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

Abstract

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. Sexspecific differences in hepatic testosterone biotransformation enzyme activities were identified in CD-i 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 6a-and 15a-hydroxylase activities were demonstrated, and the ratio of 6w and 15a-hydroxylase activities proved to be an excellent indicator of the androgen status within the animaL The male or "masculinized" testosterone 6alotISt-hydroxylase ratio was significantdy 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 6ax1l5a-hydroxylase ratio. Indole-3-carbinol treatment resulted in a dose-dependent, but highly variable, decrease in serum testosterone levels. The 6aIlSa-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 6a/150-hydroxylase ratio is a powerfil measure of androgen modulation and a sensitive indicator of exposure to androgen-disrupting chemicals in CD-1 mice. Key work androgen disruption,.biomarker, biotransformation, sexually dimorphic metabolism, testosterone.

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice

“…For example, we observed significant induction of 15α-OH testosterone in CAR-null females, and a drop in 6β-OH testosterone production in CAR-null males compared to WT males (Fig 3). Therefore, we examined the 6α/15α-OH testosterone ratio, which is much greater in females than males, controlled by androgen status, and considered a biomarker of androgen disruption in mice [62]. The 6α/15α-OH testosterone ratio is 3.2-fold higher in WT females than WT males.…”

“…Furthermore, CAR may regulate sexual dimorphism in the liver as loss of CAR activity decreases the 6α/15α-OH testosterone ratio, a biomarker of masculinization of the liver [16, 62] that may also reflect an overall drop in CYP activity [61]. CAR expression is female predominant emphasizing the need to include both genders in drug trials and toxicant biotransformation studies [49, 71].…”

Sexually dimorphic regulation and induction of P450s by the constitutive androstane receptor (CAR)

“…The female predominant 6α-hydroxylase activity also decreased in CAR-null females, but was not statistically significant. However, the 6α/15α-OH ratio, which is generally much greater in females, controlled by androgen status, and considered a biomarker of androgen disruption in mice (Wilson et al 1999), was decreased in CAR-null female mice. Because androgens are CAR inverse agonists, this suggests that CAR is involved in the androgen regulation of the gender predominant CYPs involved in 6α or 15α-OH activity.…”

Activation of CAR and PXR by Dietary, Environmental and Occupational Chemicals Alters Drug Metabolism, Intermediary Metabolism, and Cell Proliferation

“…The metabolism of testosterone and in particular the 6α/15α-hydroxlase ratio is decreased greater than 2.5-fold in female CAR-null mice compared to their wild-type counterparts. The 6α/15α-OH ratio, which is typically much greater in females, is in part controlled by androgens and considered a biomarker of androgen disruption or androgen status [194]. It is interesting that this ratio is effectively masculinized in female CAR-null mice [167].…”