BPA at low doses, early in life linked to prostate disease in rats.

Oct 28, 2010

Prins, GS, S-H Ye, L Birch, S-M Ho and K Kannon. 2010. Serum bisphenol A pharmacokinetics and prostate neoplastic responses following oral and subcutaneous exposures in neonatal Sprague-Dawley rats. Reproductive Toxicology http://dx.doi.org/10.1016/j.reprotox.2010.09.009.




 2010-1026maninhospital
cary b/flickr

 

Low levels of bisphenol A (BPA) can cause prostate disease in rats exposed as newborns to the ubiquitous chemical. The young rats exposed to BPA developed prostate gland lesions as adults. These lesions are considered the precursors to prostate cancers in humans. Regardless whether the BPA was eaten or injected into the rodents, the levels in the rats' blood were similar to levels measured in people. This study is the first to demonstrate that rodents exposed to BPA levels similar to those found in human blood develop cancer, making human exposures especially concerning.

 
 

Context

Bisphenol A (BPA) is a well-studied endocrine disruptor – a substance that can interact with hormones in the body. This chemical acts like estrogen. In rodents, low levels affect development of the male and female reproductive tracts, the brain and the mammary gland. Animals exposed to BPA also display abnormal behaviors and are often obese.

The prostate gland is an important part of the male reproductive tract. The gland produces fluids that protect sperm and prolong their life when they journey through the female reproductive tract. The developing prostate is highly sensitive to hormones, including estrogen and testosterone – the main female and male hormones. In adults, the prostate remains sensitive to these hormones.

Prostate cancer is one of the most common cancers afflicting men. More than 32,000 die in the United States each year from the disease, according to the National Cancer Institute. As men age, they are at increased risk for developing the disease. Many older men may have prostate cancer but not know it, because it can be present without any symptoms. The exact causes of prostate cancer are not known, but diet, genetics and changes in hormone levels are thought to be involved.

Several studies link BPA exposures in early life to cancers in later adult years. For instance, BPA causes pre-cancerous and cancerous lesions of the mammary gland in mice and rats. It also makes animals hypersensitive to tiny doses of carcinogens. This means that cancers form in BPA-exposed animals treated with carcinogens when no tumors would form in animals treated with small doses of carcinogens.

Concerns about BPA exposures also extend to humans. A study of American adults found that individuals with higher levels of BPA metabolites in their urine were more likely to have heart disease and diabetes. Female toddlers exposed to higher levels of BPA in the womb were more aggressive. And, smaller studies have linked BPA exposures to infertility and male sexual dysfunction.

BPA is found in a wide variety of consumer products, including reusable food and beverage containers, the linings of metal cans, electronic equipment, some thermal paper receipts and dental sealants. It leaches from these products – even when they are used as directed.

Studies from the Centers for Disease Control and Prevention (CDC) indicate that over 90 percent of Americans have BPA in their bodies. Similar detection rates are reported in Canada, Europe and Asia. BPA is found in human blood, urine, breast milk, amniotic fluid and placenta tissue.

The bulk of BPA exposures are thought to be through eating contaminated foods. Because it is also found in air, dust, water and some cash register receipts, it is likely that BPA can be absorbed through the skin and inhaled.

Researchers believe that when BPA enters the body with food, it is quickly inactivated and removed from  urine. If BPA enters in other ways – by breathing it or absorbing it through the skin – inactivation and removal is slower. For this reason, researchers study the effects of BPA on animals in ways that closely mimic real human exposures.

What did they do?

The authors either fed or injected 180 male newborn rats with 10 micrograms of BPA per kilogram of body weight – a relatively small amount – on the first, third and fifth days after birth. The authors then let the animals grow. When they reached adulthood, they were implanted with pellets that released estrogen and testosterone. The hormone treatment lasted for 16 weeks, a sufficient amount of time for alterations to occur in hormone-sensitive tissues like the prostate. The pellets mimicked the hormone levels in men that develop prostate cancer.

After the treatment, the rat prostates were removed and examined for precancerous damage known as PIN lesions prostate intraepithelial neoplasia lesions. Three different regions of the prostate were examined in each animal. The PIN scores were compared among the animals that ate BPA, were injected with BPA or were unexposed.

Because the animals were given a relatively small amount of BPA for just a few days, the authors also wanted to know how much BPA ended up in the bloodstream. This is important, because it allows comparisons between circulating levels of BPA in the rats with levels that have been previously measured in humans.

Blood was collected from rats that were fed or injected with BPA. The levels of BPA and BPA metabolites were measured using high-performance liquid chromatography (HPLC) and tandem mass spectrometry – two highly sensitive methods that can measure very small amounts of BPA in blood.

What did they find?

BPA exposures in early life caused prostate lesions in adult rats. Two regions of the prostate had significantly more PIN lesions compared to unexposed controls. The increase in PIN lesions was seen regardless of whether BPA was injected or eaten.

Interestingly, almost twice as many inflammatory cells were found in one region of the prostate in BPA-exposed animals. This is important because previous studies show that chronic inflammation may be associated with human prostate cancers. In fact, men who take anti-inflammatory drugs like aspirin may have a lower chance of developing prostate cancer.

In looking at BPA levels in the blood of exposed pups, injections and eating BPA both produced blood levels of active BPA similar to those seen in humans. BPA has been measured in human blood – including fetal blood collected from umbilical cords – in the parts-per-billion range.

However, based on how BPA entered the body, differences were seen in the amount of time it took the rats to change BPA into a different, less harmful form and remove it from the body. Animals injected with BPA had more active BPA in their blood for a longer period of time compared to animals that ate it. Over a 2-hour period, injected animals were exposed to approximately four times more active BPA than those that were fed BPA.

What does it mean?

For the first time, this rat study shows that lesions in prostate tissue form after exposure to environmentally relevant doses of BPA. Exposing rat pups to a low level of BPA – whether orally or by injection – produced blood levels similar to those measured in people, including levels that have been measured in fetal blood.

Many published studies link early-life BPA exposures to diseases in adulthood, including several that show BPA can cause cancers of the prostate and mammary glands.

Importantly, the doses tested in this study are within the range of doses used in hundreds of other animal studies. Those studies link low level BPA exposure to a range of problems in rodents, including obesity, altered development of the brain and reproductive tracts, inappropriate behaviors and mammary cancer.

The exposures produced blood levels in the parts-per-billion range, which are similar to those measured in human blood and amniotic fluid. Because of this, the authors suggest that human fetuses and neonates could be at risk from current exposure levels. The first few days after birth in the rat are equivalent to late fetal development in humans – a time when reproductive organs and glands are still developing. Therefore, parts-per-billion blood levels of BPA could harm development of the human prostate. 

It is important to know whether the way BPA enters the body affects its ability to cause harm. The authors clearly show that it does not – the PIN lesions developed no matter how the rat pups were exposed.

This is important for two reasons. First, human exposures occur through more than one route. People are likely exposed through food but also may absorb BPA through the skin and breathe it in air and dust.

Second, regulatory agencies in the United States that oversee public health and safety have largely rejected or ignored results from the published studies that injected BPA into animals. Administrators with the U.S. Environmental Protection Agency, the Food and Drug Administration and other federal agencies have held that injecting BPA causes abnormally high levels of the active compound to circulate in the blood. They contend that these ultra levels would be higher than a typical human exposure and may create adverse effects not relevant to people. 

But, this study shows that is not the case. Injecting 10 micrograms of BPA per kilogram of body weight produces blood levels that are very similar to what has been measured in humans. Prior studies injecting similar amounts of BPA into rodents should yield equally valid results that will further understanding of the adverse effects of BPA exposures.

The U.S. National Toxicology Program concluded that there is some concern that BPA could affect development of the human prostate. The scientists on the advisory panels expressed concern that BPA could influence brain development and behaviors. Very recently, Health Canada declared BPA to be a toxin.

Yet, worldwide, very little regulatory action restricts the use of BPA, which continues to be used in a wide range of consumer products. A few U.S. states, Canada and some European countries have banned its use in baby bottles. Can linings in Japan no longer contain BPA. Some companies have voluntarily removed it from reusable plastic water bottles.

Because it is released from products into food, liquids and the air, human exposures – including those to fetuses and newborns – continue to be widespread.

Resources

Bisphenol A. The Endocrine Disruptor Exchange (TEDX). 

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Bisphenol A. (PDF) September 2008. NIH Publication No. 08 – 5994.

Prostate cancer. The National Cancer Institute.

Questions and answers about bisphenol A. National Institute of Environmental Health Sciences.

Update on Bisphenol A (BPA) use in food. January 2010. U.S. Food and Drug Administration.

Vandenberg, LN, I Chahoud, JJ Heindel, V Padmanabhan, FJR Paumgartten and G Schoenfelder. 2010. Urine, serum and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environmental Health Perspectives 118(8):1055–1070.

 

 

Bisphenol A
More news about
Bisphenol A