PHARMACODYNAMIC MODEL OF THE RAT ESTRUS CYCLE IN RELATION TO ENDOCRINE DISRUPTORS
作者:
MelvinE. Andersen,
HarveyJ. Clewell,
Jeffrey Gearhart,
BruceC. Allen,
HughA. Barton,
期刊:
Journal of Toxicology and Environmental Health
(Taylor Available online 1997)
卷期:
Volume 52,
issue 3
页码: 189-209
ISSN:0098-4108
年代: 1997
DOI:10.1080/00984109708984060
出版商: Taylor & Francis Group
数据来源: Taylor
摘要:
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 xenobi- otics 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 pharma-codynamic estrus cycle models should bejuseful in aiding risk assessments for compounds causing mammary-tissue tumors associated with persistent estrus states.
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