Effects of an Endocrine Disruptor on Prostate Development and GrowthEPA Grant Number: R827403
Title: Effects of an Endocrine Disruptor on Prostate Development and Growth
Investigators: Timms, Barry G.
Institution: University of South Dakota
EPA Project Officer: Klieforth, Barbara I
Project Period: July 1, 1999 through June 30, 2002
Project Amount: $432,452
RFA: Endocrine Disruptors (1999) RFA Text | Recipients Lists
Research Category: Environmental Justice , Endocrine Disruptors , Human Health , Safer Chemicals
Description:Hypothesis 1: Feeding pregnant mice low, environmentally relevant doses of the pesticide methoxychlor (MC), or diethylstilbestrol (DES; as a positive control), as well as a medium and high dose for comparison, will result in changes in the regional epithelial growth pattern in the developing fetal mouse prostate. We will test this hypothesis by studying ductal budding patterns and morphometry (objective 1a), androgen and estrogen receptor localization, cell proliferation and programmed cell death, in the developing prostate of newborn male mice (objective 1b).
Hypothesis 2: The consequence of fetal exposure to an endocrine disruptor will be to imprint adult prostate growth characteristics in males during aging. This hypothesis will be tested by studying growth and ductal branching morphogenesis (objective 2a), steroid receptors and cell proliferation, in the prostate of mature, middle aged and old aged male mice (objective 2b).
Approach:Eight groups of male mice, comprising two controls, plus animals treated prenatally with a low, medium or high dose of MC and DES will be examined. Prostate tissue will be analyzed at four different age points using 3-dimensional serial section reconstruction, in situ hybridization to detect steroid receptors, and studies of cell proliferation and programmed cell death indices.
Expected Results:It is anticipated that the low doses will result in a) an increased number of buds and/or size of the developing prostate, and that this effect will be particularly noticeable in the dorsal region; b) a parallel increase in the cell proliferation rate in the dorsal region of the prostate; c) an increase in the number of ductal branch points or terminal tips in adulthood, and d) changes in steroid receptor localization, cell proliferation and cell death in the prostate of aging males resulting from exposure to low, physiologically relevant doses of an endocrine disruptor during fetal development.
Improvements in Risk Assessment: If the results of this study support the stated hypotheses, we anticipate that the consequential effects of low doses of environmental estrogens on development and growth of hormone responsive tissues, such as the prostate, may determine guidelines for acceptable levels of endocrine disruptors in the foodchain. Additionally, we anticipate that the proposed animal model will provide a unique and sensitive bioassay for future monitoring or evaluation of potential hormone disrupting chemicals.