Wilson V S, McLachlan J B, Falls J G, LeBlanc G A
Department of Toxicology, North Carolina State University, Raleigh, NC 27695, USA.
Environ Health Perspect. 1999 May;107(5):377-84. doi: 10.1289/ehp.99107377.
Assessment of the impact of environmental chemicals on androgen homeostasis in rodent models is confounded by high intraindividual and interindividual variability in circulating testosterone levels. Our goal was to evaluate changes in testosterone biotransformation processes as a measure of androgen homeostasis and as a biomarker of exposure to androgen-disrupting chemicals. Sex-specific differences in hepatic testosterone biotransformation enzyme activities were identified in CD-1 mice. Gonadectomy followed by replacement of individual steroid hormones identified specific sex differences in biotransformation profiles that were due to the inductive or suppressive effects of testosterone. Notably, significant androgen-dependent differences in testosterone 6[alpha]- and 15[alpha]-hydroxylase activities were demonstrated, and the ratio of 6[alpha]- and 15[alpha]-hydroxylase activities proved to be an excellent indicator of the androgen status within the animal. The male or "masculinized" testosterone 6[alpha]/15[alpha]-hydroxylase ratio was significantly less than the female or "feminized" ratio. Male mice were exposed to both an antiandrogen, vinclozolin, and to a compound that modulates serum androgen levels, indole-3-carbinol, to test the utility of this ratio as a biomarker of androgen disruption. Treatment with the antiandrogen vinclozolin significantly increased the 6[alpha]/15[alpha]-hydroxylase ratio. Indole-3-carbinol treatment resulted in a dose-dependent, but highly variable, decrease in serum testosterone levels. The 6[alpha]/15[alpha]-hydroxylase ratio increased as serum testosterone levels decreased in these animals. However, the increase in the ratio was much less variable and more sensitive than serum testosterone levels. These investigations demonstrate that the 6[alpha]/15[alpha]-hydroxylase ratio is a powerful measure of androgen modulation and a sensitive indicator of exposure to androgen-disrupting chemicals in CD-1 mice.
啮齿动物模型中循环睾酮水平存在较高的个体内和个体间变异性，这使得评估环境化学物质对雄激素稳态的影响变得复杂。我们的目标是评估睾酮生物转化过程的变化，以此作为雄激素稳态的衡量指标以及接触雄激素干扰化学物质的生物标志物。在CD-1小鼠中发现了肝脏睾酮生物转化酶活性的性别特异性差异。去势后补充个体甾体激素，确定了生物转化谱中的特定性别差异，这些差异是由睾酮的诱导或抑制作用引起的。值得注意的是，证明了睾酮6α-和15α-羟化酶活性存在显著的雄激素依赖性差异，并且6α-和15α-羟化酶活性的比率被证明是动物体内雄激素状态的一个极佳指标。雄性或“男性化”的睾酮6α/15α-羟化酶比率显著低于雌性或“女性化”比率。雄性小鼠暴露于抗雄激素药物乙烯菌核利以及一种调节血清雄激素水平的化合物吲哚-3-甲醇，以测试该比率作为雄激素干扰生物标志物的效用。用抗雄激素药物乙烯菌核利处理显著增加了6α/15α-羟化酶比率。吲哚-3-甲醇处理导致血清睾酮水平呈剂量依赖性但高度可变的下降。在这些动物中，随着血清睾酮水平下降，6α/15α-羟化酶比率升高。然而，该比率的升高变异性小得多，且比血清睾酮水平更敏感。这些研究表明，6α/15α-羟化酶比率是雄激素调节的有力衡量指标，也是CD-1小鼠接触雄激素干扰化学物质的敏感指标。
