Researchers Identify New Markers for Prostate Cancer Risk

CINCINNATI—Scientists have identified the first evidence of a direct link between chemical exposure while in the womb and prostate cancer development later in life.

The research is reported in the June edition of the journal Cancer Research by Shuk-mei Ho, PhD, professor and chair of the University of Cincinnati’s Environmental Health Department, and Gail Prins, PhD, professor of urology at the University of Illinois at Chicago.

In a laboratory study, Ho and Prins found that animals exposed to low doses of the natural human estrogen estradiol, or the environmental estrogen bisphenol A (BPA), during fetal development were more likely to develop an early form of prostate cancer in humans (prostatic intraepithelial neoplasia) than those who were not exposed.  

These findings suggest that exposure to environmental and natural estrogens during fetal development could affect the way prostate genes behave, leading to higher rates of prostate disease during aging.

BPA is a chemical regularly used in the manufacture of plastics that can leach out when heated. It is one of many man-made chemicals known as “endocrine disruptors,” which permanently alter the function of the endocrine system by mimicking the role of the body’s natural hormones. Hormones are secreted through endocrine glands and dispersed to serve different functions throughout the body.

“Our research showed that early BPA exposure made the prostate more susceptible to precancerous lesions, which are brought on by the adult animal’s exposure to elevated estradiol,” says Ho, lead author of the report. “This is an important discovery, because BPA has been found in human maternal and fetal circulation. If it has such a long-lasting effect—by reprogramming how adult tissues respond many years later—then potential exposure sources during pregnancy need to be carefully scrutinized.”

The researchers showed that early BPA exposure permanently changed methylation or “tagging” of specific stretches of DNA and the way certain genes are packaged within the nuclei of prostate cells.

“This phenomenon is known as epigenetic reprogramming,” explains Ho. “The gene expression changes, but the DNA sequences and content do not.”

They found that a specific altered gene—known as phosphodiesterase 4 (PDE4D4)—did not shut down through the natural aging process. Although the gene should normally phase out in adult life, when exposed to estradiol or BPA early in life the animals continued to produce it at high levels.

“It turns out that this specific gene plays an important role in regulating cellular function, so when it doesn’t shut down as it should, it begins to promote prostate disease instead,” says Ho.

These findings are true for an animal model, the researchers stress, but application to human prostate disease needs further study.

“We need to understand the mechanism behind disease to inspire better lifestyle changes and smart manufacturing changes that will make a broader impact on human health,” says Ho. “If we can develop strong biomarkers, we can manage and prevent diseases much earlier.”

More than 1.6 million pounds of BPA, the molecular building block of polycarbonate plastics, are produced in the United States annually. The substance is regularly used in consumer products, such as baby bottles, water bottles, microwave ovenware and plastic eating utensils and in epoxy resins to coat medical food cans and dental sealants. It is also found in carbonless paper, compact discs, adhesives, flooring and electrical appliances.

Wan-Yee Tang, of UC, and Jessica Belmonte de Frausto of UIC also contributed to the study. This research was funded by grants from the National Institutes of Health and the Department of Defense.