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1 Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States; ORD National Health and Environmental Effects Laboratory, Experimental Toxicology Division, US Environmental Protection Agency, Research Triangle Park, North Carolina, American Samoa
2 Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States; ORD National Center for Computational Toxicology, US Environmental Protection Agency, Research Triangle Park, North Carolina, United States
3 ORD National Center for Computational Toxicology, US Environmental Protection Agency, Research Triangle Park, North Carolina, United States
* To whom correspondence should be addressed. E-mail: habarton{at}alum.mit.edu.
The testicular-hypothalamic-pituitary axis regulates male reproductive system functions. Understanding these regulatory mechanisms is important for assessing the reproductive effects of environmental and pharmaceutical androgenic and antiandrogenic compounds. A mathematical model for the dynamics of androgenic synthesis, transport, metabolism, and regulation of the adult rodent ventral prostate was developed based on a model by Barton and Anderson (1998). The model describes the systemic and local kinetics of testosterone (T), 5
-dihydrotestosterone (DHT) and luteinizing hormone (LH), with metabolism of T to DHT by 5
-reductase in the liver and prostate. Also included are feedback loops for the positive regulation of T synthesis by LH, and negative regulation of LH by androgens. The model simulates maintenance of the prostate as a function of hormone concentrations and androgen receptor (AR)-mediated signal transduction. The regulatory processes involved in prostate size and function include cell proliferation, apoptosis, fluid production and 5
-reductase activity. These processes are controlled through the occupancy of a representative gene by the androgen-AR dimers. The model simulates prostate dynamics for intact, castrated, and intravenous T-injected rats. After calibration, the model accurately captures the castration-induced regression of the prostate compared to experimental data, which show that the prostate regresses to approximately 17 and 5 percent of its intact weight at 14 and 30 days post-castration, respectively. The model also accurately predicts serum T and AR levels following castration in comparison with data. This model provides a framework for quantifying the kinetics and effects of environmental or pharmaceutical exogenous endocrine active compounds on the prostate.
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