High
MTBE exposures caused rat Leydig cell (LC)
tumors in inhalation and gavage
cancer bioassays. Investigating early endocrine changes consistent with known mechanisms of LC
carcinogenesis, we gavaged adult male Sprague-Dawley rats with
MTBE in five different subchronic experiments and studied
testosterone biosynthesis in isolated rat LCs exposed in vitro to
MTBE or a major metabolite,
t-butanol. In vitro LC
testosterone production declined 29-50% following 3-h exposures to 50-100 mM
MTBE or
t-butanol. Within hours after gavaging with 1,000 or 1,500 mg/kg
MTBE, circulating
testosterone declined to 38-49% of control (p < 0.05). If sampled longer
after treatment or with lower doses,
testosterone reductions were less dramatic or nondetectable even after 28 days of treatment. Accessory organ:brain weight ratios decreased only slightly although showing dose response with 40-800 mg/kg/day after 28 days. High
MTBE doses caused slight liver weight and total P450 increases. Reduced
aromatase activity in liver and testis microsomes predicted low serum
estradiol, but
estradiol was 19% higher than
corn oil controls concurrent with
testosterone reduction 1 h after the last of 14 daily 1,200-mg/kg doses (p < 0.05). Pituitary
luteinizing hormone (LH) and
prolactin measured in both intact and orchiectomized rats, with
testosterone implants in some castrated rats providing stable levels of
testosterone, revealed no consistent direct effect on hypothalamic-pituitary function.
MTBE-treated rat livers showed no evidence of peroxisome proliferation, a characteristic of some LC
carcinogens. Considering recognized mechanisms of Leydig cell
cancer in rats, collectively these results suggested reduced LC steroidogenesis
enzyme activity as a possible mechanism underlying
MTBE LC
carcinogenesis.