Klaunig James E, Babich Michael A, Baetcke Karl P, Cook Jon C, Corton J Chris, David Raymond M, DeLuca John G, Lai David Y, McKee Richard H, Peters Jeffrey M, Roberts Ruth A, Fenner-Crisp Penelope A
Indiana University School of Medicine, Indianapolis, IN, USA.
Crit Rev Toxicol. 2003;33(6):655-780. doi: 10.1080/713608372.
Widely varied chemicals--including certain herbicides, plasticizers, drugs, and natural products--induce peroxisome proliferation in rodent liver and other tissues. This phenomenon is characterized by increases in the volume density and fatty acid oxidation of these organelles, which contain hydrogen peroxide and fatty acid oxidation systems important in lipid metabolism. Research showing that some peroxisome proliferating chemicals are nongenotoxic animal carcinogens stimulated interest in developing mode of action (MOA) information to understand and explain the human relevance of animal tumors associated with these chemicals. Studies have demonstrated that a nuclear hormone receptor implicated in energy homeostasis, designated peroxisome proliferator-activated receptor alpha (PPARalpha), is an obligatory factor in peroxisome proliferation in rodent hepatocytes. This report provides an in-depth analysis of the state of the science on several topics critical to evaluating the relationship between the MOA for PPARalpha agonists and the human relevance of related animal tumors. Topics include a review of existing tumor bioassay data, data from animal and human sources relating to the MOA for PPARalpha agonists in several different tissues, and case studies on the potential human relevance of the animal MOA data. The summary of existing bioassay data discloses substantial species differences in response to peroxisome proliferators in vivo, with rodents more responsive than primates. Among the rat and mouse strains tested, both males and females develop tumors in response to exposure to a wide range of chemicals including DEHP and other phthalates, chlorinated paraffins, chlorinated solvents such as trichloroethylene and perchloroethylene, and certain pesticides and hypolipidemic pharmaceuticals. MOA data from three different rodent tissues--rat and mouse liver, rat pancreas, and rat testis--lead to several different postulated MOAs, some beginning with PPARalpha activation as a causal first step. For example, studies in rodent liver identified seven "key events," including three "causal events"--activation of PPARalpha, perturbation of cell proliferation and apoptosis, and selective clonal expansion--and a series of associative events involving peroxisome proliferation, hepatocyte oxidative stress, and Kupffer-cell-mediated events. Similar in-depth analysis for rat Leydig-cell tumors (LCTs) posits one MOA that begins with PPARalpha activation in the liver, but two possible pathways, one secondary to liver induction and the other direct inhibition of testicular testosterone biosynthesis. For this tumor, both proposed pathways involve changes in the metabolism and quantity of related hormones and hormone precursors. Key events in the postulated MOA for the third tumor type, pancreatic acinar-cell tumors (PACTs) in rats, also begin with PPARalpha activation in the liver, followed by changes in bile synthesis and composition. Using the new human relevance framework (HRF) (see companion article), case studies involving PPARalpha-related tumors in each of these three tissues produced a range of outcomes, depending partly on the quality and quantity of MOA data available from laboratory animals and related information from human data sources.
种类繁多的化学物质——包括某些除草剂、增塑剂、药物和天然产物——可诱导啮齿动物肝脏及其他组织中的过氧化物酶体增殖。这一现象的特征是这些细胞器的体积密度和脂肪酸氧化增加，这些细胞器含有对脂质代谢至关重要的过氧化氢和脂肪酸氧化系统。研究表明，一些过氧化物酶体增殖性化学物质是非基因毒性动物致癌物，这激发了人们对开发作用模式（MOA）信息的兴趣，以理解和解释与这些化学物质相关的动物肿瘤对人类的影响。研究表明，一种与能量稳态相关的核激素受体，即过氧化物酶体增殖物激活受体α（PPARα），是啮齿动物肝细胞过氧化物酶体增殖的一个必需因子。本报告深入分析了科学现状，涉及几个对于评估PPARα激动剂的作用模式与相关动物肿瘤对人类的影响之间关系至关重要的主题。主题包括对现有肿瘤生物测定数据的综述、来自动物和人类来源的与几种不同组织中PPARα激动剂的作用模式相关的数据，以及关于动物作用模式数据对人类潜在影响的案例研究。现有生物测定数据的总结揭示了体内对过氧化物酶体增殖剂反应的显著物种差异，啮齿动物比灵长类动物更敏感。在测试的大鼠和小鼠品系中，雄性和雌性在接触多种化学物质后都会发生肿瘤，这些化学物质包括邻苯二甲酸二（2-乙基己基）酯（DEHP）和其他邻苯二甲酸盐、氯化石蜡、氯代溶剂如三氯乙烯和全氯乙烯，以及某些农药和降血脂药物。来自三种不同啮齿动物组织——大鼠和小鼠肝脏、大鼠胰腺和大鼠睾丸——的作用模式数据导致了几种不同的假定作用模式，有些以PPARα激活作为因果第一步。例如，在啮齿动物肝脏中的研究确定了七个“关键事件”，包括三个“因果事件”——PPARα激活、细胞增殖和凋亡的扰动以及选择性克隆扩增——以及一系列涉及过氧化物酶体增殖、肝细胞氧化应激和枯否细胞介导事件的关联事件。对大鼠睾丸间质细胞瘤（LCTs）的类似深入分析提出了一种作用模式，始于肝脏中的PPARα激活，但有两条可能的途径，一条继发于肝脏诱导，另一条直接抑制睾丸睾酮生物合成。对于这种肿瘤，两种提出的途径都涉及相关激素和激素前体的代谢和数量变化。第三种肿瘤类型即大鼠胰腺腺泡细胞瘤（PACTs）的假定作用模式中的关键事件也始于肝脏中的PPARα激活，随后是胆汁合成和成分的变化。使用新的人类相关性框架（HRF）（见配套文章），涉及这三种组织中每一种与PPARα相关肿瘤的案例研究产生了一系列结果，部分取决于从实验动物获得的作用模式数据的质量和数量以及来自人类数据源的相关信息。
