A study in the June 1 issue of Cancer Research presents the first evidence that exposure to low doses of environmental estrogens during development of the prostate gland in the male fetus may result in a predisposition to prostate cancer later in life.
The study, done in an animal model, also demonstrates how the predisposition may arise, and a way to identify those at risk.
Man-made compounds that can mimic the hormone action of estrogens (xenoestrogens) are widespread in the environment. One of these agents is bisphenol A (BPA), used in the manufacture of plastics and epoxy resins. The United States alone produces over 1.6 million pounds of BPA annually. BPA, which can also leach from plastics when heated, turns up in human blood and in placental and fetal tissues in even higher concentrations.
In this study, a research team led by Dr. Gail Prins of the University of Illinois at Chicago and Dr. Shuk-Mei Ho of the University of Cincinnati exposed rats to low doses of estradiol, a natural estrogen, or to BPA during the developmental period corresponding to the second and third trimester of human pregnancy. They found that this early exposure predisposed male rats to precancerous lesions of the prostate in old age.
"Most remarkably, early BPA exposure sensitized the prostate to precancerous lesions brought on by exposure of the adult animal to elevated estradiol," said Prins, professor of urology at UIC and senior author of the study. "This is highly relevant to people, because relative estradiol levels increase in aging men as a result of their increased body fat and declining testosterone levels."
The doses of estradiol and BPA used in the study were similar to levels found in human serum; in the circulation of some pregnant women; and in the fetus. Transfer of BPA from mother to fetus has been reported, and levels in male fetuses have been shown to be higher than those of female fetuses.
The researchers were able to demonstrate that early estrogen or BPA exposure permanently changed the methylation, or tagging, of specific stretches of DNA in the neonate's prostate cells, a phenomenon referred to as epigenetic reprogramming. In epigenetic reprogramming, gene expression is altered without changing DNA sequences or content. Several of the epigenetically altered sites turned out to be in important genes that regulate cellular functions.
The researchers conclude that exposure to environmental estrogens, such as BPA, or natural estrogens affect the pattern of gene expression in the prostate during development, and in so doing promote prostate disease with aging.
One of the altered genes, phosphodiesterase 4 (PDE4D4), was examined in greater detail. The researchers found that the methylation of PDE4D4 can permanently change its pattern of expression in the prostate. This gene should normally shut down in adult life, but after early exposure to estradiol or BPA, the exposed animals' prostates continued to express it at high levels. Similar high levels due to methylation of the gene were found in prostate cancer cells but not in normal cell lines.
Because the methylation marks of epigenetic reprogramming were found before any disease was observed, the methylation may be useful as a way to identify men at higher prostate disease risk, Prins said, which may have resulted from early exposure to endocrine disruptors.
"These findings are true for an animal model, and application to human prostate disease will await future studies," the authors concluded. Ho is first author of the study and professor and chairman of environmental health at the University of Cincinnati.
Wan-Yee Tang, of the University of Cincinnati, and Jessica Belmonte de Frausto of UIC also contributed to the study, which was funded by grants from the National Institutes of Health and the Department of Defense.
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