Environmental Factor, October 2010, National Institute of Environmental Health Sciences
New BPA findings help fill research gaps
Barely a year after NIEHS announced $30 million in funding to support research on the chemical bisphenol A, new grantee findings are already emerging. Gail Prins, Ph.D.(http://www.uic.edu/labs/prins/Gail.htm) , of the University of Illinois at Chicago, presented data during a seminar at NIEHS on how the dose levels and the route of administration of BPA given in her rat model are relevant to human exposure levels.
The lecture, organized by Jerry Heindel, Ph.D., an acting branch chief in the NIEHS Division of Extramural Research and Training, attracted an at-capacity audience Sept. 21. It began with an introduction to the rat model Prins uses for her work and an overview of prostate cancer - the second leading cause of cancer death in American men behind lung cancer.
Linking exposures to development of prostate cancer
To give the audience a better appreciation of her lab's neonatal rat model and how it is helping to understand the developmental origins of diseases like prostate cancer in humans, she paralleled the progressions of the disease, including how it slowly gets to a point referred to as prostate intraepithelial neoplasia (PIN), before breaking though a membrane and becoming full-blown prostate cancer.
As someone who has been studying the developmental basis of adult disease for several decades, Prins said she wanted to determine if the risk of prostate cancer could be determined by maternal or perinatal factors. Prins used a rat model, noting that prostate development in the rat originates at 19 days gestation, providing an ideal model for modulating a hormonal environment. Her lab demonstrated that right before birth and up to ten days afterwards is a critical reprogramming window for toxicants with regard to the prostate gland.
Prins said her lab developed what she referred to as a two-hit model, giving rats low doses of estrogenic compounds including BPA, soon after birth, and then testosterone and estradiol later in life, to mimic what happens with aging in humans. Using this model, she has shown that low doses of estrogen and BPA early in life would impact the susceptibility of prostate cancer later in life.
Closing the gap between human and animal studies
"The National Toxicology Program, in its 2008 evaluation of BPA, and the scientific community identified a very relevant and important research gap area that needed to be addressed," said Prins. Reviewers wanted to know if the doses given to animals were similar to what humans experience (see text box).
They also said that the oral route of exposure was preferred because other routes of exposure produced higher levels of free/active BP. Prins said she now has the data to answer both research gaps - "Knowing the internal dose of BPA, rather than the dose administered to the animal, and how the organs respond to that dose, is the biologically relevant piece of information that was missing."
She said studies published by her group demonstrated that early life exposure to environmentally relevant doses of BPA increases susceptibility to prostate carcinogenesis in animal models. She ended her talk by saying she believes these animal findings are applicable to humans.
Prins' new data is scheduled for publication online this month in Reproductive Toxicology.
(Robin Mackar is the News Director in the NIEHS Office of Communications and Public Liaison and a regular contributor to the Environmental Factor.)
Determining relevant levels of BPA
In her experiments, Prins showed that a subcutaneous injection of BPA at 10 micrograms per kilogram of body weight resulted in a serum level free/active BPA of 1.77 nanograms per milliliter after 30 minutes, which is in the range of human blood levels of free/active BPA. Thus, her dosing paradigm produced BPA levels that were relevant to human exposures.
Prins and her colleagues then designed a study to directly compare different routes of exposure of BPA, including subcutaneous and oral dosing, in a neonatal rat model. Her team then looked at how the delivery of 10 micrograms BPA per kilogram of body weight impacted the susceptibility of prostate cancer in the newborn rats exposed to BPA. The results showed that while the subcutaneous dosing did indeed show a seven-fold increased exposure in the first 30 minutes, by two hours the level of free/active BPA in the blood was similar for both dosing paradigms. Most importantly, both routes of exposure resulted in the same increased PIN level in the prostate, indicative of a precancerous toxicity seven months after the exposure. She noted that this data shows that route of exposure is not as critical as had been thought and thus the subcutaneous exposure route should be an acceptable paradigm.