蛋白组学等技术方法多角度评价锌对DU的解毒作用，深入探索锌对DU的解毒机制。
研究结果及结论
1.高于125μM的DU(硝酸铀酰)暴露后24h，均可引起HK-2细胞质膜和溶酶体膜的破坏，而导致乳酸脱氢酶(LDH)和N-乙酰-β-葡萄糖苷酶(NAG)从细胞内释放到培养液中，最终导致细胞的凋亡。另外，将Sprague Dawley大鼠急性暴露于不同剂量的DU(2.5、5、10mg/kg)，4d后观察发现，大于2.5mg/kg的DU暴露剂量均可引起明显的肾脏毒性，导致肾脏组织铀含量、血清尿素(BUN)和肌酐(Cr)均明显增高，组织病理学损伤严重，且随着DU暴露剂量的增高损伤逐渐加重。进一步研究发现，DU引起了肾脏组织氧化应激，导致抗氧化能力下降，脂质过氧化水平增高，可能是导致DU肾脏毒性的机制之一。
2.3周龄小鼠喂食不同剂量的含DU饲料4个月后，各组血生化检查均无明显异常。在中剂量组(30mg/kg)和低剂量组(3mg/kg)，免疫学影响并不明显或影响相对轻微。但在高剂量组(300mg/kg)，小鼠的天然免疫功能下降，表现为腹腔巨噬细胞分泌的NO、IL-1、IL-18、TNF-α水平降低，脾脏自然杀伤细胞(natural killer cells，NK cells)的细胞毒性作用降低；小鼠的细胞免疫和体液免疫功能异常，表现为脾脏T细胞增殖能力下降而B细胞的增殖能力提高，血清总IgG、IgE的含量增高，迟发性超敏反应实验显示足跖增厚程度下降；流式细胞术实验发现脾脏mIgM+mIgD+双阳性细胞比例增高，CD3+细胞比例降低，CD4+/CD8+脾脏T细胞的比值降低；ELISA检测发现，脾细胞经过刺激后，释放IFN-γ和TNF-α的水平降低，而释放IL-4和IL-10的水平却增高。以上结果提示，造成高剂量组小鼠免疫功能障碍的原因主要与体内辅助T细胞(Th)1/Th2细胞因子平衡紊乱，引起机体各项免疫功能的调节失常有关。
3.线粒体调节的凋亡途径和FasR调节的凋亡途径共同参与了DU引起的HK-2细胞的凋亡过程。而100μM锌预处理可明显抑制DU(500μM)引起的HK-2凋亡，通过降低细胞内活性氧的生成，增加过氧化氢酶(CAT)和还原型谷胱甘肽(GSH)的含量，抑制DU引起的sFasR和sFasL的过表达，抑制线粒体中的细胞色素c和凋亡诱导因子(AIF)释放到胞浆，抑制Caspases-9、Caspases-8和Caspases-3的激活以及促进了金属硫蛋白的表达。进一步观察发现，外源性金属硫蛋白也具有很好的抗DU引起的凋亡的作用。本研究结果证实了，锌通过一些独立的机制抑制了DU引起的凋亡，包括抗氧化效应、抑制Caspases-9、Caspases-8和Caspases-3的激活，并且金属硫蛋白可能参与了锌抗DU引起的凋亡过程。
4.锌预处理(10mg/kg)对急性DU中毒(10mg/kg)具有明显的解毒作用，明显提高了大鼠暴露于DU后30d的存活率，使暴露于DU4d后的尿铀含量增加，肝、脾、肾铀含量降低，血清BUN、Cr及尿液NAG显著降低，并使血清IL-6和TNF-α、肾脏组织金属硫蛋白MT-1、MT-2的基因表达水平明显增高，CAT含量增高，丙二醛(MDA)含量降低，病理学损伤减轻。进一步使用锌预处理MT-/-小鼠和MT+/+小鼠，发现MT+/+小鼠的铀含量明显降低，且肾脏损伤明显减轻，抗氧化能力增强；但锌预处理对MT-/-小鼠却没有明显的DU解毒效果。外源性MT的不同基因型(MT1和MT2)对DU解毒效果的研究发现，MT1和MT2均可降低MT-/-小鼠肾脏的铀含量，且MT-1可使肾脏的病理损伤明显减轻，抗氧化能力增强，而MT2的保护效果却并不明显。因此，锌的解毒作用与诱导MT的合成有关，一方面，MT可促进DU的排出；另一方面，MT可增强体内的抗氧化能力，拮抗DU对组织的损伤，并且MT1的作用更加明显。
5. MT-/-小鼠和MT+/+小鼠暴露于DU后，利用蛋白组学方法对小鼠肾脏组织蛋白的改变进行研究，发现有13个差异表达蛋白，它们的主要功能集中在糖和脂肪酸的代谢、电子传递呼吸链以及抗氧化防御系统等方面。进一步分析发现，超氧化物歧化酶(SOD)、氨基酰化酶-3(ACY-3)在暴露于DU后明显降低，且MT-/-小鼠降低更为明显，提示了这些蛋白可能参与了DU引起的肾脏中毒过程。采用免疫印迹技术对典型的差异蛋白SOD和ACY-3的表达量进行验证，所得结果与蛋白组学研究结果相吻合，再次验证了贫铀肾毒性的机制之一是引起氧化应激，并且ACY-3可能是DU发挥肾毒性的新的靶点，而MT可通过调节它们的含量在一定程度上减轻肾脏损伤。
Background and Objectives
Depleted uranium (DU) is the by-product of uranium (235U) enrichment from naturaluranium, as having235U content lower than0.712%. Due to its efficient penetration andaffordability, DU has recently been widely used in nuclear power plants, counterweights,radiation protection and military activities (such as armour material and ammunitioncomponents). However, during its production and use, DU may be released into theenvironment due to failure to follow standard procedures, thus causing environmentalpollution. DU may eventually enter the human body through the respiratory tract, digestivetract or skin, leading to contamination of local residents.
DU emits α and β particles with high linear energy transfer, and DU has the dualeffects of radioactive toxicity and heavy metal toxicity. The biological effects of DU areaffected by the exposure dose, exposure duration, the exposure pathway and many otherfactors. During acute high-dose exposures, the kidney is the main target organ of thechemical toxicity of DU, which may cause severe tubular necrosis. However, themechanism of DU-induced nephrotoxicity is not clear. Low-dose chronic exposure maycause a series of harmful effects, such as neurobehavioral abnormalities, genetic toxicity,reproductive toxicity, and cancer. However, few published studies exist on the impact ofDU on immune function in live animals. There is still no report on the effects of ingestingDU-contaminated food on the immune system, which continues to be a worldwide concern.Therefore, the present study created an acute toxicity model and a chronic toxicity modelthrough long-term ingestion of DU-containing feed. We evaluated the effect of DU on thekidney after acute exposure and the immune system after chronic exposure. We alsoexplored in depth the mechanism of DU-induced toxicity. This study was a basic for thestudy of the biological effects of DU.
In addition, the prevention and treatment of DU intoxication is still a worldwide keyand difficult point. However, at present, most of chelating agents for DU still have someinsufficiencies more or less in removal effect or security. MT is a low-molecular weight, thiol-containing protein that is found throughout the body and that participates inscavenging free radical and heavy metal detoxification. However, the mechanism involvedin the protective role of MT remains an enigma. The gene expression of MT is dependenton the zinc ions. Zinc is an efficient and safe inductor of MT. Therefore, we used zinc todetoxify the DU intoxication by inducing MT. This study provided a new idea for thedevelopment of the high-performance and low-toxicity drugs against DU in clinicapplications, and might have an important practical value.
Methods
First, human kidney cells (HK-2) and Sprague Dawley rats were used to expose to thedifferent doses of DU for creating an acute toxicity model, respectively. After24h exposureto DU, the cell viability, apoptosis and related enzyme activity were assessed in HK-2cells,and after4d exposure to DU, kidney uranium content, renal function, histopathology andantioxidant levels in tissue were measured in rats.
Second, three-week-old Kunming mice were divided into the following4groups basedon the various feeding doses (containing DU):0(control group),3(DU3group),30(DU30group), and300mg/kg feed (DU300group). After4months of exposure, the innate immunefunction and acquired immune function were evaluated.
Third, HK-2cells, Sprague Dawley rats and MT knockout mice were used to study theprotective role of zinc against DU, respectively. The methods including histomorphology,ultrastructural pathology, flow cytometry, laser scanning confocal microscope, enzymelinked immunosorbent assay (ELISA), molecular biology and proteomics were used toevaluated the detoxification of zinc against DU. The mechanism of protective role of zincagainst DU was explored in depth.
Results and Conclusion
1. After24h exposure to uranyl nitrate (more than125μM), cytoplasmic membranesand lysosomal membranes of HK-2cells damaged, and lactate dehydrogenase (LDH) andN-acethyl-β-D-glucosaminidase (NAG) were released from cell to culture medium, leadingto cell apoptosis at last. In addition, Sprague Dawley rats were exposed to different doses ofDU (2.5、5、10mg/kg). After4d exposure, DU (more than2.5mg/kg) led to obviousnephrotoxicity, including increasing kidney uranium content, blood urea nitrogen (BUN)and creatinine (Cr) levels, and serious pathological damage. The nephrotoxicity becamemore severe with higher DU dose. Further studies showed that the antioxidant function decreased and lipid peroxidation level increased in the kidney tissue after exposure to DU,which may be one of the mechanisms of DU-induced nephrotoxicity.
2. Three-week-old mice were fed with various doses of DU for4months. After4months of exposure, the biochemical parameters in blood serum of each group were all innormal level. In the DU30and DU3groups, immunological changes were either minor orindiscernible. However, in the DU300group, the innate immune function decreased,manifesting as decreased secretion of nitric oxide, interleukin (IL)-1, IL-18, and tumournecrosis factor (TNF)-α in the peritoneal macrophages, as well as reduced cytotoxicity ofthe splenic natural killer cells. Moreover, the cellular and humoral immune functions wereabnormal, as manifested by decreased proliferation of the splenic T cells, proportion of thecluster of differentiation (CD)3+cells, ratio of CD4+/CD8+cells and delayed-typehypersensitivity, and increased proliferation of the splenic B cells, total serumimmunoglobin (Ig) G and IgE, and proportion of splenic mIgM+mIgD+cells. Throughstimulation, the secretion levels of interferon (IFN)-and TNF-α in the splenic cellsreduced, and the levels of IL-4and IL-10increased. In conclusions, chronic intake ofhigher doses of DU (300mg/kg) had a significant impact on the immune function, mostlikely due to an imbalance in T helper (Th)1and Th2cytokines.
3. Mitochondrial and FasR-mediated apoptosis pathways contribute to DU-inducedapoptosis in HK-2cells. Pre-treatment with zinc (100μM) significantly inhibited DU(500μM)-induced HK-2cells apoptosis. It reduced the formation of reactive oxygen speciesin the cells, increased the catalase (CAT) and glutathione (GSH) concentrations, suppressedthe DU-induced soluble Fas receptor (sFasR) and soluble Fas ligand (sFasL)overexpression, suppressed the release of cytochrome c and apoptosis inhibitor factor (AIF)form mitochondria to cytoplasm, inhibited the activation of caspase-9, caspase-8, andcaspase-3, and induced MT expression. Furthermore, exogenous MT effectively inhibitedDU-induced cell apoptosis. In conclusions, through independent mechanisms, such asantioxidant effects, inhibition of the activation of caspase-9, caspase-8, and caspase-3, andinduction of MT expression, zinc inhibits DU-induced apoptosis.
4. Pre-treatment with zinc (10mg/kg) had significantly higher survival rates than ratswithout zinc pre-treatment at30d post depleted uranium administration. At4d postadministration, the former had higher urine uranium content but lower liver and kidneyuranium content. Meanwhile, serum BUN and Cr levels and urine NAG concentrations significantly decreased; Gene expression levels of MT-1and MT-2in kidney tissuessignificantly increased; and CAT levels increased and malonaldehyde (MDA) levelsdecreased, both significantly. Compared to rats exposed only to DU, rats with zincpre-treatment had insignificant renal tubular epithelial cell necrosis and less transparenttubes. With regard to mice, after DU injection, both MT+/+and MT-/-mice showedsignificantly increased uranium content of the renal tissues and serum Cr and BUN.Meanwhile, renal tissues displayed severe renal pathological damage. However, thesechanges were more evident in MT-/-mice. Zinc pre-treatment significantly decreaseduranium content in renal tissues with increasing MT content, and alleviated renal damage inMT+/+mice, which was not observed in MT-/-mice. Furthermore, exogenous MT1andMT2all could significantly decrease the kidney uranium content at4d post DUadministration in MT-/-mice. MT1also alleviated renal damage, and increased theantioxidant activity, while MT2could not. In conclusion, MT, not zinc, plays a crucial rolein antagonising the nephrotoxicity of DU. The underlying mechanism includes DUexcretion, which is facilitated by the stable binding of MT to DU in the kidney, and theantioxidant activity of MT, which cleans excess reactive oxygen species and preventssuperoxide generation from the renal tissue, especially MT1.
5. An expression proteomic analysis involving two-dimensional electrophoresis andmatrix-assisted laser desorption ionization time-of-flight mass spectrometry was used toidentify proteins changes between MT+/+and MT-/-mice after exposure to DU. Thirteenproteins were identified, whose functions were focus on glycometabolism, fatty acidmetabolism, electron transport respiratory chain and antioxidant defense system. Furtherstudies showed that, the levels of superoxide dismutase (SOD) and amino-acylase3(ACY-3) decreased after exposure to DU. They decreased more significant in MT-/-mice,which suggested these proteins might participate in DU-induced toxicity. Western blot wasused to assess the expression of SOD and ACY-3, and the results were in accord with theproteomic analysis. The results also verified that one of the mechanisms of DU-inducednephrotoxicity was oxidative stress. In addition, ACY-3might be a new target ofDU-induced nephrotoxicity, and MT could alleviate the DU-induced kidney damagethrough modifying SOD and ACY-3expressions.
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