林丹与抗生素对黑腹果蝇肿瘤细胞迁移的联合毒性与氧化应激效应研究
Combined Effects of Lindane and Antibiotics on Tumor Migration and Antioxidant Responses in Drosophila melanogaster
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摘要: 有机氯农药(OCPs)与抗生素分别代表持久性有机污染物与新污染物，二者共存于环境介质中，然而其联合毒性尚缺乏系统研究。围绕癌症发生与治疗中的关键环节肿瘤细胞迁移效应，以林丹代表OCPs，以磺胺甲恶唑(SMX)、盐酸四环素(TET)代表抗生素，基于黑腹果蝇模式生物，探究林丹及其与SMX或TET的二元混合物的联合效应。单独暴露的效应表明，林丹在40～100 ng·g-1浓度范围内显著增强了果蝇幼虫眼部与脑部肿瘤细胞向前庭核复合体(VNC)的迁移率(P<0.05)，该效应随浓度升高逐渐增强；SMX在最高浓度组400 ng·g-1显著增强了肿瘤细胞迁移水平；TET在600～1 000 ng·g-1显著增强了肿瘤细胞迁移，并表现出浓度依赖关系。采用直接均分法设计的二元混合物效应表明，林丹与SMX或TET的二元混合物都显著增强了肿瘤细胞迁移水平，随着林丹浓度的升高，肿瘤细胞迁移效应也逐渐增强；与独立作用(IA)模型预测值相比，混合物均表现出协同作用。对氧化应激相关指标的检测表明，林丹、SMX、TET以及二元混合物普遍增加了活性氧自由基(ROS)，减少了谷胱甘肽(GSH)。林丹与SMX的联合作用中肿瘤细胞迁移效应与过氧化氢酶(CAT)呈负相关，林丹与TET的联合作用并未表现如此相关性，该差异与SMX、TET诱发氧化应激效应存在差异有关。同时，林丹与SMX、林丹与TET这2类二元混合物的效应表现出不同的层次聚类分析结果。林丹与SMX联合作用诱发的肿瘤细胞迁移效应与ROS和超氧化物歧化酶(SOD)有相似聚类关系，林丹与TET联合作用诱发的肿瘤细胞迁移效应与ROS表现出最相近的聚类关系。该结果再次表明SMX、TET氧化应激效应的不同对其与林丹联合作用的影响，也表明抗生素类别可显著影响混合物潜在致毒途径。Abstract: Organic chlorine pesticides (OCPs) and antibiotics represent persistent organic pollutants and emerging pollutants, respectively. They can coexist in various environmental matrix, while their combined effects were seldom explored. Lindane was chosen to represent OCPs, and sulfamethoxazole (SMX) and tetracycline hydrochloride (TET) were chosen to represent antibiotics. The present study focused on the influences on tumor migration which is essential for both carcinogenesis and cancer treatment and aimed to explore the effects of the binary mixtures on the model organism Drosophila melanogaster. The individual effects showed that lindane significantly enhanced the tumor migration from the eye and brain of the larvae to the ventral nerve cord (VNC) in the concentration range of 40～100 ng·g-1 (P<0.05). SMX enhanced the tumor migration at the highest concentration of 400 ng·g-1, while TET increased the tumor migration from 600 to 1 000 ng·g-1 with a concentration-dependence. The binary mixtures were designed by direct equipartition method. The binary mixtures that contained lindane and SMX or TET significantly enhanced the tumor migration, with a dependence on the lindane’s concentrations. Compared with the predicted effects by independent action (IA) model, the binary mixtures showed synergistic toxicity interactions. Determination on the antioxidant responses showed that, lindane, SMX, TET and the binary mixtures commonly increased reactive oxygen species (ROS) while decreased glutathione (GSH). The effects of binary mixtures containing lindane and SMX on tumor migration were negatively correlated with their influences on catalase (CAT) activities, while such correlation was not observed in the effects of mixtures containing lindane and TET. Such difference was attributed to the different effects of SMX and TET on the antioxidants. Moreover, the effects of binary mixtures containing lindane and SMX, and those containing lindane and TET showed different hierarchical clustering positions. The effects of binary mixtures containing lindane and SMX on tumor migration were closely connected with both ROS and superoxide dismutase (SOD), while those of binary mixtures containing lindane and TET were closely connected with ROS. Such differences supported the attribution to the individual effects of SMX or TET on the antioxidants and also indicated that the antibiotic types can influence the toxicity mechanism of the binary mixtures.
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