Lewis J G, Graham D G, Valentine W M, Morris R W, Morgan D L, Sills R C
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Toxicol Sci. 1999 May;49(1):124-32. doi: 10.1093/toxsci/49.1.124.
Even though atherosclerotic cardiovascular disease (ACVD) is the number one cause of death in the United States, the effects of environmental toxicants on this process are less well studied than the effects of chemicals on the second leading cause of death, cancer. There is considerable epidemiological evidence that workers exposed to carbon disulfide (CS2) have increased rates of ACVD, and there is conflicting evidence of the atherogenic potential of CS2 from animal studies. Chemical modification, such as oxidation of low-density lipoproteins (LDL), is tightly associated with increased LDL uptake by macrophages and the development of arterial fatty streaks. CS2 has been previously demonstrated to modify several proteins in vitro including LDL, and others in vivo through derivatization and covalent cross-linking. To investigate both the capacity of CS2 to induce arterial fatty deposits by itself, and its ability to enhance the rate of fatty deposit formation induced by a western style, high fat diet, groups of 20 female C57BL/6 mice were exposed to 0, 50, 500, or 800 ppm CS2 by inhalation. Half the animals in each group were placed on an atherogenic high fat diet and half on a control diet (NIH-07). Animals were sacrificed after 1, 4, 8, 12, 16, or 20 weeks of exposure, and the rates of fatty deposit formation under the aortic valve leaflets were evaluated. Exposure of mice on the control diet to 500 and 800 ppm CS2 induced a small but significant increase in the rate of fatty deposit formation over non-exposed controls. A more striking result was observed in the animals on the high fat diet. There was marked enhancement of the rate of fatty deposit formation in mice exposed to 500 and 800 ppm over the animals on the high fat diet alone. In addition, there was a small but significant enhancement in mice exposed to 50 ppm over the rate of fatty deposit formation induced by the high fat diet alone. Analysis of erythrocyte spectrin for protein cross-linking revealed a dose-dependent formation of alpha- and beta-heterodimers in animals on both diets. These data demonstrate that CS2 is atherogenic at high concentrations, but more importantly, suggest that, in conjunction with other risk factors, CS2 at relatively low concentrations can enhance atherogenesis.
尽管动脉粥样硬化性心血管疾病（ACVD）是美国头号死因，但与化学物质对第二大致死原因癌症的影响相比，环境毒物对这一过程的影响研究较少。有大量流行病学证据表明，接触二硫化碳（CS2）的工人患ACVD的几率增加，而动物研究中关于CS2致动脉粥样硬化潜力的证据相互矛盾。化学修饰，如低密度脂蛋白（LDL）的氧化，与巨噬细胞对LDL摄取增加以及动脉脂肪条纹的形成密切相关。此前已证明CS2在体外可修饰包括LDL在内的多种蛋白质，在体内可通过衍生化和共价交联修饰其他蛋白质。为了研究CS2自身诱导动脉脂肪沉积的能力，以及其增强西式高脂肪饮食诱导的脂肪沉积形成速率的能力，将20只雌性C57BL/6小鼠分为几组，通过吸入分别暴露于0、50、500或800 ppm的CS2环境中。每组动物一半置于致动脉粥样硬化的高脂肪饮食中，另一半置于对照饮食（NIH-07）中。在暴露1、4、8、12、16或20周后对动物实施安乐死，并评估主动脉瓣叶下脂肪沉积的形成速率。食用对照饮食的小鼠暴露于500和800 ppm的CS2中，与未暴露的对照组相比，脂肪沉积形成速率出现了虽小但显著的增加。在食用高脂肪饮食的动物中观察到了更显著的结果。暴露于500和800 ppm的小鼠，其脂肪沉积形成速率比仅食用高脂肪饮食的动物有明显增强。此外，暴露于50 ppm的小鼠，其脂肪沉积形成速率比仅由高脂肪饮食诱导的速率有虽小但显著的增强。对红细胞血影蛋白进行蛋白质交联分析发现，两种饮食的动物体内均出现了剂量依赖性的α和β异二聚体形成。这些数据表明，高浓度的CS2具有致动脉粥样硬化作用，但更重要的是，表明在存在其他风险因素的情况下，相对低浓度的CS2也可增强动脉粥样硬化的发生。
