Alterations in endocrine responses in male Sprague-Dawley rats following oral administration of methyl tert-butyl ether

Methyl tert-butyl ether (MTBE) is an oxygenated fuel additive used to decre ase carbon monoxide emissions during combustion. MTBE is a nongenotoxic che mical that induces Leydig cell tumors (LCT) in male rats. The mechanism of MTBE-induced LCT is not known; however, LCT induced by other nongenotoxic c hemicals have been associated with the disruption of the hypothalamus-pitui tary-testicular (HPT) axis. The objective of this study was to determine wh ether MTBE functions as an endocrine-active compound by affecting levels of specific hormones involved in the maintenance of the HPT axis. Nine-week-o ld male Sprague-Dawley rats were administered MTBE by gavage at 0, 250, 500 , 1000, or 1500 mg MTBE/kg/day for 15 or 28 consecutive days and sacrificed 1 h following the last dose. Relative testis weights were increased only i n high-dose animals treated for 28 days, and no testicular lesions were obs erved at any dose level. Adrenal gland, liver, and kidney weights were also increased. Histologic changes included protein droplet nephropathy of the kidney and centrilobular hypertrophy of the liver. Interstitial fluid and s erum testosterone levels as well as serum prolactin levels were decreased o nly in animals treated with 1500 mg MTBE/kg/day for 15 days. At 28 days, se rum triiodothyronine (T-3) was significantly decreased at 1000 and 1500 mg MTBE/kg/day compared to control animals, and a decrease in serum luteinizin g hormone and dihydrotestosterone was observed at 1500 mg MTBE/kg/day. Thes e results indicate that MTBE causes mild perturbations in T-3 and prolactin ; however, the changes in testosterone and LH levels did not fit the patter n caused by known Leydig cell tumorigens.