内分泌干扰物的非单一剂量-效应研究进展

传统毒理学理论认为,有毒物质产生毒害作用的剂量-效应关系是线性单调的,线性剂量-效应关系也是目前管理毒理学中计算化学品安全剂量的理论基础。但越来越多的研究显示,内分泌干扰物的剂量-效应关系通常不是线性的,而是U型、倒U型或更复杂的非单调剂量-效应曲线形式。以典型案例的形式介绍了近年来生理激素和内分泌干扰物非单调剂量-效应的研究进展,总结了目前认为形成非单调剂量-效应关系的机制。在此基础上,讨论了内分泌干扰物的非单一剂量-效应给目前管理毒理学中的化学品风险评价带来的挑战,并提出该领域未来的研究方向。     

抗生素对微生物的联合与低剂量毒性研究进展

目前抗生素已成为一类不可忽视的环境污染物,它在环境中呈"混合-持久-低剂量"的暴露特征。因此,研究抗生素毒性效应,特别是它的联合毒性以及低剂量下毒性兴奋效应,对抗生素污染物生态风险的评价极其重要。以抗生素联合毒性的研究进展为主线,重点概述了抗生素二元混合物的急性和慢性联合毒性研究,指出了抗生素混合物间存在相互作用,它们的联合毒性并非表现为简单的加和或独立效应,且抗生素急性-慢性联合表现出的毒性效应也存在差异;发现了不仅单一抗生素具有Hormesis效应,低剂量抗生素二元混合物也具有Hormesis作用。但目前低剂量抗生素二元混合物对微生物的毒性兴奋效应研究较少,其毒性兴奋效应的预测和评价还有待进一步完善,以期为环境中抗生素的联合生态研究和风险评价提供理论依据。     

低剂量杀虫剂对昆虫的兴奋性效应(Insecticides-Induced Hormesis on Insects)

传统的杀虫剂毒理学应用线性非阈值模型评价杀虫剂的毒力及风险,但是没有考虑到低剂量杀虫剂所产生的毒物兴奋效应(Hormesis).杀虫剂对昆虫的低剂量兴奋效应主要表现在对昆虫的发育历期、体重和生殖力以及毒力等方面所产生的影响.在概述毒物低剂量兴奋效应理论及研究方法的基础上,重点介绍了杀虫剂对昆虫的低剂量兴奋性效应研究进展及其与杀虫剂亚致死剂量效应的区别,最后讨论了杀虫剂的兴奋效应对农业害虫防治所带来的影响.     

农药内分泌干扰效应研究进展

农药作为农业生产过程中的一类重要生产资料,主要用作杀虫剂、杀菌剂和除草剂等。由于农药的大量使用,目前在各类农产品及各种环境介质中都能被检测到,对饮食健康和环境安全带来潜在危害。研究发现,许多农药为内分泌干扰物,其能够干扰人类和其他生物体的内分泌系统正常功能。本文在总结国内外相关研究的基础上,对农药内分泌干扰效应的作用机理及筛选模型进行总结,对有机氯、有机磷和拟除虫菊酯等各类农药的内分泌干扰效应研究进展进行综述,并提出深入探究农药致毒作用机制和低剂量下多种农药联合毒性是本领域的重要研究方向。     

农药内分泌干扰效应研究进展

农药作为农业生产过程中的一类重要生产资料，主要用作杀虫剂、杀菌剂和除草剂等。由于农药的大量使用，目前在各类农产品及各种环境介质中都能被检测到，对饮食安全和环境健康带来潜在危害。研究发现，许多农药为内分泌干扰物，其能够干扰人类和其它生物体的内分泌系统正常功能。本文在总结国内外相关研究的基础上，对农药内分泌干扰效应的作用机理及筛选模型进行总结，对有机氯、有机磷和拟除虫菊酯等各类农药的内分泌干扰效应研究进展进行综述，并提出深入探究农药致毒作用机制和低剂量下多种农药联合毒性是本领域的重要研究方向。     

多溴二苯醚及其代谢物的内分泌干扰活性和构效关系研究进展

多溴二苯醚(Polybrominated diphenyl ethers,PBDEs)作为一种良好的防火溴系阻燃剂(Brominated flame retardants,BFRs)广泛应用于各种家用和工业产品.研究表明,PBDEs容易从产品中溢出而进入环境.近年来,PBDEs及其代谢物已在各种环境介质和生物体中被广泛检出.毒理学研究发现,PBDEs及其代谢物具有生殖毒性、免疫毒性、神经毒性和内分泌干扰作用.在总结国内外相关研究基础上,论文综述了PBDEs及其代谢物的内分泌干扰活性,重点集中在对甲状腺激素活性、雌激素活性、雄激素活性及影响性激素转化和代谢的芳香化酶、CYP17酶、雌二醇磺基转移酶(E2SULT)活性的影响;分析了具有不同测试终点内分泌干扰活性的化合物的结构特征.研究发现,在内分泌干扰活性方面,PBDEs母体化合物的影响较小,主要是PBDEs代谢物产生的影响,特别是羟基化代谢物引起了较严重的内分泌干扰作用,即PBDEs化合物是一类通过代谢而被活化的内分泌干扰前趋物.为评价PBDEs及其代谢物对人和其他生物的健康危害,应加强其内分泌干扰活性机制的研究,以及具有同类型作用模式的PBDEs及其代谢物定量结构-活性关系的研究.     

计算毒理学在内分泌干扰物筛选上的应用和展望

内分泌干扰物通过干扰内分泌系统导致多种疾病,如生殖疾病、肥胖症甚至癌症。然而,面对环境中大量潜在的内分泌干扰物,传统的体外、体内评估方法由于成本高、耗时长等问题,难以实现内分泌干扰物的高通量筛查。计算毒理学逐渐发展成为被美国环保局(Environmental Protection Agency,EPA)、经济合作与发展组织(Organization for Economic Co-operation and Development,OECD)等机构所推荐的内分泌干扰物筛选与预测方法。本文综述了计算毒理学在内分泌干扰物筛选上的进展,主要包括分子对接和分子动力学模拟的应用,并对有害结局路径(adverse outcome pathway,AOP)的方法进行介绍和展望。     

典型氯酚类化合物对水生生物的毒性研究进展

氯酚类化合物(CPs)是一类广泛存在于水环境中的有机污染物。这类化合物具有环境稳定性、生物累积性和生物毒性，因而其在水环境中的生态毒理效应一直是人们关注的焦点。在水体中存在最普遍的酚类化合物主要有2,4-二氯酚(2,4-DCP)，2,4,6-三氯酚(2,4,6-TCP)和五氯酚(PCP)。本文对近几年来这3种典型氯酚类化合物的水生态毒理学研究进行了总结，主要包括它们对水生生物的急性毒性、氧化损伤、发育毒性、内分泌干扰、遗传毒性、致癌性、免疫毒性、细胞毒性以及复合毒性的效应和机制，同时对目前存在的问题和进一步的研究方向进行了讨论和展望。     

多氯联苯羟基化代谢物及其雌激素效应研究进展

多氯联苯作为一种环境内分泌干扰物,具有一定的雌激素干扰效应,导致动物雌激素水平紊乱或功能异常,从而影响生殖、发育或行为。羟基多氯联苯是多氯联苯最主要的活性代谢产物,已经在动物和人体组织中被检出。羟基多氯联苯的化学性质和分子空间构象使其雌激素干扰效应可能较母体化合物更强。因此,它们对人类和动物机体的潜在影响以及由此带来的新的毒理学问题成为内分泌干扰研究领域的热点之一,相关的毒性作用机制需要进一步探索。本文对多氯联苯的代谢途径、羟基多氯联苯在生物体内的暴露水平、雌激素干扰效应及作用机制进行综述。     

新型溴代阻燃剂TBB和TBPH的生态毒理研究进展

新型溴代阻燃剂2-乙基己基-四溴苯甲酸(2-ethylhexyl-2,3,4,5-tetrabromobenzoate,TBB)和2,3,4,5-四溴-苯二羧酸双(2-乙基己基)酯(bis(2-ethylhexyl)2,3,4,5-tetrabromophthalate,TBPH)作为传统溴代阻燃剂多溴联苯醚(poly brominated diphenyl ethers,PBDEs)的替代品,广泛应用于工业和人类日常生活用品中,已在各种环境介质和生物体甚至人体中被检测出,由此可能对生态环境和人类健康产生潜在的风险.本文对TBB和TBPH这2种新型溴代阻燃剂的最新生态毒理学研究进展进行了综述,介绍了 TBB和TBPH在各类环境介质和生物体中的分布、环境归趋、人群暴露状况以及有关的生物毒性效应.最后对TBB和TBPH研究存在的问题进行了梳理分析,提出了研究展望,以期促进TBB和TBPH的环境风险和人类健康风险评价的深入研究.     

受体功能区结构与环境内分泌干扰效应生物差异的关系

环境中存在的多种内分泌干扰物能够与生物体内的天然激素受体选择性结合并产生多种生物效应,由于受体功能区三维结构的不同,其内分泌干扰活性存在着种间、种内、组织间等的种种差异,限制了不同物种间毒性效应的外推研究,增加了环境内分泌干扰物筛选和风险评价的难度.论文综述了基于受体介导的环境内分泌干扰物生物活性与相应受体选择性及受体功能区结构关系的研究进展,并利用分子模拟方法分析探讨了雌激素受体与部分化合物结合作用模式,讨论了目前存在的问题,对以后有关方面的研究提出了建议.     

污染物对鱼类的甲状腺激素干扰效应及其作用机制

环境中可以影响生物体甲状腺激素合成、运输、作用和代谢等过程的化学污染物称为甲状腺激素干扰物(TDCs),TDCs被认为是继环境雌激素之后最重要的一类内分泌干扰物.鱼类甲状腺的结构、甲状腺激素的转运和功能等与哺乳动物有较大差别.与哺乳动物相比,污染物干扰鱼类甲状腺激素的研究还较为缺乏.在介绍鱼类甲状腺结构、功能以及甲状腺激素在鱼体内动态过程的基础上,分析了污染物对鱼类的甲状腺激素干扰效应及其作用机制,探讨了今后鱼类甲状腺激素干扰研究的主要方向.污染物能对鱼类甲状腺激素水平、相关酶活性及甲状腺结构等产生直接影响;同时,污染物还可以通过干扰鱼类甲状腺系统对由甲状腺激素调节的重要生理过程如生长、繁殖和发育等产生间接影响.污染物主要通过干扰鱼类甲状腺激素的合成与分泌、转运、清除以及与甲状腺激素受体(TR)的相互作用等机制对鱼类产生不利影响.在污染物对鱼类甲状腺激素干扰的研究中,今后应重点关注环境中"新型"卤化有机污染物、鱼类早期发育过程与甲状腺激素干扰效应的关系、TR介导机制以及TDCs的筛选方法等.     

农药的内分泌干扰研究

环境污染物引起的内分泌干扰成为全球性环境问题之一.本文介绍了内分泌干扰物的检测方法.并从除草剂、杀虫剂、杀菌剂等三个方面介绍了农药所引起的内分泌干扰现象.在此基础上,简介手性农药内分泌干扰问题的重要性和研究现状,并进行展望.     

Hormonaktive Xenobiotika

Developmental and reproductive processes are most sensitive to the toxic effects of environmental chemicals. Especially alarming is the fact that many groups of industrial chemicals and pesticides are capable of disrupting the endocrine system in man and animals. Of great concern is the reduction in the sperm count in Europe, but also the worldwide increase in a great number of reproductive and developmental disturbances observed in both man and wildlife. A correlation to a high chemical burden has been demonstrated for many different animal species as well as for women. An important consideration in assessing the potential effects of environmental chemicals on the endocrine system is the time at which such an exposure occurs. In the adult organism, hormones initiate functional processes; these effects are usually transient. In early life, hormones control developmental processes and are capable of producing permanent changes in organ structure and function (organizational effects). Therefore, chemical disruption of hormonal functions during development can result in permanent functional changes of the afflicted organ.     

环境内分泌干扰物对鱼类性别决定的影响研究进展

水体中的环境内分泌干扰物能够影响鱼类性别决定过程,对鱼类产生明显的雌、雄性化效应.为深入研究环境内分泌干扰物对鱼类性别决定的影响及其机制,论文介绍了鱼类性别决定基因SRY和DMY基因在鱼类性别决定中的作用,以及Sox、DMRT、CYP和Vasa、Dax1、Foxl2等鱼类性别决定相关基因对鱼类性别决定的调控作用,综述了各类环境内分泌干扰物引起的鱼类雌、雄性化效应的最新研究进展,在此基础上探讨了环境内分泌干扰物影响鱼类性别决定的作用机制,并展望了该领域今后的重点研究方向.     

Investigating potential for effects of environmental endocrine disrupters on wild populations of amphibians in UK and Japan: status of historical databases and review of methods.

Concern over global declines among amphibians has resulted in increased interest in the effects of environmental contaminants on amphibian populations, and more recently, this has stimulated research on the potential adverse effects of environmental endocrine disrupters in amphibians. Laboratory studies of the effects of single chemicals on endocrine-relevant endpoints in amphibian, mainly anuran, models are valuable in characterizing sensitivity at the individual level and may yield useful bioassays for screening chemicals for endocrine toxicity (for example, thyroid disrupting activity). Nevertheless, in the UK and Japan as in many other countries, it has yet to be demonstrated unequivocally that the exposure of native amphibians to endocrine disrupting environmental contaminants results in adverse effects at the population level. Assessing the potential of such effects is likely to require an ecoepidemiological approach to investigate associations between predicted or actual exposure of amphibians to (endocrine disrupting) environmental contaminants and biologically meaningful responses at the population level. In turn, this demands recent but relatively long-term population trend data. We review two potential sources of such data for widespread UK anurans that could be used in such investigations: records for common frogs and common toads in several databases maintained by the Biological Records Centre (UK Government Centre for Ecology and Hydrology), and adult toad count data from 'Toads on Roads' schemes registered with the UK wildlife charity 'Froglife'. There were little abundance data in the BRC databases that could be used for this purpose, while count data from the Toads on Roads schemes is potentially confounded by the effects of local topology on the detection probabilities and operation of nonchemical anthropogenic stressors. For Japan, local and regional surveys of amphibians and national ecological censuses gathering amphibian data were reviewed to compile survey methodologies and these were compared with methods used in the UK and other countries. Substantial consensus exists in amphibian survey methodologies and this should be exploited in the initiation of coordinated monitoring programs for widespread and common anuran amphibians in Japan and the UK to generate long-term robust and standardized population trend data. Such data would support comparative ecoepidemiological assessments of the impact of environmental endocrine disrupters in these two cooperating countries.     

受体报告基因实验及其在维甲酸和维甲酸X受体干扰物监测中的应用

受体报告基因实验具有快速、经济、灵敏、方便等诸多优势,在高通量筛选类或抗雌雄激素等通过核受体起作用的环境内分泌干扰物方面得到了广泛的应用。环境中的维甲酸和维甲酸X受体干扰物如有机锡等有着类似的作用机制,研究者也开始采用受体报告基因实验的方法对该类污染物进行筛选与监测。本文综述了受体报告基因实验的技术方法,包括报告基因和宿主细胞的选择,并介绍了该方法在人工合成的维甲酸和维甲酸X受体干扰物筛选以及环境样品中该类污染监测中的应用。综述总结了应用受体报告基因实验检测环境内分泌干扰物研究中的不足并对该方法的未来发展进行了展望,希望为该方法在环境监测和评估中的应用提供新的思路。     

A review on environmental distributions and risk management of phenols pertaining to the endocrine disrupting chemicals in Taiwan

Some phenols, including pentachlorophenol, dichlorophenol, alkylphenols (nonylphenol & octylphenol) and bisphenol-A, have been identified as endocrine disrupting chemicals (EDCs). These phenolic EDCs are extensively used in a wide range of household products, thus posing potential health risks for humans exposed to them. From the viewpoints of ecotoxicology, human health and regulations, it is urgent to restrict the emissions and releases of these estrogenic chemicals from the industrial processes and commercial products. This review article first focused on the physicochemical properties of phenolic EDCs and their industrial/commercial uses. Furthermore, their environmental distributions and regulatory frameworks for integrated risk management of these chemicals in Taiwan were conducted as a case study. Emphasis was thus put on the cross-ministerial joint venture (i.e., environment, health, agriculture, labor, and industry authorities), and the government policy on the risk management of EDCs. Finally, some recommendations for pollution prevention and toxicity reduction of phenolic EDCs were also addressed and analyzed to progress towards a sustainable society in Taiwan.     

壬基酚长期暴露对斑马鱼雄鱼第二性征、精子活力的影响(Effects of Long-Term Exposure to Nonylphenol on Secondary Sexual Characteristics and Sperm Motility of Male Zebrafish（Brachydanio rerio）)

研究了不同浓度下(0(对照)、0.1、1、10、100μg·L-1)壬基酚(NP)长期暴露对斑马鱼(Brachydanio rerio)雄鱼第二性征、精子活力的影响.结果表明,NP暴露对斑马鱼第二性征的影响显著,可导致雄性个体出现泄殖乳突、腹部膨大等典型雌性化特征.100μg·L-1NP暴露导致76.9%的雄鱼出现泄殖乳突.NP暴露对斑马鱼精子激活率的影响显著,随NP暴露浓度升高精子激活率下降,呈现负相关的剂量-效应关系.NP暴露对斑马鱼精子寿命和精子剧烈运动时间均有显著影响.低剂量(0.1μg·L-1)和高剂量(100μg·L-1)NP暴露下精子寿命及其剧烈运动时间显著缩短,而中等剂量(10μg·L-1)NP对上述指标影响不显著(p>0.05).斑马鱼第二性征、精子活力可作为指示水体环境雌激素毒理学效应的敏感指标.     

Interactions of Endocrine-active environmental chemicals with the nuclear receptor PXR

There is growing concern about the human-health impact of environmental chemicals that have the potential to disrupt normal endocrine function. Endocrine disrupting chemicals (EDCs) include structurally diverse organochlorine pesticides, polychlorinated biphenyls (PCBs), plasticizers, fungicides, herbicides and pharmaceutical compounds, and can have a profound impact on development, and on reproductive, neurological and immune system functions. While many studies have focused on the role of androgen receptor, estrogen receptor and aryl hydrocarbon receptor in mediating the effects of EDCs, other nuclear receptors that regulate steroid hormone action and metabolism may also serve as targets of EDC action. This review focuses on two classes of EDCs, PCBs and phthalate monoesters, both of which have been shown to interact with pregnane X receptor (PXR), a member of the nuclear receptor superfamily that regulates a large number of target genes, many of which have important roles in steroid metabolism and transport. Recent findings on the ability of PCBs and phthalate monoesters to activate PXR are discussed and the potential role of PXR and other intracellular receptor proteins in mediating toxicities associated with EDC exposure is considered. Finally, we discuss several gaps in our knowledge regarding the actions of EDCs and the difficulties associated with the evaluation of risks associated with exposure to these endocrine active environmental chemicals.