环境致癌物协同作用及其机制研究
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摘要
淮河流域肿瘤发病率异常增高已经成为我国面临的一项重大公共卫生问题,淮河水的污染可能是这一事件的主要诱因,因此需要对淮河水污染与肿瘤的相关性进行评估。污染的水体是一个复杂的致癌物的混合体,其中存在着大量已知或未知的致癌因子,包括化学物质、病毒或物理性因子,癌症的发生往往是这些致癌因子协同作用的结果。因此,有必要研究致癌物间在肿瘤发生过程中的协同及其相互作用的机制,并采取有效手段对水体的综合致癌活性进行检测。
体外细胞转化技术是一种高度模拟体内细胞恶性转化的体外检测系统,可有效用于各类致癌物的筛选和检测。本文通过对培养基类型、血清浓度、受试物对细胞的作用时间、细胞转化程序等参数的优化,建立了适合于致癌物间协同致癌活性检测的Balb/c 3T3细胞转化实验系统。利用该优化的方法,对二乙基亚硝胺(DEN)、黄曲霉毒素(AFB_1)、微囊藻毒素(MC-LR)、2,3,7,8-四氯代二苯并-对-二噁英(TCDD)等已知或可疑致癌物的单独或联合致癌活性进行了检测,对淮河流域地面水和饮用水的致癌能力进行了调查,并采用软琼脂培养、血清依赖实验和SCID小鼠致瘤实验等方法验证转化细胞的恶性度。结果发现,DEN、AFB1和MC-LR三种不用类型的致癌物质在建立的转化系统上均呈现明显的致癌性,转化频率与药物浓度存在着剂量反应关系。DEN与TCDD联合作用时,细胞的恶性转化频率成倍增加,DEN与MC-LR联合作用时,转化频率低于MC-LR单独作用。在淮河流域采集的地面水在未经浓缩的原水浓度下不具有细胞毒性,但却有显著的促转化作用,并且促细胞恶性转化频率随水样浓缩倍数的增加面增加。小于10m的浅井水样品在100倍浓缩度时呈阳性结果,深井水样品在各浓缩度下均未表现出促转化活性。转化灶细胞接种SCID小鼠后可形成明显的肿瘤。
研究表明TCDD能提高DEN向终致癌物代谢所需的细胞色素氧化酶的表达,因而我们猜测TCDD通过此途径与DEN协同致癌。但细胞转化抑制实验表明,多环芳烃受体(AhR)拮抗剂a-NF不能抑制DEN与TCDD间的协同促转化作用。实时荧光定量RT-PCR对细胞Cyp1a1和Cyp2a5基因转录水平的研究发现,TCDD单独作用时,可明显上调Cyp1a1和Cyp2a5的转录水平,但DEN与TCDD联合作用时,Cyp1a1和Cyp2a5的转录却是受到抑制的。
上述研究结果表明:(1)优化的Balb/c 3T3细胞转化检测系统能有效可靠地用于致癌物、致癌物间协同作用及水体致癌活性的检测。(2) MC-LR、DEN及AFB_1均具有致癌性,TCDD不具有促细胞恶性转化的活性,但与DEN有明显的协同致癌作用。与二阶段模型中的促癌作用不同,MC-LR与DEN共同作用时不具有协同作用。(3)淮河流域受污染地面水具致癌性,并影响到浅层地下水,但致癌性较地面水明显下降,并随井深度而降低。这一结论还需更多样品检测数据予以证实。(4) DEN与TCDD间的协同致癌作用并非通过提高Cyp2a5的转录水平,从而加强DEN向终致癌物代谢发挥作用。其机制可能涉及更复杂的分子调控机制,尚需深入研究。
The higher incidence of tumor in Huaihe River basin has become a serious public health event. The water pollution may contribute to this event. So, to evaluate the relativity between water pollution and tumorigenesis is required. A polluted water sample is a mixture that contains various types of potential carcinogens, such as chemicals and virus. These carcinogens often cooperate to cause cancer. Therefore, it is necessary to study this synergistic effects and their mechanism, and to assay the carciongenic potency of waters using an appropriated method.
Cell transformation has been defined as the induction of certain phenotypic alterations in cultured cells that are characteristic of tumorigenic cells. It has been shown to be a multistage process which closely models the various stages of in vivo carcinogenesis. Cell transformation assay can provide some crucial evidence specific to the tumorigenic potential of various types of carcinogens, which cannot be supplied by genotoxicity testing. In this paper, an improved cell transformation assay protocol was established by selecting appropriate cell cultures media, concentration of fetal bovine serum (FBS), administration ways and program of cell transformation. Using this improved method, the carcinogenic potencies of diethylnitrosamine (DEN), aflatoxin B_1 (AFB_1) and microcystin-LR (MC-LR) were examined. Synergistic effects between DEN and MC-LR, DEN and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) were tested as well. The results show that any of DEN, AFB1 and MC-LR can induce cell malignant transformation significantly and show dose-response relationships. When administered together, the tranforamtion frequency induced by DEN plus TCDD are three times higher than that induced by DEN alone, and 15 times higher than TCDD. But for DEN plus MC-LR, the transformation frequency was decreased when they worked together than MC-LR alone.
Then, three water samples, one river water sample and two well water samples, from Huaihe River basin were tested. The River water sample, even without being condensed, can induce significantly higher cell transformation frequency than control, and the transformation frequency increase with the increase of concentration multiple. The water sample from shallow well can induce a significantly higher transformation frequency when it is condensed at least 100 times, however, the water sample from a deeper well doesn't show the ability to induce cell malignant transformation.
The mechanism of the synergistic effect between DEN and TCDD was explored as we found this effect between them. We speculated that TCDD up regulated the expression of cytochrome P450 oxygenases which can metabolize DEN to its ultimate carcinogen form. According to this speculation, the AhR inhibitorα-NF will inhibit the synergistic effect between TCDD and DEN. However, the cell transformation inhibition assay shows thatα-NF doesn't work. The results of real time RT-PCR show that the transcription level of Cyp 1a1 and Cyp 2a5 gene are up regulated by TCDD alone, but down regulated after DEN was administer together with TCDD.
From these results above we can conclude that: (1) The improved Balb/c 3T3 cell transformation assay is reliable and time-saving, and can be efficiently used in the study of synergistic carcinogenic effects among carcinogens, and the carcinogenic test of water sample. (2) MC-LR, DEN and AFB_1 each have carcinogenic potency. TCDD have little ability to induce cell malignant transformation, but it is a potent cocarcinogen with DEN. Different to the result of two-stage model, there exist no synergistic effect between DEN and MC-LR when they are administered at the same time. (3) The river water of Huaihe basin has the ability to induce tumor. The carcinogenicity of Well water is weaker than surface water, and reduces with the increase of well depth. This conclusion needs to be verified by assaing more water samples. (4) The interaction between DEN and TCDD isn't the result that TCDD enhance the expression of cytochrome P450-linked DEN-bioactiving oxygenases. The mechanism may involve in more complex regulation procession which is worthy of a closer study.
体外细胞转化技术是一种高度模拟体内细胞恶性转化的体外检测系统,可有效用于各类致癌物的筛选和检测。本文通过对培养基类型、血清浓度、受试物对细胞的作用时间、细胞转化程序等参数的优化,建立了适合于致癌物间协同致癌活性检测的Balb/c 3T3细胞转化实验系统。利用该优化的方法,对二乙基亚硝胺(DEN)、黄曲霉毒素(AFB_1)、微囊藻毒素(MC-LR)、2,3,7,8-四氯代二苯并-对-二噁英(TCDD)等已知或可疑致癌物的单独或联合致癌活性进行了检测,对淮河流域地面水和饮用水的致癌能力进行了调查,并采用软琼脂培养、血清依赖实验和SCID小鼠致瘤实验等方法验证转化细胞的恶性度。结果发现,DEN、AFB1和MC-LR三种不用类型的致癌物质在建立的转化系统上均呈现明显的致癌性,转化频率与药物浓度存在着剂量反应关系。DEN与TCDD联合作用时,细胞的恶性转化频率成倍增加,DEN与MC-LR联合作用时,转化频率低于MC-LR单独作用。在淮河流域采集的地面水在未经浓缩的原水浓度下不具有细胞毒性,但却有显著的促转化作用,并且促细胞恶性转化频率随水样浓缩倍数的增加面增加。小于10m的浅井水样品在100倍浓缩度时呈阳性结果,深井水样品在各浓缩度下均未表现出促转化活性。转化灶细胞接种SCID小鼠后可形成明显的肿瘤。
研究表明TCDD能提高DEN向终致癌物代谢所需的细胞色素氧化酶的表达,因而我们猜测TCDD通过此途径与DEN协同致癌。但细胞转化抑制实验表明,多环芳烃受体(AhR)拮抗剂a-NF不能抑制DEN与TCDD间的协同促转化作用。实时荧光定量RT-PCR对细胞Cyp1a1和Cyp2a5基因转录水平的研究发现,TCDD单独作用时,可明显上调Cyp1a1和Cyp2a5的转录水平,但DEN与TCDD联合作用时,Cyp1a1和Cyp2a5的转录却是受到抑制的。
上述研究结果表明:(1)优化的Balb/c 3T3细胞转化检测系统能有效可靠地用于致癌物、致癌物间协同作用及水体致癌活性的检测。(2) MC-LR、DEN及AFB_1均具有致癌性,TCDD不具有促细胞恶性转化的活性,但与DEN有明显的协同致癌作用。与二阶段模型中的促癌作用不同,MC-LR与DEN共同作用时不具有协同作用。(3)淮河流域受污染地面水具致癌性,并影响到浅层地下水,但致癌性较地面水明显下降,并随井深度而降低。这一结论还需更多样品检测数据予以证实。(4) DEN与TCDD间的协同致癌作用并非通过提高Cyp2a5的转录水平,从而加强DEN向终致癌物代谢发挥作用。其机制可能涉及更复杂的分子调控机制,尚需深入研究。
The higher incidence of tumor in Huaihe River basin has become a serious public health event. The water pollution may contribute to this event. So, to evaluate the relativity between water pollution and tumorigenesis is required. A polluted water sample is a mixture that contains various types of potential carcinogens, such as chemicals and virus. These carcinogens often cooperate to cause cancer. Therefore, it is necessary to study this synergistic effects and their mechanism, and to assay the carciongenic potency of waters using an appropriated method.
Cell transformation has been defined as the induction of certain phenotypic alterations in cultured cells that are characteristic of tumorigenic cells. It has been shown to be a multistage process which closely models the various stages of in vivo carcinogenesis. Cell transformation assay can provide some crucial evidence specific to the tumorigenic potential of various types of carcinogens, which cannot be supplied by genotoxicity testing. In this paper, an improved cell transformation assay protocol was established by selecting appropriate cell cultures media, concentration of fetal bovine serum (FBS), administration ways and program of cell transformation. Using this improved method, the carcinogenic potencies of diethylnitrosamine (DEN), aflatoxin B_1 (AFB_1) and microcystin-LR (MC-LR) were examined. Synergistic effects between DEN and MC-LR, DEN and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) were tested as well. The results show that any of DEN, AFB1 and MC-LR can induce cell malignant transformation significantly and show dose-response relationships. When administered together, the tranforamtion frequency induced by DEN plus TCDD are three times higher than that induced by DEN alone, and 15 times higher than TCDD. But for DEN plus MC-LR, the transformation frequency was decreased when they worked together than MC-LR alone.
Then, three water samples, one river water sample and two well water samples, from Huaihe River basin were tested. The River water sample, even without being condensed, can induce significantly higher cell transformation frequency than control, and the transformation frequency increase with the increase of concentration multiple. The water sample from shallow well can induce a significantly higher transformation frequency when it is condensed at least 100 times, however, the water sample from a deeper well doesn't show the ability to induce cell malignant transformation.
The mechanism of the synergistic effect between DEN and TCDD was explored as we found this effect between them. We speculated that TCDD up regulated the expression of cytochrome P450 oxygenases which can metabolize DEN to its ultimate carcinogen form. According to this speculation, the AhR inhibitorα-NF will inhibit the synergistic effect between TCDD and DEN. However, the cell transformation inhibition assay shows thatα-NF doesn't work. The results of real time RT-PCR show that the transcription level of Cyp 1a1 and Cyp 2a5 gene are up regulated by TCDD alone, but down regulated after DEN was administer together with TCDD.
From these results above we can conclude that: (1) The improved Balb/c 3T3 cell transformation assay is reliable and time-saving, and can be efficiently used in the study of synergistic carcinogenic effects among carcinogens, and the carcinogenic test of water sample. (2) MC-LR, DEN and AFB_1 each have carcinogenic potency. TCDD have little ability to induce cell malignant transformation, but it is a potent cocarcinogen with DEN. Different to the result of two-stage model, there exist no synergistic effect between DEN and MC-LR when they are administered at the same time. (3) The river water of Huaihe basin has the ability to induce tumor. The carcinogenicity of Well water is weaker than surface water, and reduces with the increase of well depth. This conclusion needs to be verified by assaing more water samples. (4) The interaction between DEN and TCDD isn't the result that TCDD enhance the expression of cytochrome P450-linked DEN-bioactiving oxygenases. The mechanism may involve in more complex regulation procession which is worthy of a closer study.
引文
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