alpha 2u-globulin nephropathy, renal cell proliferation, and dosimetry of inhaled tert-butyl alcohol in male and female F-344 rats

tert-Butyl alcohol (TBA) has been shown to cause kidney tumors in male rats following chronic administration in drinking water. The objective of the p resent study was to determine whether TEA induces alpha 2u-globulin (alpha 2u) nephropathy (alpha 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 TEA vapors 6 h/day for 10 consecutive days to assess alpha 2u -nephropathy and renal cell proliferation and for 1 and 8 days to evaluate the dosimetry of TEA following a single and repeated exposure scenario. Pro tein droplet accumulation was observed in kidneys of male rats exposed to 1 750 ppm TEA, with alpha 2u-globulin immunoreactivity present in these prote in droplets. A statistically significant increase in alpha 2u concentration in the kidney, as measured by an enzyme-linked immunosorbent assay, was ob served in male rats exposed to 1750 ppm TEA with a exposure-related increas e in renal cell proliferation. Renal alpha 2u concentration was positively correlated with cell proliferation in male rat kidney, No histological lesi ons or increased renal cell proliferation was observed in female rats expos ed to TEA compared to controls. The TEA kidney:blood ratio was higher at al l concentrations and time points in male rats compared with female rats, wh ich suggests that TBA is retained longer in male rat kidney compared with f emale rat kidney. Together these data suggest that TEA causes alpha 2u-N in male rats, which is responsible for the male rat-specific increase in rena l cell proliferation.