Impact/Purpose:

A biologically-based, systems-level model will be developed describing the regulation of the prostate by androgens. The model will extend an existing model for the male rat central axis, which describes feedback between luteinizing hormone and testosterone production in the testes, to include the prostate and conversion of testosterone to dihydrotestosterone (DHT). The prostate model will describe binding of androgens to the androgen receptor, 5α-reductase catalyzed production of DHT, and gene regulation affecting cell proliferation, apoptosis, and prostatic fluid production. The model will combine pharmacokinetic models for endogenous hormones (i.e., testosterone, DHT, LH) and exogenous antiandrogens (e.g., finasteride, flutamide or casodex, vinclozolin), and a pharmacodynamic model for androgen-dependent prostate functions. Linkages of this model with genomics data obtained with castration, testosterone treatments, or antiandrogen treatment will be explored to assist in developing perspectives on how such data would fit into quantitative risk assessments.

Description:

The prostate is an androgen-dependent tissue that is an important site of disease in human males as well as an important indicator of androgen status in animals. The rat prostate is used for studying antiandrogenic drugs as well as for evaluation of endocrine disruption (e.g., Hershberger Assay). Pubertal changes in the prostate have been observed to be as sensitive to environmental antiandrogens as in utero effects. The goal of this research is to model the biology of prostate androgen function on a systems level to determine the factors responsible for the dose-response observable with androgens and antiandrogens in the male rat. This includes investigation of the roles of positive and negative feedback loops in prostatic response following castration and dosing with testosterone and/or antiandrogens.

Record Details:

Record Type:PROJECT

Projected Completion Date:09/30/2008

OMB Category:Other

Record ID: 149109

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Project Information:

Progress :A model has been constructed that recapitulates the time-dependent changes in prostate following castration of male rats resulting in decreased serum testosterone, prostatic androgen receptor, and prostate weight. The model currently poorly describes the dose-response for less drastic changes in testosterone; this is under investigation. A classical compartmental model for finasteride, a therapeutic 5α-reductase inhibitor, has been linked to the biologically-based model for the rat endogenous hormone function. Opportunities to link the model with genomics data are being explored.

Approach :A biologically-based, systems-level model will be developed describing the regulation of the prostate by androgens. The model will extend an existing model for the male rat central axis, which describes feedback between luteinizing hormone and testosterone production in the testes, to include the prostate and conversion of testosterone to dihydrotestosterone (DHT). The prostate model will describe binding of androgens to the androgen receptor, 5α-reductase catalyzed production of DHT, and gene regulation affecting cell proliferation, apoptosis, and prostatic fluid production. The model will combine pharmacokinetic models for endogenous hormones (i.e., testosterone, DHT, LH) and exogenous antiandrogens (e.g., finasteride, flutamide or casodex, vinclozolin), and a pharmacodynamic model for androgen-dependent prostate functions. Linkages of this model with genomics data obtained with castration, testosterone treatments, or antiandrogen treatment will be explored to assist in developing perspectives on how such data would fit into quantitative risk assessments.

Relevance :This project is designed to evaluate how perturbations of endogenous biological systems produce observable dose-response behaviors using a widely used endpoint, rat prostatic response to androgen status. In addition, insights will be obtained concerning the potential utility of genomic data for dose-response analysis in relation to more traditional toxicological endpoints.

Project IDs:

ID Code :IIID-4

Project type :Partner Specific