Toxicological Sciences 61, 176-186 (2001)
Copyright © 2001 by the Society of Toxicology
SYSTEMS TOXICOLOGY |
2u-Globulin Nephropathy, Renal Cell Proliferation, and Dosimetry of Inhaled tert-Butyl Alcohol in Male and Female F-344 Rats
CIIT Centers for Health Research, PO Box 12137, Six Davis Drive, Research Triangle Park, North Carolina 27709-2137
tert-Butyl alcohol (TBA) has been shown to cause kidney tumors in male rats following chronic administration in drinking water. The objective of the present study was to determine whether TBA induces 
2u-globulin (2u) nephropathy (2u-N) and enhanced renal cell proliferation in male, but not female, F-344 rats, and whether the dosimetry of TBA to the kidney is gender specific. Male and female F-344 rats were exposed to 0, 250, 450, or 1750 ppm TBA vapors 6 h/day for 10 consecutive days to assess 2u-nephropathy and renal cell proliferation and for 1 and 8 days to evaluate the dosimetry of TBA following a single and repeated exposure scenario. Protein droplet accumulation was observed in kidneys of male rats exposed to 1750 ppm TBA, with 2u-globulin immunoreactivity present in these protein droplets. A statistically significant increase in 2u concentration in the kidney, as measured by an enzyme-linked immunosorbent assay, was observed in male rats exposed to 1750 ppm TBA with a exposure-related increase in renal cell proliferation. Renal 2u concentration was positively correlated with cell proliferation in male rat kidney. No histological lesions or increased renal cell proliferation was observed in female rats exposed to TBA compared to controls. The TBA kidney:blood ratio was higher at all concentrations and time points in male rats compared with female rats, which suggests that TBA is retained longer in male rat kidney compared with female rat kidney. Together these data suggest that TBA causes 2u-N in male rats, which is responsible for the male rat-specific increase in renal cell proliferation.
Key Words: tert-butyl alcohol (TBA); 2u-globulin (2u)..
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