代谢组学在毒理学研究中的应用

近20年来,基因组学和蛋白组学等系统生物学学科的发展突飞猛进,为毒理学研究带来良好发展机遇,大大促进了毒理学及相关研究领域的发展.然而,基因组和蛋白组的研究不能提供机体对外源性毒物刺激的整体应答信息,更不能反映出基因、疾病、环境、毒物等众多因素的交互作用,具有很大的局限性.作为系统生物学另一重要组成部分的"代谢组学",通过考察机体受毒物刺激后体液或组织中代谢物的整体动态变化轨迹,结合模式识别的多元分析方法,快速筛选毒性相关的分子标志物,进而更系统、更全面的揭示毒物作用于机体的典型特征,为相关毒性作用模型建立、环境或药物中毒性化学物的快速高通量筛选以及相关疾病的预防与治疗提供重要的科学依据.本文将从环境毒理学、靶器官毒性、毒性机制等方面人手,对"代谢组学"在毒理学中的应用进行综述.     

代谢组学在毒理学研究中的应用

代谢组学是关于生物内源代谢物整体及其变化规律的科学。代谢组学方法源于毒理学研究,并促进了毒理学的研究进程。代谢组学不仅能为毒性的筛选提供快速和准确的方法,也为毒性作用机制研究提供了动态的研究技术,还为毒性生物标志物研究提供了新的方法。本文简要综述了代谢组学技术及其在毒理学研究中的应用进展。     

分子毒理学研究的现状与展望

近 2 0年来 ,细胞与分子生物学理论与技术的飞速发展赋予毒理学工作者新的启迪和工具 ,从而改变了传统毒理学研究的基本格局 ,真正实现了从整体和器官水平向细胞和分子水平的飞跃 ,在阐明毒物对机体损伤作用和致癌过程的分子机制方面取得了重要的突破 ,形成了一些新的研究热点 ,建立了许多新的分子生物标志物的检测方法 ,成为沟通毒理学实验研究与人群流行病学调查的“共同语言” ,使宏观与微观研究有机地结合起来 ,改变了化学物质危险度评价的模式 ,大大促进了环境医学和其他生物科学的发展。一、分子毒理学研究的几个热点1.机体对环境应激…     

毒理学机制研究与"组学"

毒理学机制研究是环境与职业卫生相关疾病控制领域的重要方面。随着科学技术的进步，毒理学机制研究有了较大发展。近年来，“组学”在毒理学机制研究中的应用引起界内学者的普遍关注。“组学”，如基因组学（Genomics）和蛋白质组学（Pmteomics），是生命科学的前沿，具有以“通量化”的优势，但同时具有局限性，不仅在检测成本、定量、标准化等方面尚需完善，在能否回答基因间精细关系等科学问题方面也存在明显的不足。针对某些情况下“组学”概念及技术被不恰当使用的问题，Pognan曾尖锐地指出：基因组学，蛋白质学，毒理代谢组学，希望不是“时髦组学”。     

生物芯片分析技术在环境毒理学与环境流行病学研究中的应用

目的生物芯片分析作为新兴的现代毒理学研究技术之一,弥补和克服了传统毒理学的不足,可以快速、高通量地对毒物暴露信息进行处理,并根据毒物暴露信息的差异性分析筛选毒物作用敏感靶目标。生物芯片包括基因芯片、蛋白质芯片、细胞芯片和组织芯片,它们被广泛地应用于生命科学研究及其实践的各个领域。生物芯片的飞速发展推动了环境污染物快速评价技术的发展,改变了传统的环境流行病学评估模式。本文通过分析生物芯片在基因组学、蛋白组学、细胞学及组织分析中的原理及应用,探讨它们在环境毒理学与环境流行病学研究中存在的问题及研究展望。     

PM_(2.5)毒理学实验染毒方法及毒理学效应

PM_(2.5)(又称大气细颗粒物)是雾霾天气造成健康危害的主要成分。目前PM_(2.5)的体内毒理学实验有以下几种常见的染毒方法:采用空气浓缩富集系统进行吸入染毒、重污染环境下直接吸入染毒、气管滴注染毒、尾静脉注射染毒法。PM_(2.5)的毒理学研究主要包括体内的大小鼠肺部和心血管的毒理学效应研究以及体外的机制研究等。此外,PM_(2.5)对模式生物秀丽隐杆线虫也有一定的毒性作用。现对上述PM_(2.5)的毒理学研究方法及技术进展作一综述。     

毒理学研究中常用的分子生物学技术及其原理

作为研究外源性化学、物理、生物等因素对生物体负面效应的科学，毒理学这门古老的科学面临着生命科学高速发展所带来的机遇和挑战。从分子水平揭示毒理学机制是当今毒理学的活跃领域，并分化出一门新的学科：分子毒理学。目前，人类基因组计划已经完成，人类基因组学建立的方法、技术平台以及公布的DNA序列，为毒理学机制研究打下了良好的基础。分子克隆、基因导入是机制研究的常用工具。     

流式细胞术在毒理学检测中的应用

流式细胞术是一种高通量、多参数细胞分子生物学检测技术 ,随着流式细胞仪性能改进和测定方法的发展 ,已成为实验研究和临床检测的重要手段 ,并渗入毒理学检测的多个方面 ,带动了毒理学检测技术的发展。本文就近年流式细胞术在毒理学检测中的应用进行了综述     

毒理学基础(一)化学毒物的基本概念

1.化学毒物和毒理学的定义化学毒物是在生物组织中达到一定剂量,能对生物系统产生有害作用,如损伤生理功能或破坏生命的化学物。毒理学是研究化学毒物对生物体毒性作用的科学。随着工业的发展,化学物的种类迅速增加,药物、农药、环境污染物、工业化学物、食品添加剂等日益增多。为了人类的健康、保证安全,要预先估计化学物的毒性,评价其出现毒性的概率。研究毒物作用的性质和机理,有助于采取有效的预防和治疗措施。     

Aufgaben der regulatorischen Toxikologie

Regulatory toxicology aims at protecting the population and environment from toxic effects of chemicals, pesticides, food additives, cosmetics, drugs, medical products, genetic engineering products, natural toxins, etc. by establishing and applying safety standards. Different institutions are involved: authorities (regulation), industry (characterization of toxicity), universities (mechanisms of action), and contract institutes (compilation, testing). Toxicologists are involved in the regulation processes primarily at the levels of risk assessment and risk estimation. As a result of the progress in molecular and cell biology,new and innovative test methods evolve at high speed (in vitro systems, “omics,” knock out mice). At the same time there is political compulsion to employ alternative methods. Therefore, the validation of new test systems is a major scientific challenge for regulatory toxicology. Moreover, there is need for harmonization in many areas, including evaluation paradigms (adversity, safety factors, low-dose extrapolation). A study group in the German Society for Toxicology works on these tasks.     

Molecular biomarkers of oxidative stress in aquatic organisms in relation to toxic environmental pollutants

The potential of oxygen free radicals and other reactive oxygen species (ROS) to damage tissues and cellular components, called oxidative stress, in biological systems has become a topic of significant interest for environmental toxicology studies. The balance between prooxidant endogenous and exogenous factors (i.e., environmental pollutants) and antioxidant defenses (enzymatic and nonenzymatic) in biological systems can be used to assess toxic effects under stressful environmental conditions, especially oxidative damage induced by different classes of chemical pollutants. The role of these antioxidant systems and their sensitivity can be of great importance in environmental toxicology studies. In the past decade, numerous studies on the effects of oxidative stress caused by some environmental pollutants in terrestrial and aquatic species were published. Increased numbers of agricultural and industrial chemicals are entering the aquatic environment and being taken up into tissues of aquatic organisms. Transition metals, polycyclic aromatic hydrocarbons, organochlorine and organophosphate pesticides, polychlorinated biphenyls, dioxins, and other xenobiotics play important roles in the mechanistic aspects of oxidative damage. Such a diverse array of pollutants stimulate a variety of toxicity mechanisms, such as oxidative damage to membrane lipids, DNA, and proteins and changes to antioxidant enzymes. Although there are considerable gaps in our knowledge of cellular damage, response mechanisms, repair processes, and disease etiology in biological systems, free radical reactions and the production of toxic ROS are known to be responsible for a variety of oxidative damages leading to adverse health effects and diseases. In the past decade, mammalian species were used as models for the study of molecular biomarkers of oxidative stress caused by environmental pollutants to elucidate the mechanisms underlying cellular oxidative damage and to study the adverse effects of some environmental pollutants with oxidative potential in chronic exposure and/or sublethal concentrations. This review summarizes current knowledge and advances in the understanding of such oxidative processes in biological systems. This knowledge is extended to specific applications in aquatic organisms because of their sensitivity to oxidative pollutants, their filtration capacity, and their potential for environmental toxicology studies.     

在体-离体生物感受细胞模型在毒理学评价中的应用进展

在体-离体生物感受细胞模型采用在体暴露评估、离体结局分析以及系统环境关键组分筛选的方法,评估环境污染物通过影响机体内环境稳态而导致的健康效应和毒作用机制。该模型整合了人群现场的真实暴露与实验室细胞分子机制研究,结合了体外和体内模型的优势,弥补了单一的毒理学评价模型的不足,从宏观人群研究和微观机制探索之间的介尺度层面,为...     

Alternative models for toxicity testing of xenobiotics

The alternatives to whole-animal testing include endpoint assays, cell and tissue cultures, use of tissue slices, toxicokinetic modelling, and structure-activity relationships and databases. The use of in vitro systems (subcellular fractions, cell lines, primary cell cultures, tissue slices, organ cultures, etc.) as research tools in toxicology is widespread. In the past few years, the apoptosis phenomena were followed by very precise intracellular changes where, through programmed cell death, a cell can be removed from a population. The in vitro systems are ideally suited for investigations of the molecular, cellular and physiological mechanisms of chemically induced toxicity, which cannot readily be studied in vivo for known target organ and target species toxicity studies and for answering specific questions about toxic effects. The main justification for developing in vitro toxicity tests is that they will make toxicology a more scientifically based practice. It is increasingly apparent that the development and incorporation of stepwise testing strategies, combining experimental data from a range of alternative methods (physicochemical techniques, quantitative structure-activity relationships--QSAR, metabolic and kinetic modelling and in vitro tests), provide the most advanced way to predict toxicity, reducing at the same time the number of laboratory animals used for testing.     

苯并咪唑杀菌剂的雄性生殖毒性作用机制研究进展

近年来,随着不孕不育人数的快速增加,外源性化学物的生殖毒理学研究已成为目前毒理学研究热点之一。苯并咪唑杀菌剂是世界各国工农业生产中常用的杀菌剂。虽然苯并咪唑的毒性较低,但对雄性生殖系统有明显的损伤作用,被WHO列为可疑环境内分泌干扰物。该文对苯并咪唑的雄性生殖毒性及其作用机制进行了综述,以引起人们重视农药杀菌剂的毒性作用,为今后深入研究苯并咪唑的生殖毒性作用机制提供思路。     

微阵列技术在毒理学研究中的应用

毒理基因组学是一门研究与环境因素所致健康危险性有关的人类基因组的新学科。这是毒理学和基因组技术结合所产生的一门新的学科分技。微阵列技术即基因芯片技术包括芯片制备、待检样品制备、探针杂交、检测和数据处理。微阵列技术在毒理学主要应用于可疑毒物的鉴定、作用机制的研究、剂量-反应关系的评价、化学混合物中交互反应的鉴定、暴露的生物标记和易感性的生物标记。例如微阵列技术已用于研究人膀胱癌的生物标记以及氯化镉、苯并（a）芘和三氯乙烯相关基因调控的指纹。还介绍了一种全自动、多用途、新型的分子生物学工作站NanoChip分子生物系统。     

提高研究水平的策略：环境相关疾病导向性分子毒理学研究

提高所在科研团队SCI论文的影响因子和他引次数，是从事自然科学研究同仁的共同愿望。近5年来本实验室采用了一种新的毒理学研究策略——“环境相关疾病导向性分子毒理学研究”，使课题组SCI论文的数量和影响因子迅速提升。为了与毒理学界同仁分享心得，受《公共卫生与预防医学》杂志社的邀请，特撰写本短文。     

Toxicity characterization of environmental chemicals by the US National Toxicology Program: an overview

The US National Toxicology Program (NTP) is an interagency program whose mission is to evaluate agents of public health concern by developing and applying the tools of modern toxicology and molecular biology. Chemicals substances or physical agents selected for toxicology and carcinogenesis evaluations by the NTP are usually studied in a series of subacute (14-day exposure), subchronic (90-day exposure) and chronic (2-year exposure) studies in rodents. The NTP has published more than 500 reports of the findings and conclusions from its toxicology and carcinogenesis studies. In more specialized studies, the NTP also evaluates adverse effects on the structure and function of the immune, reproductive, nervous, and respiratory systems. The program attempts to evaluate and appropriately incorporate new technologies to improve the way we study the toxicity of chemicals. For example, the program has extensively evaluated several transgenic mouse models for their potential use as short-term cancer screens and has been a full participant in an international effort to examine their usefulness in pharmaceutical registration. Toxicogenomics, an emerging scientific field that examines the expression of thousands of genes simultaneously in response to chemical exposure, holds promise for future application to better understand the underlying mechanisms of chemical toxicity. A number of public health issues being addressed by the NTP are not only of national importance but also have global impact, such as the potential for endocrine disruptors to influence development and carcinogenesis and the safety of herbal medicines and dietary supplements. The program participates in the preparation of national and international toxicity testing guidelines and the findings from NTP studies are widely used for risk assessments by international organizations and federal agencies. The NTP maintains databases that contain toxicity, and health and safety information on a large number of chemicals. These databases are available from the NTP web site (http://ntp-server.niehs.nih.gov) and are accessed over 100000 times a month from around the world.     

The role of the "Clinica del Lavoro Luigi Devoto" in international research

During its long history, the Clinica del Lavoro Luigi Devoto has produced numerous internationally recognized scientific contributions in the specific field of occupational medicine and health, and in other broader areas as, for example, immunology, toxicology, cytogenetics. Pivotal in this activity was the figure of Enrico C. Vigliani, director of the Clinica for over 35 years. We mention here, in particular, the results of the study of "early" markers of lead intoxication; the research on the carcinogenicity of benzene and aromatic amines; the study of the pathogenesis of silicosis and byssinosis; the study of cytogenetic damage after exposure to industrial toxic chemicals; the technical research for dust abatement in mines. Such research also played a major role in the development of pulmonary medicine, toxicology and immunology in Italy, and conferred scientific dignity on the newborn "industrial hygiene" discipline thanks to the work of Nicola Zurlo. Today, the Clinica's research is maintained at international standards especially by the work of thematic Research Centers recently established within the Clinica, covering fields such as occupational and environmental toxicology, occupational oncology, ergonomics, respiratory disease and allergy, psycho-social risk factors. These Centers are also devoted to the development of innovative methods in epidemiology, toxicology, psychology, molecular biology, and ergonomic measurement for the identification and evaluation of health risks at work.     

美国毒理学信息规划概况

美国从1967年开始实施毒理学信息规划.该规划的目的是建立有关毒理学数据库,到目前为止已建有十几人在全球有影响的数据库.这些数据库涉及到毒理学的各种领域,为毒理学研究提供参考信息以及为用户提供查询服务.本文对有关的数据库作了简要介绍.