两阶段模型预测抗生素对蛋白核小球藻时间依赖混合毒性

发布时间：2018-06-05 03:10

本文选题：抗生素混合物 + 均匀设计射线法　；参考：《安徽建筑大学》2016年硕士论文

【摘要】：抗生素是由微生物(包括细菌、真菌、放线菌属等)或高等动植物在生活过程中所产生的一类具有抵抗微生物活性的天然、半合成或人工合成化合物。按化学结构分,可分为氨基糖苷类、β-内酰胺类、四环素类、喹诺酮类、大环内酯类、多肽类、酰胺醇类、林可酰胺类等。抗生素主要用于预防和治疗人类和动物疾病,后来也作为一种生长促进剂添加在饲料中促进动物的生长发育。然而,由于抗生素的大量生产和严重的滥用现象,一部分不可被人畜机体吸收利用的抗生素进入环境频度高,对生态平衡和生物体造成危害。实际环境中的污染物普遍具有低剂量和混合暴露的特征,污染物随暴露时间的延长具有不同的毒性变化规律。因此,对环境中相关抗生素及其混合物的时间依赖毒性评估具有重要的现实意义。本文针对抗生素及其混合物在不同暴露时间具有不同的毒性变化规律的现象,以蛋白核小球藻作为指示生物,以20种不同类型的抗生素作为目标化合物,采用时间依赖微板毒性分析法测定了它们在(0、12、24、48、72和96 h)6个不同时间下的毒性。运用两阶段模型法评估混合物的时间依赖毒性,根据单个抗生素的时间依赖毒性测试结果,应用均匀设计射线法设计每类抗生素的五元混合物体系共28条射线和20种抗生素的多元混合体系15条射线,考察它们的时间毒性变化规律。本文的主要内容与成果总结如下:(1)20种抗生素在48~96h具有良好的浓度-响应关系,不同抗生素的毒性随时间变化的规律不同:大部分抗生素的毒性随时间延长而显著增加,妥布霉素在前4个时间点内几乎没有毒性,然后毒性随时间延长而显著增加;哌拉西林钠、氨苄西林钠和恩诺沙星的毒性随时间延长先增加再减小;盐酸金霉素、盐酸强力霉素、美他环素和盐酸四环素的毒性随时间延长先减小再增加,诺氟沙星几乎没有毒性。(2)4组五元混合物28条射线和3组多元混合物15条射线在各时间点具有良好的浓度-响应关系,且具有时间依赖性,但不同混合物体系的毒性变化规律不同:如氨基糖苷类抗生素混合物有的随时间延长毒性逐渐增强,有的开始具有hormesis效应,随时间逐渐减弱;β-内酰胺类抗生素几乎没有明显的毒性,而是具有明显的hormesis效应,其它两组混合体系的毒性随时间延长逐渐增加;五元混合物体系的毒性与混合物中某组分浓度比pi之间有较好的线性关系。(3)以浓度加和作用模型CA为参考模型,五元混合物毒性基本上呈加和作用,以IA为参考模型,发现部分20种抗生素的混合物毒性偏离了IA模型出现了协同或拮抗作用,具有浓度依赖性和时间依赖性。总之,除了呈现出hormesis效应、协同或拮抗作用的抗生素混合物,两阶段模型能较好地评估大多数抗生素混合物的时间依赖毒性。
[Abstract]:Antibiotics are natural, semi-synthetic or synthetic compounds produced by microorganisms (including bacteria, fungi, actinomycetes, etc.) or higher plants and animals during their life. According to the chemical structure, it can be divided into aminoglycosides, 尾-lactams, tetracyclines, quinolones, macrolides, polypeptides, amides, lincomides, etc. Antibiotics are mainly used in the prevention and treatment of human and animal diseases, and later as a growth promoter to promote the growth and development of animals. However, due to the large production of antibiotics and serious abuse, some antibiotics which can not be absorbed and used by human and animal organisms have a high frequency of entry into the environment, which is harmful to ecological balance and organisms. The pollutants in the real environment generally have the characteristics of low dose and mixed exposure, and the pollutants have different toxic changes with the prolongation of exposure time. Therefore, time dependent toxicity assessment of related antibiotics and their mixtures in the environment is of great practical significance. In view of the phenomenon that antibiotics and their mixtures have different toxic changes at different exposure time, Chlorella Proteinuca is used as indicator organism and 20 different types of antibiotics as target compounds. Time dependent microplate toxicity analysis was used to determine their toxicity at 6 different time periods. A two-stage model was used to assess the time-dependent toxicity of the mixture, based on the results of the time-dependent toxicity tests for individual antibiotics. In this paper, a uniform design ray method was used to design a mixture system of 28 rays and 20 kinds of antibiotics in a five-component mixture system of each antibiotic, and 15 rays were used to investigate their temporal toxicity. The main contents and results of this paper are summarized as follows: 20 kinds of antibiotics have a good dose-response relationship at 48 ~ 96h. The toxicity of different antibiotics varies with time: the toxicity of most antibiotics increases significantly with time. Tobramycin had little toxicity at the first four time points and then increased significantly with time; the toxicity of piperacillin sodium, ampicillin sodium and enrofloxacin increased first and then decreased with time; chlortetracycline hydrochloride, chlortetracycline hydrochloride, The toxicity of doxycycline hydrochloride, metacycline and tetracycline hydrochloride decreases first and then increases over time. The toxicity of norfloxacin was almost non-toxic. The five-component mixture of four groups (28 rays) and the multicomponent mixture of 3 groups (15 rays) had a good concentration-response relationship at each time point and were time-dependent. However, the toxicity changes of different mixtures are different: for example, the toxicity of aminoglycoside antibiotic mixtures increases gradually with time, and some of them begin to have hormesis effect. 尾-lactam antibiotics had no obvious toxicity, but had obvious hormesis effect, and the toxicity of the other two groups increased gradually with the prolongation of time. There is a good linear relationship between the toxicity of the five-element mixture system and the concentration of a certain component in the mixture than pi. The reference model is CA. The toxicity of the five-element mixture is basically additive, and IA is the reference model. It was found that the toxicity of some of the 20 antibiotics deviated from the IA model and had synergistic or antagonistic effects in a concentration-and time-dependent manner. In a word, in addition to the mixture of antibiotics with hormesis effect, synergistic or antagonistic effect, the two-stage model can better evaluate the time-dependent toxicity of most antibiotic mixtures.
【学位授予单位】：安徽建筑大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：X171.5

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