Methyl tert-butyl ether causes alpha 2u-globulin nephropathy and enhanced renal cell proliferation in male Fischer-344 rats

Methyl tert-butyl ether (MTBE), a fuel additive blended into unleaded gasoline to decrease carbon monoxide emissions, induces renal tumors in male, but not female, rats exposed by inhalation to greater than or equal to 3000 ppm MTBE. A number of chemicals that induce male rat-specific renal tumors also cause a syndrome unique to male rats referred to as alpha 2u-globulin nephropathy (alpha 2u-N). The objective of the present study was to determine if MTBE induces an alpha 2u-N and renal cell proliferation in male F-344 rats. Male and female F-344 rats were exposed to MTBE vapors of 0, 413, 1516, or 3013 ppm for 6 hr/day for 10 consecutive days. Significant proximal tubule necrosis and protein droplet accumulation were observed in kidneys from male rats exposed to 1516 and 3013 ppm MTBE. Significantly greater labeling indices were observed in all groups of MTBE-exposed male rats. alpha u-globulin immunoreactivity was present in and confined to protein droplets in male rat kidney. A mild dose-related increase in alpha 2u concentration in the kidney, as measured by an enzyme-linked immunosorbent assay, was observed in male rats exposed to MTBE, with a statistically significant increase in alpha 2u concentration in male rats exposed to 3013 ppm MTBE. There was a strong positive correlation (r = 0.994) with exposure concentration between cell proliferation and alpha 2u concentration in male rat kidney. No significant differences were observed in female rats for any of these responses. Further analysis of kidney cytosol failed to demonstrate the accumulation of any protein besides alpha 2u in MTBE-exposed male rat kidney. These findings demonstrate that MTBE causes a mild induction of alpha 2u-N and enhanced renal cell proliferation in male, but not female, F-344 rats, suggesting a role for alpha 2u-N in renal tumorigenesis. (C) 1997 Academic Press.