Alteration in sexually dimorphic testosterone biotransformation profiles as a biomarker of chemically induced androgen disruption in mice

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 c hanges in testosterone biotransformation processes as a measure of androgen homeostasis and as a biomarker of exposure to androgen-disrupting chemical s. Sex-specific differences in hepatic testosterone biotransformation enzym e activities were identified in CD-1 mice. Gonadectomy followed by replacem ent of individual steroid hormones identified specific sex differences in b iotransformation profiles that were due to the inductive or suppressive eff ects of testosterone. Notably, significant androgen-dependent differences i n testosterone 6 alpha- and 15 alpha-hydroxylase activities were demonstrat ed, 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 ma le or "masculinized" testosterone 6 alpha/15 alpha-hydroxylase ratio was si gnificantly less than the female or "feminized" ratio. Male mice were expos ed to both an antiandrogen, vinclozolin, and to a compound that modulates s erum androgen levels, indole-3-carbinol, to test the utility of this ratio as a biomarker of androgen disruption. Treatment with the antiandrogen vinc lozolin significantly increased the 6 alpha/15 alpha-hydroxylase ratio. Ind ole-3-carbinol treatment resulted in a dose-dependent, but highly variable, decrease in serum testosterone levels. The 6 alpha/15 alpha-hydroxylase ra tio increased as serum testosterone levels decreased in these animals. Howe ver, the increase in the ratio was much less variable and more sensitive th an serum testosterone levels. These investigations demonstrate that the 6 a lpha/15 alpha-hydroxylase ratio is a powerful measure of androgen modulatio n and a sensitive indicator of exposure to androgen-disrupting chemicals in CD-1 mice.