A widely-used, understudied chemical alters inflammation.

Dec 12, 2008

Gumy C, C Chandsawangbhuwana, AA Dzyakanchuk, DV Kratschmar, ME Baker and A Odermatt. 2008. Dibutyltin Disrupts Glucocorticoid Receptor Function and Impairs Glucocorticoid-Induced Suppression of Cytokine Production. PLoS ONE doi:10.1371/journal.pone.0003545.



Synopsis by Jennifer Adibi and Wendy Hessler


cells in lab dish
kaibara87/ Flickr.
Cultured cells in a laboratory.

 

Dibutyltin, an understudied chemical used widely in PVC plastics, can interfere with the natural ability of human and animals cells to control important immune responses and inflammation.

The results may help understand why asthma and allergies are increasing in people.

 

 

 

Context

Organotins are a class of widely used, yet understudied industrial chemicals. The synthetic compounds are used in manufacturing to stabilize polyvinyl chloride (PVC) plastics and in wood preservatives and antifouling paints to kill pests. The molecules consist of a tin unit with either one (mono), two (di), three (tri) or four (tetra) attached hydrocarbon groups.

 DBT is  used to heat seal PVC plastics. This use means it is found widely in plastic products, including pipes and bottles.

Humans are exposed to DBT through PVC pipes that distribute drinking water and possibly, by eating contaminated fish. Unfortunately, no studies have been published to date that attempt to determine what levels are in people or what sources of exposure might be.

Very little is known about the health and environmental effects of DBT and many of the other organometals. It is known they can harm the liver, nerves and the immune system in mammals. Studies that have been published indicate that this class of chemicals is likely to produce harmful and irreversible effects on the developing fetus.

A chemical cousin of DBT, tributyltin (TBT) is a well-studied endocrine disruptor. For example, pregnant mice given a single low-dose of TBT during pregnancy was sufficient to cause obesity in the offspring (Grün F et al. 2006). TBT can interfere with the earliest stages of programming of fat cells causing the offspring to be predisposed to obesity. TBT is also a proven hormone disruptor that causes female snails and other marine mollusks to develop a penis.

Less is known about DBT's effects, but it more strongly affects the immune system than TBT. It is not understood how the chemical causes these effects.

Cortisol and other natural glucocorticoid hormones are made and released from the adrenal glands that sit atop each kidney. They aid in the conversion of carbohydrates, fats and proteins for energy (called metabolism). Stress activates the hormones, which help maintain blood pressure and insulin levels.

The glucocorticoid receptor is present throughout the body. It plays a critical role in mediating the response to stress and injury. Glucocorticoids are important during pregnancy for protecting the fetus from high levels of the mother’s stress hormones.

These steroid hormones also help control immune system responses and the accompanying inflammation. An overactive immune system contributes to many chronic health problems, such as allergies and arthritis. Physicians prescribe glucocorticoid drugs to treat dermititis, arthritis, asthma and other immune-based conditions. Rates of allergies and asthma have been rising in the last two decades. 

What did they do?

A international team of researchers used human and nonhuman cells to determine the effects of dibutyltin (DBT) on the immune system. They were particularly interested in the chemical's influence on the glucocorticoid hormone receptor. Using a systematic approach, the scientists from the University of California at San Diego and the University of Basel in Switzerland ran a series of related experiments to decipher if and how DBT might interfere with glucocorticoid hormones and the immune system.

First, they tested whether the chemical was able to block hormones from binding glucocorticoid receptors and interacting with DNA. A followup test determined exactly where the chemical interfered with the process. Using three-dimensional computer technology that accounts for the complex folding of the receptor protein and the atomic structure of DBT, they simulated how the DBT molecule could lodge itself into a specific pocket within the glucocorticoid receptor.

To test how this interaction affects physiology, they measured the ability of DBT to alter the expression of two liver enzymes called phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine-aminotransferase (TAT). The two enzymes are essential to normal sugar and fat metabolism. The production of these enzymes is normally controlled by the hormone cortisol binding with the glucocorticoid receptor. 

Since DBT is known to affect the immune system, they tested DBT's ability to alter production of cytokines in special immune cells called macrophages. The researchers dissected the relationship even further by looking at the effect of DBT on the expression of nuclear factor kappa beta (NFκB), a key molecule in the immune response.


What did they find?

The results of these extensive experiments shows that DBT is toxic to immune cells at very low (nanomolar) concentrations similar to what have been measured in human blood. Using human and non-human cells, the authors determined that DBT is able to compete with the body’s natural hormone cortisol to block the action of the glucocorticoid receptor (GR).

Specifically, the authors showed with high confidence that DBT can bind to the glucocorticoid receptor and block cortisol from binding to it. Consequently, DBT can affect other important cell processes that are controlled by the binding. In these experiments, DBT inhibited the expression of genes involved in sugar and fat metabolism and in the inflammation response.

DBT dramatically blocked the normal anti-inflammatory effects of cortisol. Instead of inhibiting the release of cytokines, which can prevent excessive swelling, macrophage cells exposed to increasing amounts of DBT secreted increasing concentrations of two cytokines (IL-6 and TNF alpha). DBT, by itself, did not have an effect. The effect was seen only when the cells were given a combination of DBT and a synthetic version of cortisol called dexamethasone.

What does it mean?

This is one of a few studies to offer insight into the potential harmful effects of dibutyl tin and the class of chemicals called organotins. The results are significant in that researchers employed a rigorous panel of experiments to test the hypothesis that dibutyl tin can interfere with the body’s normal response to inflammation. Their results showed convincingly that DBT is potentially toxic to the human immune system.

Normally cortisol and similar hormones play an important role in the resolving inflammatory reactions. The glucocorticoid receptor is expressed throughout the body. If the actions of these hormones are indeed being blocked, it is plausible that inflammatory reactions can go unchecked and can result in chronic conditions such as allergies and asthma.

This study was conducted entirely with isolated cells cultured in a plastic dish in the laboratory (called in vitro). Before these findings can be translated to human health, similar experiments need to be done in whole animals. Biologic markers can be measured in humans and related to DBT exposure to confirm the relevance of these findings to human health.

The authors point out that even though TBT and DBT are both organotins, they differed in their biologic actions. TBT has been named an “environmental obesogen” because it can effectively and reproducibly produce obesity in rat pups when given during pregnancy. The effect can be explained partly by TBT's interaction with a receptor in a cell's nucleus, called the peroxisome proliferator activated receptor subtype gamma (PPAR gamma).

DBT does not interact with PPAR gamma, and therefore does not produce the same effects as TBT. In a similar vein, TBT and other organotins tested in this study did not block the glucocorticoid receptor as DBT did. However, TBT and DBT share a common structure, and in some cases, common sources. Given these similarities and yet difference in function, it is not yet clear if these chemicals should be treated as separate and distinct or if they should be considered as a common class of environmental pollutants.

Based on this and previous studies, there is growing concern that organotins may be causing irreversible effects on the metabolic and immune systems. If these compounds influence the developing fetus, the effects can lead to obesity, asthma and other metabolic and immune disorders.

The results and possible human health consequences are of concern given the widespread use of DBT and other organotin compounds. It is essential that studies are done to determine at what level humans are exposed to this chemical and how it might be adversely affecting human health.


Resources

 

Grün F and B Blumberg. 2007. Perturbed nuclear receptor signaling by environmental obesogens as emerging factors in the obesity crisis. Endocrinology. 147 (6 Suppl): S50-5.

Grün F, H Watanabe, Z Zamanian, L Maeda, K Arima, R Cubacha, DM Gardiner, J Kanno, T Iguchi and B Blumberg. 2006. Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. Molecular Endocrinology 20:2141-55.

 

 

 

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