Human placenta cells die after BPA exposure.

Feb 02, 2010

Benachour, N and A Aris. Toxic effects of low doses of Bisphenol-A on human placental cells. Toxicology and Applied Pharmacology doi:10.1016/j.taap.2009.09.005.




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Exposure to very low concentrations of the plastic monomer bisphenol A (BPA) causes cellular damage and death in cultured human placenta cells, researchers report. The doses used for this study are similar to blood levels found in pregnant women. A particularly worrying finding is that effects were most pronounced at the lowest – rather than the highest – concentrations of BPA indicating that placental development could be particularly sensitive to BPA exposure.  Damage to the placenta can induce a range of adverse pregnancy outcomes including premature birth, preeclampsia or even pregnancy loss.  It is not known if exposure to BPA is associated with adverse pregnancy outcomes in humans.

 

Context

Bisphenol A (BPA) is a common ingredient in a wide variety of products. It is a high production volume chemical with global output exceeding 6 billion pounds annually.

BPA is the monomer used to make polycarbonate plastics.  Many polycarbonate bottle manufacturers, including Nalgene and most baby bottle producers, voluntarily agreed to stop using BPA last year, but older containers likely contain it. 

In addition, BPA is the monomer used to make resins that line the interior of metal food and beverage cans. BPA is also found in thermal paper, medical devices, medical tubing, dental sealants, eye glasses, compact discs, plastic water pipes and many other products. Because BPA is used in carbonless paper receipts at high levels, and because these are recycled, recycled paper can contain BPA, including, for example, the recycled cardboard used to make pizza boxes.

BPA is released from products into food, drink and the air.  It is also in dust and can be breathed or absorbed through the skin. People are frequently exposed through contaminated food and beverages because the chemical readily leaches from containers, especially when heated. The magnitude of exposure created by handling carbonless receipts (e.g., credit card receipts) has not yet been determined.  It is likely to be significant.

Nearly all Americans have BPA in their blood, according to the U.S. Centers for Disease Control and Prevention. Children have higher levels than adults.

There is ample evidence that BPA acts as an endocrine disruptor in laboratory animals, even at low doses. Whether or not significant health effects in humans result from BPA exposure remains controversial. Urinary levels of BPA have recently been associated with chronic disease in humans including heart disease and diabetes as well as behavioral changes in toddlers.

The Environmental Protection Agency considers a "safe" level of exposure to be 50 micrograms per kilogram of body weight per day. Recent experiments with primates indicate human exposure may be much higher than this on a regular basis.

The Food and Drug Administration (FDA) recently reversed its long-held position of the chemical's safety, now finding "some concern" for children's health. The agency is conducting more studies and will also evaluate BPA's safety in medical devices, a process that may conclude early next year. The National Toxicology Program (NTP) has stated that there is "some concern" that BPA may have adverse effects on the “brain, behavior and prostate gland in fetuses, infants, and children. 

What did they do?

The researchers obtained placentas from five women who had normal pregnancies and deliveries. Human cytotrophoblast cells were collected from the placentas and cultured. This type of placental cell is important for the exchange of oxygen, nutrients and waste products between mother and fetus.

The cells were exposed to BPA for 24 hours at one of seven different concentrations, ranging from 0.002 to 200 micrograms per milliliter (µg/ml). These doses were selected because they approximate levels of BPA measured in fetal and maternal blood.  The researchers then looked to see if BPA exposure damaged the cells.

Release of the protein adenylate kinase was used as a marker of cell death because this protein “leaks” from cells with damaged membranes. Presence of the protein cytokeratin 18 was used as an indicator of apoptosis, a specific type of cell death.  Apoptosis is a normal part of placental development but altering the rate or degree to which this takes place can indicate abnormal placental growth.

What did they find?

Damage to the cell membrane was 1.3 to 1.7 times higher in placental cells exposed to BPA for 24 hours compared to cells that were not exposed to BPA.  Apoptosis was 2 to 3 times higher in the BPA treated cells.  These results indicate that cellular development was adversely affected by BPA.

BPA also increased the expression of tumor-necrosis factor alpha (TNF-α), a protein associated with apoptosis.  This finding was used as another indicator of increased cell death in the cultured cells.  Elevated expression was most pronounced at the lowest, not the highest, BPA exposure levels and provides further evidence that BPA can induce cell death in the placenta. This pattern, known as a non-monotonic (or 'inverted-U') dose-response curve, has been observed in multiple experiments with BPA previously and is a characteristic of many endocrine disruptors and endogenous hormones.

What does it mean?

These results indicate that BPA, at levels within the range a pregnant woman is likely to be exposed, can damage human placental cells in ways that could affect fetal development. 

BPA impacted cell death through two different mechanisms. Higher doses of BPA increased the rate of apoptosis type cell death but lower doses weakened cell membranes, an effect that also damaged and ultimately killed the placental cells.

The altered timing and amounts of cell death can lead to adverse pregnancy outcomes, such as preeclampsia, prebirth growth restriction, prematurity and pregnancy loss. While the results do not show BPA causes these conditions in people, the study provides a model for how BPA may change the signals and chemical controls that guide the development of  important pregnancy cells.

Importantly, the exposure levels tested are similar to those measured in pregnant women's blood, placental tissue and chord blood.

This work was done in cultured human placental cells, a techniqe that has both benefits and drawbacks.  One advantage of using this type of cell culture model instead of a laboratory animal model is that it uses human cells. Rodent placenta structure is very different from humans so BPA may produce different effects in rodents than humans.

A potential drawback of cell culture, however, is that it requires the direct application of BPA, a process that bypasses metabolism and therefore the opportunity for BPA to be changed into a less active form. To control for this, the researchers were careful to use a range of doses that have been measured in human blood.

The results of this study provide yet more evidence that exposure to BPA is a potental threat to human reproductive health.

Resources

An overview of Bisphenol-A. The Endocrine Disruptor Exchange.

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

Braun J, K Yolton, K Dietrich, R Hornung, X Ye, A Calafat, and BP Lanphear. 2010. Prenatal Bisphenol A exposure and early childhood behavior. Environmental Health Perspectives doi: 10.1289/ehp.0900979.

Kliman, HJ. From trophoblast to human placenta.  Encyclopedia of Human Reproduction.

Lang I, TS Galloway, A Scarlett, WE Henley, M Depledge, RB Wallace and D Melzer.  Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adultsJournal of the American Medical Association 300(11):1303-1310.

National Report on Human Exposure to Environmental Chemicals. U.S. Centers for Disease Control and Prevention.

Potential Human Reproductive and Developmental Effects of Bisphenol A (PDF). NIH Publication No. 08 – 5994. National Toxicology Program-CERHR Monograph, September 2008.

 

 

 

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