INVESTIGATION OF A MECHANISM FOR LEYDIG-CELL TUMORIGENESIS BY LINURON IN RATS
INVESTIGATION OF A MECHANISM FOR LEYDIG-CELL TUMORIGENESIS BY LINURON IN RATS
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DOI：
10.1006/taap.1993.1060
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发表时间：
1993-04-01
影响因子：
3.8
通讯作者：
BIEGEL, LB
中科院分区：
文献类型：
--
作者：
COOK, JC;MULLIN, LS;BIEGEL, LB
在先前进行的一项为期2年的研究中，在喂食含有除草剂利谷隆的饲料的Crl：CD BR（CD）大鼠中观察到间质细胞腺瘤呈浓度依赖性增加。利谷隆在一组6项遗传毒性试验中显示为阴性;因此，研究了肿瘤发生的非遗传毒性机制。利谷隆在结构上与非甾体类抗雄激素药物氟草胺相关。氟替卡松也被证明在1年内产生Leydig细胞瘤，推测是由于下丘脑-垂体-睾丸（HPT）轴破坏后发生的促黄体激素（LH）持续分泌过多。为了研究利谷隆是否具有抗雄激素活性，向性不成熟和成熟的CD大鼠施用200 mg/kg利谷隆或10 mg/kg氟草胺（阳性对照）2周。测量附性器官重量和血清激素水平，以评估雄激素状态和HPT轴的变化。还分析了利谷隆多代生殖研究的血清激素水平。此外，进行竞争性受体结合研究以评价利谷隆结合雄激素受体的能力。利谷隆降低性未成熟和成熟利谷隆处理大鼠的附属性器官重量。在性成熟利农隆处理的大鼠中观察到血清雌二醇和LH水平升高。在多代生殖研究中，P1和F1雄性大鼠的血清雌二醇和LH水平也升高。这些附属性器官和激素变化与抗雄激素氟吡隆组观察到的变化一致，唯一的例外是血清睾酮，暴露于氟吡隆后血清睾酮升高，但暴露于利谷隆后血清睾酮未升高。利谷隆不能增加睾酮水平可能反映了利谷隆作为抗雄激素的效力低于氟吡隆，氟吡隆是一种有效的抗雄激素。此外，利谷隆与[3 H]睾酮竞争结合雄激素受体。竞争雄激素受体的IC 50数据表明利谷隆的效力比氟草胺低约3.5倍。这些数据与使用氟吡隆观察到的效果一致，并证明利谷隆是一种不如氟吡隆有效的抗雄激素药物。总的来说，这些数据支持利谷隆通过抗雄激素机制产生间质细胞瘤的假设，其中LH的持续分泌过多似乎是间质细胞增生和腺瘤发展的原因。
In a previously conducted 2-year study, a concentration-dependent increase in Leydig cell adenomas was observed in Crl:CD BR (CD) rats fed diets containing the herbicide linuron. Linuron has been shown to be negative in a battery of six tests for genotoxicity; therefore, a nongenotoxic mechanism of tumorgenesis was investigated. Linuron is structurally related to the nonsteroidal antiandrogen, flutamide. Flutamide has also been shown to produce Leydig cell tumors within 1 year, presumably due to sustained hypersecretion of luteinizing hormone (LH) which occurs following disruption of the hypothalamic-pituitary-testicular (HPT) axis. To investigate whether linuron possesses antiandrogenic activity, sexually immature and mature CD rats were administered either 200 mg/kg linuron or 10 mg/kg flutamide (positive control) for 2 weeks. Accessory sex organs were weighed and serum hormone levels were measured to assess androgen status and alterations in the HPT axis. Serum from a multigeneration reproduction study with linuron was also analyzed for serum hormone levels. In addition, competitive receptor binding studies were conducted to evaluate the ability of linuron to bind to the androgen receptor. Linuron decreased accessory sex organ weights in sexually immature and mature linuron-treated rats. Increased serum estradiol and LH levels were observed in sexually mature linuron-treated rats. Serum estradiol and LH levels were also elevated in P1and F1male rats from the multigeneration reproduction study. These accessory sex organ and hormonal changes are consistent with those seen with the antiandrogen flutamide, the only exception being serum testosterone, which was elevated following exposure to flutamide but not to linuron. The inability of linuron to increase testosterone levels may reflect the lower potency of linuron as an antiandrogen compared with that of flutamide, which is a potent antiandrogen. Additionally, linuron competed with [3H]testosterone for binding to the androgen receptor. The IC50data for competition to the androgen receptor suggest that linuron is approximately 3.5 times less potent than flutamide. These data are consistent with the effects seen with flutamide and demonstrate that linuron is a less potent antiandrogen than flutamide. Collectively, these data support the hypothesis that linuron produces Leydig cell tumors via an antiandrogenic mechanism where sustained hypersecretion of LH appears to be responsible for the development of Leydig cell hyperplasia and adenomas.