Does exposure of baby boys -- in utero or in infancy -- to bisphenol A, a man-made chemical which mimics natural estrogens, predispose them to prostate cancer later in life?
A five-year, $2.6 million grant to a University of Illinois at Chicago researcher and her colleague aims to answer this question by shedding light on the mechanism by which it may occur.
Gail Prins, professor of urology at the UIC College of Medicine and lead investigator on the grant, and her colleague, Shuk-Mei Ho, professor and chair of environmental health at the University of Cincinnati, established in earlier studies in animals that perinatal exposure to BPA at very low doses results in increased sensitivity to estrogen as the male animal ages and an increased risk of developing prostate cancer.
Demonstrating a similar link in humans in an epidemiological study is difficult because of the small dosages and long lag time between exposure and effect. With the new grant, from the National Institute of Environmental Health Sciences, Prins and Ho will attempt to unravel the genetic mechanism by which the dose-response effect in animals is thought to occur.
Scientists think that sensitization to estrogen due to a much earlier exposure to an estrogen-like compound is an "epigenetic" phenomenon -- a heritable change in gene function that occurs without a change in the DNA sequence, as in mutation.
In this model, the early environment of the fetus causes chemical changes in DNA, called imprinting, which may cause later changes in gene expression. These epigenetic changes, which result in increased or decreased expression of a gene -- or changes in the type of tissues in which the gene is expressed -- can have profound affects on the development of an organism, Prins said. And there is increasing evidence that these changes may be implicated in the origin of a number of adult diseases, like prostate cancer.
"We hypothesize that early 'imprinting' of the prostate gland by exposure to small doses of BPA is the result of specific modifications which permanently affect gene expression in the gland," Prins said.
"As men age, they produce less testosterone and relatively more estrogen. Our work with animals has shown that exposure of the 'BPA-imprinted' prostate gland to this more estrogen-rich environment is the key to the heightened risk of developing cancer."
BPA is a key chemical in the production of polycarbonate plastic and epoxy resins and is found in products ranging from baby bottles to tin can linings. BPA may break down and leach into food or beverages when it is heated. More than a billion pounds of BPA is produced in the United States each year. The U.S. Centers for Disease Control and Prevention has found BPA in 92 percent of Americans age six or older.
The new study will work with both an animal model and human prostate-like structures and is designed to characterize the dose-response and the period of susceptibility in the developing male, to determine which genes are modified and turned on or off as a result. The researchers also plan to test directly whether the epigenetically modified genes play an active role in the later development of cancer of the prostate gland.
"It's our hope that the findings of this study will serve as a model for human exposures to prevalent environmental hormonal disruptors with suspected carcinogenic potential," said Prins.
The study may also lead to improved methods of screening men who may already be at risk, Prins said.
"In addition to increasing our understanding of how BPA affects these changes on a molecular level, identification of the specific gene modifications caused by early exposure to BPA may provide us with biomarkers for identifying men at higher risk for prostate cancer as a result of environmental exposures," said Prins.
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