Prescott-Mathews J S, Wolf D C, Wong B A, Borghoff S J
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Toxicol Appl Pharmacol. 1997 Apr;143(2):301-14. doi: 10.1006/taap.1996.8085.
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 > or =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 alpha2u-globulin nephropathy (alpha2u-N). The objective of the present study was to determine if MTBE induces an alpha2u-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. alpha2u-Globulin immunoreactivity was present in and confined to protein droplets in male rat kidney. A mild dose-related increase in alpha2u 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 alpha2u 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 alpha2u 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 alpha2u in MTBE-exposed male rat kidney. These findings demonstrate that MTBE causes a mild induction of alpha2u-N and enhanced renal cell proliferation in male, but not female, F-344 rats, suggesting a role for alpha2u-N in renal tumorigenesis.
甲基叔丁基醚（MTBE）是一种添加到无铅汽油中的燃料添加剂，用于减少一氧化碳排放。吸入浓度≥3000 ppm MTBE的雄性大鼠会诱发肾肿瘤，而雌性大鼠则不会。许多能诱发雄性大鼠特异性肾肿瘤的化学物质还会引发一种雄性大鼠特有的综合征，称为α2u球蛋白肾病（α2u-N）。本研究的目的是确定MTBE是否会在雄性F-344大鼠中诱发α2u-N和肾细胞增殖。将雄性和雌性F-344大鼠连续10天每天暴露于浓度为0、413、1516或3013 ppm的MTBE蒸气中6小时。在暴露于1516和3013 ppm MTBE的雄性大鼠肾脏中观察到明显的近端小管坏死和蛋白滴积累。在所有暴露于MTBE的雄性大鼠组中观察到标记指数显著更高。α2u球蛋白免疫反应存在于雄性大鼠肾脏的蛋白滴中，并局限于蛋白滴。通过酶联免疫吸附测定法测量，在暴露于MTBE的雄性大鼠中观察到肾脏中α2u浓度有轻度的剂量相关增加，在暴露于3013 ppm MTBE的雄性大鼠中α2u浓度有统计学显著增加。雄性大鼠肾脏中的细胞增殖与α2u浓度之间存在很强的正相关（r = 0.994），与暴露浓度有关。在雌性大鼠中，这些反应均未观察到显著差异。对肾脏胞质溶胶的进一步分析未能证明在暴露于MTBE的雄性大鼠肾脏中除α2u外还有任何蛋白质积累。这些发现表明，MTBE在雄性F-344大鼠中会轻度诱发α2u-N并增强肾细胞增殖，而雌性大鼠则不会，这表明α2u-N在肾肿瘤发生中起作用。
