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1999 Progress Report: Effects of Early Exposure to Xenoestrogens on the Prostate GlandEPA Grant Number: R826299
Title: Effects of Early Exposure to Xenoestrogens on the Prostate Gland
Investigators: Prins, Gail S.
Institution: University of Illinois at Chicago
EPA Project Officer: Fields, Nigel
Project Period: December 29, 1997 through December 28, 2000
Project Period Covered by this Report: December 29, 1998 through December 28, 1999
Project Amount: $586,384
RFA: Endocrine Disruptors (1997) RFA Text | Recipients Lists
Research Category: Economics and Decision Sciences , Endocrine Disruptors , Health , Safer Chemicals
Objective:The objective of the work presently conducted at our laboratory is to evaluate effects of xenoestrogen exposure on the prostate gland and whether such exposure can result in increased incidences of prostatic abnormalities during aging. Past work on rodents clearly indicates that brief exposure to natural estrogens during early developmental periods results in permanent alterations of the prostate (imprinting), including differentiation defects, altered gene expression and squamous metaplasia, dysplasia, hyperplasia and adenoma formation with aging. Synthetic environmental contaminants with estrogenic properties might likewise affect the prostate gland, even at low doses. Hence, the present project tests the hypothesis that brief exposure to environmentally relevant doses of estrogenic chemicals during prostate development will produce abnormal growth patterns and predispose to prostate cancer. Secondly, the study will try to determine the molecular mechanisms by which xenoestrogens affect the prostate.
Progress Summary:During the first year, significant progress was made accomplishing Specific Aim I, to determine whether xenoestrogens can imprint the prostate and to determine dose-response relationships for the tested chemicals. In our first experiments, we focused on the dose-depending effects of neonatal treatment of Sprague-Dawley rats with either nonylphenol (NP) or bisphenol A (Bis A). The results suggested that neonatal exposure to low doses of NP may advance puberty in male rats, since preputial gland separation (PGS) occurred significantly earlier and ventral prostate (VP) and testis weights were increased in 35 days-old animals. At day 90, values were not different from control or high-dose animals. Furthermore, we observed that NP super-masculinized several liver enzymes, which are known to be hormonally regulated and can be imprinted in the male rat. Since the last report, we repeated the experiment to verify the results. We also performed a dose-response experiment with estradiol benzoate (EB) to compare the effects of natural estrogens to those observed for NP. Once again, animals were treated at days 1, 3, and 5 of life with a 7-log range of doses (0.0001 to 100 mg/animal/day) of EB, and were sacrificed at days 35 and 90, respectively. The prostates were microdissected, weighed, and frozen for histology. Puberty was monitored by preputial gland separation, anogenital distance at day 21, liver enzymes at day 45, and hormone levels at day 35 (T, LH, FSH, PRL). The repeat-experiment testing NP could not confirm our first results. Ventral prostate and testis weights at day 35 were not altered by neonatal treatment with low-dose NP. Preputial separation occurred at no earlier date in any of the treatment groups. An additional monitoring of epididymal sperm counts also revealed no difference between control and any dose of NP. In the EB dose-response experiment, neonatal low dose (0.001 mg/animal/day) treatment resulted in significant increases of ventral, lateral, and dorsal prostate weights at day 35, whereas high doses (10 and 100 mg/animal/day) reduced prostate weights significantly. This inverted-u function was not observed at day 90, where only prostates of animals treated with the high dose EB were significantly smaller. Preputial gland separation was not reached at a significantly earlier point in any treatment group, although animals treated with the highest doses did not reach PGS at all. Differing observations of repeated experiments using environmental contaminants with estrogenic activity can have several reasons that might be of significant importance for how in vivo experiments testing such substances are designed. The grade of the contaminant can vary between batches. This is particularly true for NP, which at industrial grade is composed of two isomers. Although special soy- and alfalfa-free diet was used, differences in the composition of the diet may be responsible for inconsistent results. However, the most likely explanation for the observed differences may be the fact that different rodent strains are differently susceptible to estrogens. This has been repeatedly reported for both mouse and rat strains. Consequently, we are in the process of testing our present results in similar experimental designs using Fisher 344 rats that are known to be more sensitive to estrogen treatment. The results from the EB dose-response experiment indicate that possible effects of low doses of estrogen on the developing prostate may not necessarily be correlated to an advancement of puberty, but rather a direct effect on the organ. To test this hypothesis, we have established an organ culture system at our laboratory.
Future Activities:In the future, we will use the organ culture system established in our laboratory to test the effects of xenoestrogens on the prostate. This experimental design will help to: (1) further understand the direct effects of estrogens on the developing prostate during the time of differentiation and duct morphogenesis; and (2) determine the possible direct effects of synthetic substances with estrogenic activities on the prostate development. It will enable us to screen various xenobiotics with estrogenic properties in a relatively short time frame, before submitting them to further in vivo experiments. Therefore, the combination of in vitro and in vivo experiments will provide a rather balanced approach not only to determine possible dose dependent alterations of normal prostate development in an explant culture system, but also to verify these observations in the more relevant in vivo context. By direct comparison with both estradiol and DES, the results of the proposed study will, thus, help to determine possible potentials of environmental estrogens to propagate adverse health effects for the developing prostate in wild population and humans. This approach also will help to accomplish Aim II: Determine whether the actions of various xenoestrogens are mediated through changes in the expression of ER and AR within the prostate gland, and Aim III: Determine whether the specific xenoestrogens that imprint the prostate alter the prostatic expression of ERb, and whether this novel steroid receptor mediates their effects.
Journal Articles on this Report : 3 Displayed | Download in RIS Format
|Other project views:||All 7 publications||4 publications in selected types||All 3 journal articles|
||Gilleran JP, Putz O, DeJong M, DeJong S, Birch L, Pu YB, Huang LW, Prins GS. The role of prolactin in the prostatic inflammatory response to neonatal estrogen. Endocrinology 2003;144(5):2046-2054||
||Prins GS, Birch L, Habermann H, Chang WY, Tebeau C, Putz O, Bieberich C. Influence of neonatal estrogens on rat prostate development. Reproduction Fertility and Development 2001;13(4):241-252||
||Putz O, Schwartz CB, Kim S, LeBlanc GA, Cooper RL, Prins GS. Neonatal low- and high-dose exposure to estradiol benzoate in the male rat: I. Effects on the prostate gland. Biology of Reproduction 2001;65(5):1496-1505.||