Tag Archives: BPA

Mice moms, sons end up diabetic after short BPA exposure during pregnancy.

Mice moms, sons end up diabetic after short BPA exposure during pregnancy.

Jul 01, 2010

Alonso-Magdalena, P, E Vieira, S Soriano, L Menes, D Burks, I Quesada and A Nadal. Bisphenol-A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring. Environmental Health Perspectives http://dx.doi.org/10.1289/ehp.1001993.


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Brief exposure to low levels of bisphenol A during pregnancy may contribute to diabetic symptoms in the mother and her sons – but not daughters – finds a study with mice. BPA, which acts like estrogen and can interfere with normal hormone activity, caused changes in the mothers that resembled gestational diabetes. The mothers gained weight and could not properly regulate insulin, sugars and fats, even four months after the pregnancy. Their male pups showed similar deficits in metabolism, even though they had only been indirectly exposed for a brief period as fetuses.

Context

Intricate body systems process and store energy from food. When needed, sugars and fats are released. These mechanisms are delicately balanced. When they go awry, metabolic problems such as diabetes and obesity can occur. At no time are these systems more vulnerable than during pregnancy, when the energetic demands of the fetus compete with the mother’s regulation of her own body (Haig 1993).

Normally, insulin release causes sugars to be stored in cells for later use. During pregnancy, the body becomes increasingly resistant to insulin. This ensures that enough sugar remains in circulation to feed the growing fetus. Typically, the mother compensates by secreting more insulin so that blood sugar levels are kept in check.

These check and balance systems are easily derailed. When the mother’s body fails to adjust its insulin release, gestational diabetes – which afflicts up to 10 percent of pregnant women – may occur. Most cases of gestational diabetes resolve soon after birth, but many serious consequences may remain for both the mother and child. The children are often dangerously large at birth, and both mothers and offspring may find themselves at increased risk of obesity and Type II diabetes.

Because estrogen may play an important role in regulating the normal changes in metabolism during pregnancy (Nadal et al. 2009), anything that disrupts the body’s normal estrogenic activity may also throw the blood sugar regulation systems into upheaval, causing metabolic symptoms, and possibly contributing to diabetes or obesity.

The environmental chemical bisphenol A (BPA) – found in products throughout the modern world – is a compound that mimics natural estrogens. Concern first surfaced because it can leach from widely-used polycarbonate plastics, which were used a food packaging and water bottles. Recently, several reports brought attention to its overwhelming prevalence in canned goods (Consumer Reports 2009National Workgroup for Safe Markets 2010).

From food to household electronics to sales receipts, BPA is so commonly used in consumer goods that 95 percent of Americans have measureable levels in their blood. During pregnancy, BPA can pass from mother to the developing fetus.

Alarm bells were first raised about the chemical’s safety when animal studies showed that BPA could affect development of the reproductive system and the brain. More recently, concern has turned to whether BPA exposure may also impact metabolism. Several recent studies have linked BPA to diabetes, obesity and other symptoms of impaired metabolism in humans (Lang et al. 2008) and animal models (Alonso-Magdalena et al. 2006).

What did they do?

The researchers examined whether there were long-term metabolic effects on the mother and her pups exposed to BPA for a week during pregnancy.

Researchers injected pregnant mice with BPA from days 9 to 16 of pregnancy, which roughly corresponds to the development stage of middle to late pregnancy in humans. Some of the injected mice received a low dose of 10 micrograms per kilogram (μg/kg) of BPA each day while others received a high-dose of 100 μg/kg each day. Currently, the U.S. Environmental Protection Agency (EPA) and the Food and Drug Administration (FDA) consider anything below 50 μg/kg per day to be a low, and thus, “safe” dose.

The researchers measured glucose in the blood to determine if the pregnant mice processed sugars and responded to insulin – a hormone that helps the body store sugars after a meal. After birth, they continued to monitor the mothers and their offspring for their ability to metabolize sugar and insulin. They also examined how well the animals processed fats and how well their pancreases worked. The researchers compared these measures from BPA-treated mice to untreated mice and determined the physiological differences between the two groups.

What did they find?

Pregnancy typically entails some degree of insulin resistance, and this effect was amplified in the BPA-exposed mice, particularly in those receiving the lower dose of BPA. When compared to the untreated pregnant mice, their cells were less able to efficiently process and store sugars and their liver and muscle tissues showed a reduced insulin response similar to that seen in diabetic conditions.

Four months after giving birth, the BPA-treated mothers were heavier than the controls, even though their diets were the same. The mice in the high-dose group – but not the low-dose groups – had clear deficits in their cells’ ability to use insulin to store sugars. In both BPA-treated groups, levels of triglycerides – a type of lipid or fat – in the blood were elevated.

The mouse pups born to BPA-treated mothers also showed differences from control mouse pups. The low-dose pups were heavier at birth than controls – as is frequently the case with babies born to mothers with gestational diabetes. Yet, the high-dose pups actually weighed less than the controls.

As they aged, the BPA groups showed similar metabolic problems to their mothers. Although no significant differences were seen at three months of age, by six months, male – but not female – offspring in both BPA groups showed clear abnormalities in their ability to use insulin to store sugars. This deficit was consistently apparent in the blood tests and when the pancreatic cells were examined.

What does it mean?

Exposure to low levels of BPA at a crtical time in pregnancy may influence metabolic function during and after pregnancy, setting the stage for long-term gestational diabetes in the mothers and development of diabetes in sons as they age.

This study adds to a growing body of research evidence that, when taken together, suggests BPA causes health problems in animals and quite possibly in humans. Much of the research has focused on reproductive and developmental risks.

This study is one of a number of recent ones investigating whether BPA might have effects on metabolic conditions such as diabetes and obesity. But, it is the first to examine the mother’s risk of developing diabetes during pregnancy. While the recent studies have found some conflicting results, this new study’s methodological strengths mke the findings of particular concern.

Earlier this year, another group of researchers reported that prenatal and early postnatal BPA exposure in mice did not appear to lead to problems with blood sugar regulation, although they did find faster rates of growth during early development (Ryan et al. 2010).The new study improves upon earlier work, however, in that it is particularly comprehensive in its methods and approaches problems of insulin resistance and blood sugar regulation using a number of different methods. From sugar metabolism tests to measures of gene expression to blood chemistry, the multiple lines of evidence in this study all point to BPA having profound negative effects on the body’s ability to properly control blood sugar.

Beyond its methodological strengths, this new study adds two important nuances to our understanding of how BPA may impact metabolism. First, the study showed that even if BPA exposure occurs during a very brief period, the disruption in blood sugar regulation can be long-lasting. The female mice received BPA for only a seven day window during pregnancy, and yet were affected even months later, with higher weights and abnormal blood sugar and lipid levels.

In humans, of course, we are exposed continuously throughout our lifetimes as we ingest BPA in our food and pick it up through plastics and other sources every day. How this constant exposure might affect our bodies’ abilities to regulate blood sugars and other body systems remains an open ended question. However, these early results in mice are enough to merit additional research.

Second, the new study shows intergenerational effects. Males who were exposed to BPA as fetuses through their mothers displayed long-term metabolic problems resembling diabetes, even though they were never exposed to the chemical after birth. Because the body’s systems develop very early in life – often before birth – early exposures can cause permanent changes in body functions. In this case, through the ability to act as a pseudo-estrogen, BPA seems to permanently “program” body responses to sugar, causing an inability in the mice process the sugar – a condition that may mirror some of the most troubling current human health problems.

Aspects of the findings are also puzzling. Surprisingly, only male offspring were affected in this way by BPA exposure. The researchers hypothesize that perhaps the female offspring’s own estrogen production protected against the dysregulation, but further investigation would be needed to address that question.

In addition, low and high-dose BPA exposures didn’t yield the same findings. While both levels of exposure clearly produced negative health effects, it remains uncertain why the mice might respond differently to the two doses. The lower dose more closely approximates average human exposure levels. Ideally, future experiments will need to simulate the typical method of human exposure – ingestion through food – rather than injection.

Still, many questions remain unanswered, and more research is needed to fully understand how BPA impacts regulatory systems.

Resources

Alonso-Magdalena, P, S Morimoto, C Ripoll, E Fuentes and A Nadal. 2006. The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance. Environmental Health Perspectives 114(1):106-12.

Calafat, AM, Z Kuklenyik, JA Reidy, SP Caudill, J Ekong and LL Needham. 2005. Urinary concentrations of Bisphenol A and 4-Nonylphenol in a human reference population. Environmental Health Perspectives 113:391-5.

Concern over canned foods. 2009. Consumer Reports, December.

Haig, D. 1993. Genetic conflicts in human pregnancy. Quarterly Review of Biology 68(4):495-532.

Lang, IA, TS Galloway, A Scarlett, WE Henley, M Depledge, RB Wallace and D Melzer. 2008. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. Journal of the American Medical Association 300(11):1303-10.

Nadal, A, P Alonso-Magdalena, S Soriano, AP Ropero and I Quesada. 2009. The role of oestrogens in the adaptation of islets to insulin resistance. Journal of Physiology 587(Pt 21):5031-7.

National Workgroup for Markets. 2010. Silver lining: An investigation into bisphenol A in canned foods (PDF).

Ryan, KK, AM Haller, JE Sorrell, SC  Woods, RJ Jandacek and RJ Seeley. 2010. Perinatal exposure to Bisphenol-A and the development of the metabolic syndrome in CD-1 mice. Endocrinology 151(6):2603-12.

Dream of plastics from carbon dioxide is a reality.

Dream of plastics from carbon dioxide is a reality.

Jun 01, 2010

Zhang, Y and J Young Gerentt Chan. 2010. Sustainable chemistry: imidazolium salts in biomass conversion and CO2 fixation. Energy and Environmental Science http://dx.doi.org/10.1039/b914206a.

Synopsis by Adelina Voutchkova
Certain classes of organic molecules can be instrumental in both capturing carbon dioxide from the air and incorporating it into new plastic materials, which could lessen the need for raw petroleum.

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Chemists have made progress in finding environmentally friendly ways to capture and reuse carbon dioxide (CO2). Specifically, significant new advances have been made in the ability to absorb CO2 from the atmosphere and incorporate it into new raw materials – including benign alternatives to BPA-based plastics.

Certain classes of organic molecules have been discovered to be instrumental in capturing carbon dioxide from the air and incorporating it into new plastic materials. This process eliminates petroleum as an input, and generates more benign materials in the process.

In this and several other recent articles, researchers report how a class of chemicals – called “ionic liquids” – can efficiently capture and incorporate CO2 into chemicals, which can then be turned into a plastic. Such plastics can contain about 40 percent by weight of incorporated CO2.

CO2 is an excellent chemical building block; it is renewable, abundant and considered environmentally friendly. Plants efficiently convert CO2 into food through photosynthesis. Scientists, however, have long struggled to reproduce this process at an industrial scale. Before recent advances, the methods that existed were very inefficient, rendering them economically unviable.

Two research groups may have stumbled on a much more efficient method. Using chemicals called imidazoliums and N-heterocyclic carbenes (NHCs), researchers in Singapore report they were able to couple CO2 with molecules called “epoxides” to form polycarbonates – plastics used in everything from water bottles to compact disks. Importantly, in addition to finding a new use for carbon dioxide, these polycarbonates do not contain bisphenol A. It turns out that while virtually all commercial polycarbonate plastics today are made using bisphenol A as the basic building block, there are alternatives, as demonstrated by this research.

The imidazolium salts are stable chemicals that can repeatedly “grab” CO2 molecules and hand them over to be incorporated into bigger molecules. This makes them valuable in processes that convert CO2 to other chemical products as well. In addition, they are more benign and the reactions less severe than the metals typically used.

In sum, this research demonstrates two significant advances, first in demonstrably moving forward the capacity to harness and use CO2 in industrial applications, second in its successful application in developing a benign alternative to a problematic chemical.

© EnvironmentalHealthNews 2003-2004

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1 June Dream of plastics from carbon dioxide is a reality. Chemists have made progress in finding environmentally friendly ways to capture and reuse carbon dioxide. New advances have been made in the ability to absorb CO2 from the atmosphere and incorporate it into new raw materials – including benign alternatives to BPA-based plastics. Environmental Health News.

16 December How to make plastic with less petroleum–just add CO2. Using technology developed at Cornell University, Novomer gets additional funding to develop a plastic-manufacturing process that requires less oil by folding in carbon dioxide. Scientific American.

10 April New process converts C02 into plastic products. If plans to remove carbon dioxide–the primary greenhouse gas –from smokestacks succeed, the gas could be harnessed and turned into plastic products, new research claims. Xinhua News Agency, China.

9 April CDs and DVDs to be made with CO2 emissions. Scientists have devised a new way to enable pop groups and film stars with a conscience to save the planet: Their CDs and DVDs can now be made from carbon dioxide. London Daily Telegraph, United Kingdom.

6 May What can we do with carbon dioxide? Scientists are trying to find ways to convert the plentiful greenhouse gas into fuels and other value-added products, some saying that target areas should focus on using CO2 to replace large-volume starting materials derived from petroleum and natural gas. Chemical & Engineering News.

Thought-provoking story describes alternatives to bisphenol A.

Thought-provoking story describes alternatives to bisphenol A.

Posted by Evan Beach at Feb 27, 2010 09:30 AM | Environmental Health Sciences

A February 23rd article in the Washington Post provides a well researched overview of potential substitutes for bisphenol A (BPA) in food containers. It raises important issues about scientists’ state of knowledge about exposures to chemicals in packaging materials and the food supply.

BPA is widely used in food can linings, and exposures through canned food are thought to be related to the frequency with which BPA is detected in the urine of the US population.  This application of BPA has also proven to be one of the most difficult in terms of finding a substitute technology.  The Washington Post article provides an excellent summary of the properties needed for high performance steel can linings and industry efforts to replace BPA-containing materials.

One of the most striking parts of the story is the revelation that one food company that switched to BPA-free steel cans is still finding trace amounts of BPA in its products. The source of contamination remains unknown.  This adds to growing evidence that estrogenic chemicals are so widely used in manufacturing supply chains that it has become difficult to pinpoint how and where in the process they are able to migrate into food and drink. For example, a 2009 study found that bottled water showed estrogenic effects after it was stored in Tetra Pak liners.  It is still unclear whether this was a result of the packaging materials themselves or some other aspect of the manufacturing process.

These findings suggest that our problems will not be solved just by replacing BPA in food can linings.  As discussed in the Post article, BPA is used in thousands of consumer products, increasing the chances of cross-contamination.  What’s not mentioned, though, is that BPA is not the only estrogen mimic showing up in food.  The problem is more systematic, begging the question, will the potential alternatives discussed in the story be any safer?

It is very difficult for a chemist sketching new molecules in a notebook to predict whether those structures will lead to a toxic product or a safe product.  This has led to situations described by NIEHS director Linda Birnbaum as like “jumping from the fry pan into the fire” when it comes to substitutes, as she said in reference to alternative flame retardants.

A possible solution to this issue is greater cooperation between environmental health scientists and green chemists, who are seeking to better understand the connections between chemical properties and toxic endpoints.  Progress in this area would make it easier to recognize chemical hazards as a design flaw.

The Post article did a good job bringing up difficult issues regarding chemicals in the food supply, and provided a rare focus on the quest for replacements.  Other journalists could follow suit and begin asking more pointed questions that dig deeper into how chemicals can be made safer.

“Science versus theology: the bisphenol A debate continues” – Pumphandle blog entry by Sarah Vogel

View the original Pumphandle blog post here.

Science versus theology: the bisphenol A debate continues

March 2, 2010 in Environmental Health | by The Pump Handle

by Sarah Vogel

If you thought the scientific debate about bisphenol A was over or even quieting down, you haven’t been reading the latest issues of Toxicological Sciences. (What are you doing with your spare time?) Last month in an editorial piece published in the journal, Richard Sharpe queried: “Is It Time to End Concerns over the Estrogenic Effects of Bisphenol A?”  His answer was an unequivocal ‘yes’, based on the latest study from Ryan et al. (published in the same issue) that found no reproductive effects from bisphenol A exposure in rats.  The study, according to Sharpe, “throws cold water on this controversy.”

Not so fast.  On Wednesday, February 17, 2010, the journal published a second letter to the editors, “Flawed Experimental Design Reveals the Need for Guidelines Requiring Appropriate Positive Controls in Endocrine Disruption Research,” by Fred vom Saal and 23 other researchers.  In a position quite contrary to Sharpe’s, the letter pointed to an important design flaw in the study.

This latest iteration of the controversy is about a fundamental and persistent challenge in the research on bisphenol A and other endocrine disrupting chemicals—what is the appropriate study design.  Issues of animal selection, route of exposure, animal feed and housing, and appropriate use of positive controls all point to the complexity of studying extremely low levels of endocrine disruptors.

These are not trivial issues.  Proper study design is essential to conducting good science, and charges of inappropriate design have been used to discredit research findings of adverse effects of as well as no effects of bisphenol A at low-doses.

This most recent letter critical of the Ryan et al. paper points to a flaw in the selection of dosing levels for the positive control.  To understand the argument requires a basic understanding of a positive control.

Let’s start with a very different example recently shared with me.  Say you have an unknown substance in the garage that you think might be a fertilizer.  To test this hypothesis you take two dishes of seeds and treat one with water and the other with the unknown substance and see what happens.  When there is no growth in the seeds of either treatment, you could conclude that the substance isn’t a fertilizer.  But what if the seeds you had started with were already dead?  So, you decide that a better way to test the unknown substance is to take three dishes of seeds and treat one with water, one with the unknown substance and a third with Miracle-Gro. This way if the seeds grow with Miracle-Gro you know they’re alive and reactive to fertilizer.  And if the seeds grow with the unknown substance and the ones in the water don’t, you know it’s a fertilizer. In this example, Miracle-Gro is the positive control and water the negative control.

But what happens if it turns out that when testing your seeds, you find that you have to use 10 times the amount of Miracle-Gro that is recommended to make the seeds grow?  What if your unknown substance is a fertilizer, but over the years of sitting in your garage has become less potent?  Your seeds might grow if you were to use a ton of the substance but because you didn’t have that much you only tested a small amount.  So in your study you use water, a small concentration of your fertilizer and a ton of Miracle-Gro.  You find that only the seeds doused with Miracle-Gro response positively.  This could lead you to incorrectly conclude that the unknown substance is not a fertilizer.

How does this apply to the critique of the Ryan et al. paper?  In their study the researchers used a positive control, ethinylestradiol (EE), the hormone used in birth control.  However, they had to use extremely high doses to trigger the reproductive endpoints of interest (e.g. sexually dimorphic behavior, age at puberty, reproductive function).  They basically had to douse these rats with this estrogen to elicit a positive response—that is, to make the positive control work.  If they had used lower concentrations they would have observed no effects.  At the lowest concentration of EE used, 5 µg/mg, Ryan et al reported no effects in the animals.  The letter by vom Saal et al. noted that the pharmacologically effective dose of EE in oral contraceptives used in humans is less than 0.5 µg/mg.  So the rats used in Ryan et al.’s lab were not sensitive to levels of EE above the concentration used to avert pregnancy in women.

Given that it took such high concentrations of the positive control to elicit a positive effect, the researchers should have selected much high concentrations of BPA. This is because as demonstrated by the positive controls, the animals are insensitive to estrogen.

The details of this scientific debate can be confusing, particularly for the non-scientists.  But what it unsettling about Sharpe’s commentary is that he turned what should have been a scientific debate into a theological discussion.  Sharpe used the recent findings by Ryan et al. to paint a simplistic picture of the bisphenol A debate as a struggle between rational facts observed by scientists and exemplified in the Ryan et al. article, and “believers” of false hypotheses propagated by “nonscientific” media, blogs and website. According to Sharpe, these “believers” argue that bisphenol A has estrogenic effects at low doses, whereas scientists prove otherwise.

Simplifying a complex scientific debate using theological arguments ironically achieves the exact opposite intent of Sharpe’s editorial.  Rather than pulling this debate out of the mire, Sharpe drags it back in, and in the process, pulls it away from the rich scientific debate that needs to occur, particularly in the pages of scientific journals.

It is a credit to the 24 bisphenol A researchers that they did not take offense to this characterization of their work and careers.  They chose to stick to the scientific aspects of the debate and provide recommendations for appropriate use of positive controls.

In publishing the recent letter to the editor, Toxicological Sciences pushes scientific progress forward one small step by encouraging healthy and constructive skepticism and scientific debate.  Now we must wait for the next installment: a response from Ryan et al.

Sarah Vogel received her PhD from  Columbia University in the Department of Sociomedical Sciences’ Center for the History and Ethics of Public Health and Medicine; her dissertation was entitled “Politics of Plastic: the economic, political and scientific history of bisphenol A.” She holds master’s degrees in public health and environmental management from Yale University. She authored the case study “Battles Over Bisphenol A” at DefendingScience.org.