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 i n 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-spe cific 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 rena l cell proliferation in male F-344 rats. Male and female F-344 rats we re exposed to MTBE vapors of 0, 413, 1516, or 3013 ppm for 6 hr/day fo r 10 consecutive days. Significant proximal tubule necrosis and protei n droplet accumulation were observed in kidneys from male rats exposed to 1516 and 3013 ppm MTBE. Significantly greater labeling indices wer e observed in all groups of MTBE-exposed male rats. alpha u-globulin i mmunoreactivity was present in and confined to protein droplets in mal e rat kidney. A mild dose-related increase in alpha 2u concentration i n the kidney, as measured by an enzyme-linked immunosorbent assay, was observed in male rats exposed to MTBE, with a statistically significa nt increase in alpha 2u concentration in male rats exposed to 3013 ppm MTBE. There was a strong positive correlation (r = 0.994) with exposu re concentration between cell proliferation and alpha 2u concentration in male rat kidney. No significant differences were observed in femal e 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 prolife ration in male, but not female, F-344 rats, suggesting a role for alph a 2u-N in renal tumorigenesis. (C) 1997 Academic Press.