Subchronic studies in Sprague-Dawley rats to investigate mechanisms of MTBE-induced Leydig cell cancer.
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.
de Peyster
Ann
A
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, USA. adepeyst@mail.sdsu.edu
MacLean
Kathryn J
KJ
Stephens
Beth A
BA
Ahern
Lisa D
LD
Westover
Christian M
CM
Rozenshteyn
Diana
D
D000280:Administration, Inhalation; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D002273:Carcinogens / Q000009:adverse effects / Q000633:toxicity*; D003345:Corticosterone / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D006062:Gonadotropins / Q000378:metabolism; D007984:Leydig Cell Tumor / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D008738:Methyl Ethers / Q000009:adverse effects / Q000633:toxicity*; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D020675:Peroxisomes / Q000502:physiology; D010907:Pituitary Hormones / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000633:toxicity; D013739:Testosterone / Q000097:blood / Q000378:metabolism; D036401:Toxicity Tests, Chronic; D014407:Tumor Cells, Cultured; D015430:Weight Gain / Q000187:drug effects
D002273:Carcinogens; D006062:Gonadotropins; D008738:Methyl Ethers; D010907:Pituitary Hormones; D012997:Solvents; C043243:methyl tert-butyl ether; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D003577:Cytochrome P-450 Enzyme System; D001141:Aromatase; D003345:Corticosterone