Environmental Atherosclerosis Studies

我们早期的研究清楚地表明，NIEHS优先考虑的化学物质二硫化碳（CS2）会增强动脉粥样硬化，特别是在高脂血症的情况下，这强烈表明有必要将这一美国主要死亡原因作为影响人类疾病的环境因素的化学测试和机制研究的终点。由于这一领域的研究不足，在进行昂贵且耗时的研究之前，应该确定并测试适当的动脉粥样硬化动物模型。虽然有鸟类、狗、兔子和啮齿动物的动脉粥样硬化模型，但啮齿动物在品系特征、近交系的可用性、易于遗传操作和成本方面具有明显的优势。大量的动脉粥样硬化机制研究利用了小鼠；尤其是那些经过基因工程改造的老鼠，它们参与脂质代谢的各种基因（即载脂蛋白e和低密度脂蛋白受体）被破坏或改变，使动物更容易发生动脉粥样硬化。小鼠的大部分血清脂质为高密度脂蛋白（HDL），几乎没有低密度脂蛋白（LDL），因此不会发生动脉粥样硬化。然而，如果某些品系（如C57BL/6）被置于高脂肪饮食（HFD）中，它们会出现高脂血症，脂蛋白出现在低和中密度带，动物会出现仅限于主动脉瓣下主动脉根部的动脉粥样硬化。在这个模型中，CS2主要在HFD上的动物中显著增强病变。对这种模式有一些批评。首先，这些动物天生对动脉粥样硬化有很强的抵抗力，因此必须采用一种相当极端的饮食，这种饮食有几种毒副作用，包括胆结石、肝梗阻和脾脏肉芽肿。其次，动脉粥样硬化的数量在数量和解剖学上是有限的。第三，病变主要由泡沫细胞和细胞外脂质组成，没有增殖成分，因此不能反映更晚期人类疾病的组成。

Our earlier studies clearly demonstrating that an NIEHS priority chemical, carbon disulfide (CS2) enhanced atherosclerosis, especially in the setting of hyperlipidemia, strongly indicates the need to include this leading cause of death in the USA as an endpoint in chemical testing and mechanistic research into environmental factors influencing human disease. Because of the paucity of research into this area, appropriate animal models of atherosclerosis should be identified and tested before expensive and time consuming studies are undertaken. While there are avian, dog, rabbit, and rodent models of atherosclerosis, rodents have clear advantages in terms of strain characterization, availability of inbred strains, ease of genetic manipulation, and cost. A large amount of mechanistic work in atherosclerosis has utilized the mouse; especially mice that have been genetically engineered such that various genes involved in lipid metabolism (i.e. Apo-E and the LDL receptor) have been disrupted or altered making the animals more prone to the development of atherosclerosis. Mice carry most of their serum lipids in high density lipoproteins (HDL) and have virtually no low density lipoproteins (LDL) and develop no atherosclerosis. However, if some strains such as C57BL/6 are placed on a high fat diet (HFD) they develop hyperlipidemia, lipoproteins appear in the low and intermediate density bands, and the animals develop atherosclerosis limited to the aortic root under the aortic valves. This is the model in which CS2 significantly enhanced lesions mostly in animals on the HFD. There are several criticisms of this model. Firstly, the animals are very resistant to atherosclerosis naturally and a rather extreme diet has to be employed that has several toxic side effects including gallstones, hepatic obstruction, and granulomas in the spleen. Secondly, the amount of atherosclerosis is limited quantitatively and anatomically. Thirdly, the lesions consist mainly of foam cells and extra cellular lipid with no proliferative component and thus do not reflect the composition of more advanced human disease.