Methyltert-Butyl Ether Causes α2u-Globulin Nephropathy and Enhanced Renal Cell Proliferation in Male Fischer-344 Rats

Abstract

Methyltert-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 ≥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 α2u-globulin nephropathy (α2u-N). The objective of the present study was to determine if MTBE induces an α2u-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. α2u-Globulin immunoreactivity was present in and confined to protein droplets in male rat kidney. A mild dose-related increase in α2u 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 α2u 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 α2u 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 α2u in MTBE-exposed male rat kidney. These findings demonstrate that MTBE causes a mild induction of α2u-N and enhanced renal cell proliferation in male, but not female, F-344 rats, suggesting a role for α2u-N in renal tumorigenesis.