Andersen M E, Clewell H J, Gearhart J, Allen B C, Barton H A
ICF Kaiser Engineers, Inc., Research Triangle Park, North Carolina 27709, USA.
J Toxicol Environ Health. 1997 Oct 24;52(3):189-209. doi: 10.1080/00984109708984060.
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 be associated with elevated estradiol (E2) and prolactin during the period of persistent estrus. A pharmacodynamic estrus cycle (PD-EC) model for the Sprague-Dawley rats has been developed in an attempt to analyze the physiological basis of early-onset persistent estrus and to examine 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 solely on cyclical changes in E2 and luteinizing hormone (LH). An LH surge was scheduled when a hypothetical estrus cycle-related protein (EC-RP) under transcriptional control by the E2 receptor reached a critical concentration. In the model, aging-related cumulative hypothalamic E2 exposure impaired the LH surge by reducing the rate of production of the EC-RP. The progressively decreasing intercycle resynthesis rate leads first to longer, variable-length cycles and finally to persistent estrus at about 12 mo of age. This model construct is consistent with early-onset persistent estrus related to neonatal E2 exposures, with acyclicity associated with high-dose E2 exposure in the adult, and with persistent estrus conditions associated with exposures to xenobiotic endocrine modulators that are either weak E2 antagonists or weak E2 agonists. With further development these pharmacodynamic estrus cycle models should be useful in aiding risk assessments for compounds causing mammary-tissue tumors associated with persistent estrus states.
几种实验大鼠品系有较高的乳腺肿瘤背景发生率，并且在大约12月龄时会出现持续的、无排卵的发情状态。肿瘤发生率的增加被认为与持续发情期雌二醇（E2）和催乳素水平升高有关。为分析早发性持续发情的生理基础，并研究下丘脑 - 垂体 - 卵巢轴中内分泌调节性外源性物质加速持续发情发作的潜在相互作用位点，已建立了Sprague-Dawley大鼠的药效学发情周期（PD-EC）模型。这个最初的发情周期模型仅关注E2和促黄体生成素（LH）的周期性变化。当受E2受体转录控制的假设性发情周期相关蛋白（EC-RP）达到临界浓度时，安排LH峰出现。在该模型中，与衰老相关的下丘脑E2累积暴露通过降低EC-RP的产生速率损害了LH峰。逐渐降低的周期间再合成速率首先导致周期变长、长度可变，最终在大约12月龄时导致持续发情。这种模型构建与新生儿期E2暴露相关的早发性持续发情、成年期高剂量E2暴露相关的无周期性以及与暴露于弱E2拮抗剂或弱E2激动剂的外源性内分泌调节剂相关的持续发情状态一致。随着进一步发展，这些药效学发情周期模型应该有助于对导致与持续发情状态相关的乳腺组织肿瘤的化合物进行风险评估。
