PHARMACODYNAMIC MODEL OF THE RAT ESTRUS CYCLE IN RELATION TO ENDOCRINE DISRUPTORS

Several strains of laboratory rats have a high background incidence of mammary tumors and develop a persistent, anovulatory estrus condition at about 12 mo of age. The increased tumor incidence is believed to S e associated with elevated estradiol (E2) and prolactin during the per iod of persistent estrus. A pharmacodynamic estrus cycle (PD-EC) model for the Sprague-Dawley rats has been developed in an attempt to analy ze the physiological basis of early-onset persistent estrus and to exa mine the potential sites of interactions in the hypothalamic-pituitary -ovarian axis for endocrine-modulating xenobiotics that accelerate the onset of persistent estrus. This initial estrus cycle model focused s olely on cyclical changes in E2 and luteinizing hormone (LH). An LH su rge was scheduled when a hypothetical estrus cycle-related protein (EC -RP) under transcriptional control by the E2 receptor reached a critic al concentration. In the model, aging-related cumulative hypothalamic E2 exposure impaired the LH surge by reducing the rate of production o f the EC-RP. The progressively decreasing intercycle resynthesis rate leads first to longer, variable-length cycles and finally to persisten t estrus at about 12 mo of age. This model construct is consistent wit h early-onset persistent estrus related to neonatal E2 exposures, with acyclicity associated with high-dose E2 exposure in the adult, and wi th persistent estrus conditions associated with exposures to xenobioti c endocrine modulators that are either weak E2 antagonists or weak EZ agonists. With further development these pharmacodynamic estrus cycle models should be useful in aiding risk assessments for compounds causi ng mammary-tissue tumors associated with persistent estrus states.