US EPA

675578 

Journal Article 

Pharmacokinetic model for testosterone and its metabolites, dihydrotestosterone and estradiol, in the perinatal rat 

Clewell, R; Andersen, ME 

2004 

1 

Toxicologist
ISSN: 0731-9193 

TOX/4002292 

78 

1-S 

English 

Male sexual development is dependent upon both adequate testosterone (T) levels and specificity of timed surges in T production and release. In order to evaluate time-dependent changes in T levels, a physiologically-based pharmacokinetic model has been developed, which describes T production, distribution and conversion to its active metabolites, dihydrotestosterone (DHT and estradiol (E2) in the perinatal male rat. Physiological and hormone-specific kinetic paramteres, such as T production rates and affinity constants for metabolizing enzymes, were available from literature. The T, DHT and E2 models include diffusion-limited compartments for testes, brain and body. The three models are linked via conversion of T to DHT and E2 described with Michaelis-Menten metabolism in the blood. Thus, mass is transferred from the T model to the appropriate metabolite model. Fitted paramters included tissue permeability, first order metabolism of E2 and DHT and maximum capacity for DHT and E2 production. The current model successfully reproduces age-dependent changes in fetal and neonatal testes T and serum T, DHT and E2 levels from gestation day (GD) 15 to post-natal day 3. Two peaks in serum T occur in development, the first on GD 18 and another at 1 to 3 hours after birth. Changing T production appears to be responsible for the prenatal T surge and the model adequately reproduces measured T using production rates from published in vitro data. The post-natal T surge, however, is much shorter-lived than that in the fetus, and the increase in serum levels is much greater (3-fold increase in serum T). The mechanism of this observed hormone surge is unknown, although T stored in the testes may be released at birth. This testes-release hypothesis is supported by the ability of the model to fit measured data based on this mode of action. This model will be used to develop a predictive tool in the assessment of perinatal risk resulting from decreased T production induced by perinatal exposure to endocrine active compounds, such as di-n-butyl phthalate.