Subchronic studies in Sprague-Dawley rats to investigate mechanisms of MTBE-induced Leydig cell cancer
De Peyster, A; Maclean, KJ; Stephens, BA; Ahem, LD; Westover, CM; Rozenshteyn, D
HERO ID
40265
Reference Type
Journal Article
Year
2003
Language
English
PMID
| HERO ID | 40265 |
|---|---|
| In Press | No |
| Year | 2003 |
| Title | Subchronic studies in Sprague-Dawley rats to investigate mechanisms of MTBE-induced Leydig cell cancer |
| Authors | De Peyster, A; Maclean, KJ; Stephens, BA; Ahem, LD; Westover, CM; Rozenshteyn, D |
| Journal | Toxicological Sciences |
| Volume | 72 |
| Issue | 1 |
| Page Numbers | 31-42 |
| Abstract | 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 29û50% following 3-h exposures to 50û100 mM MTBE or t-butanol. Within hours after gavaging with 1000 or 1500 mg/kg MTBE, circulating testosterone declined to 38û49% 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 40û800 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. |
| Doi | 10.1093/toxsci/kfg011 |
| Pmid | 12604832 |
| Wosid | WOS:000181305300004 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | ECRIB.Toxicol. Sci. 72: 31-42. |
| Is Public | Yes |
| Language Text | English |
| Keyword | methyl t-butyl ether (MTBE); rats; mechanisms; Leydig cell cancer; endocrine disruption |
| Is Qa | No |