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ToxSci Advance Access originally published online on February 18, 2003
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Toxicological Sciences 72, 31-42 (2003)
Copyright © 2003 by the Society of Toxicology

CARCINOGENICITY

Subchronic Studies in Sprague-Dawley Rats to Investigate Mechanisms of MTBE-Induced Leydig Cell Cancer

Ann de Peyster1, Kathryn J. MacLean, Beth A. Stephens, Lisa D. Ahern, Christian M. Westover and Diana Rozenshteyn

Division of Occupational and Environmental Health, Graduate School of Public Health, Hardy Tower 119, 5500 Campanile Drive, San Diego State University, San Diego, California 92182

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 1000 or 1500 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 1200-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.

Key Words: Methyl t-butyl ether (MTBE); rats; mechanisms; Leydig cell cancer; endocrine disruption.


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