Exposure of C57BL/6 mice to carbon disulfide induces early lesions of atherosclerosis and enhances arterial fatty deposits induced by a high fat diet
AbstractEven 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 (CS 2 ) have increased rates of ACVD, and there is conflicting evidence of the atherogenic potential of CS 2 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. CS 2 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 CS 2 to induce arterial 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 CS 2 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 CS 2 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 ॅ- and ॆ-heterodimers in animals on both diets. These data demonstrate that CS 2 is atherogenic at high concentrations, but more importantly, suggest that, in conjunction with other risk factors, CS 2 at relatively low concentrations can enhance atherogenesis. Keywords: carbon disulfide; atherosclerosis; arterial fatty deposits; foam cells; high fat diet; spectrin; and inhalation.