Environmental Atherosclerosis Studies

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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.