Exposure of C57BL/6 mice to carbon disulfide induces early lesions of atherosclerosis and enhances arterial fatty deposits induced by a high fat diet

Even though atherosclerotic cardiovascular disease (ACVD) is the number one cause of death in the United States, the effects of environmental toxicant s on this process are less well studied than the effects of chemicals on th e second leading cause of death, cancer. There is considerable epidemiologi cal evidence that workers exposed to carbon disulfide (CS2) have increased rates of ACVD, and there is conflicting evidence of the atherogenic potenti al of CS2 from animal studies. Chemical modification, such as oxidation of low-density lipoproteins (LDL), is tightly associated with increased LDL up take 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 b y itself, and its ability to enhance the rate of fatty deposit formation in duced by a western style, high fat diet, groups of 20 female C57BL/6 mice w ere exposed to 0, 50, 500, or 800 ppm CS2 by inhalation, Half the animals i n each group were placed on an atherogenic high fat diet and half on a cont rol diet (NIH-07), Animals were sacrificed after 1, 4, 8, 12, 16, or 20 wee ks of exposure, and the rates of fatty deposit formation under the aortic v alve leaflets were evaluated. Exposure of mice on the control diet to 500 a nd 800 ppm CS2 induced a small but significant increase in the rate of fatt y deposit formation over non-exposed controls. A more striking result was o bserved in the animals on the high fat diet, There was marked enhancement o f the rate of fatty deposit formation in mice exposed to 500 and 800 ppm ov er the animals on the high fat diet alone. In addition, there was a small b ut significant enhancement in mice exposed to 50 ppm over the rate of fatty deposit formation induced by the high fat diet alone, Analysis of erythroc yte spectrin for protein cross-linking revealed a dose-dependent formation of alpha- and beta-heterodimers in animals on both diets, These data demons trate that CS2 is atherogenic at high concentrations, but more importantly, suggest that, in conjunction with other risk factors, CS2 at relatively lo w concentrations can enhance atherogenesis.