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Organotins

Organotins and diabetes/obesity
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Organotins include chemicals like tributyltin (TBT), a wood preservative and marine anti-fouling paint and fungicide, now banned (in part due to their ability to turn female snails into males, but that's another story). Dibutyltin (DBT) is used as a stabilizer in PVC plastic and a metabolite of TBT. Human exposure may result from dietary sources (e.g., seafood) or contaminated drinking water (Graceli et al. 2013), as well as house dust (Kannan et al. 2010).

TBT is considered an obesogen, a chemical that can promote obesity by increasing the number of fat cells, the storage of fat in existing fat cells, changing the metabolic rate, altering hormonal control of appetite or satiety, or shifting energy balance to favor the storage of calories (Graceli et al. 2013), in other words, an obesogen can either directly or indirectly lead to increased fat accumulation and obesity (Janesick and Blumberg, 2012).

In 2006, Dr. Felix Grün and Dr. Bruce Blumberg first proposed the "obesogen hypothesis," stating that "inappropriate receptor activation by organotins will lead directly to adipocyte [fat cell] differentiation and a predisposition to obesity and/or will sensitize exposed individuals to obesity and related metabolic disorders under the influence of the typical high-calorie, high-fat Western diet" (Grün and Blumberg, 2006). Their hypothesis has since been supported by many of the studies described below, and applied to other chemicals as well.

The obesogenic effects of TBT are thought to be due largely to its ability to bind with hormone receptors called PPARγ (peroxisome proliferator-activated receptor gamma), receptors that play important roles in adipogenesis (the maturation of pre-fat cells into fat cells), fat storage, and glucose metabolism.

Body Weight and Insulin Resistance

Human Studies

There are very few studies of organotins in humans. One small Finnish study found that levels of organotins in the placenta were associated with increased weight gain during the first three months of life, although not after that (Rantakokko et al. 2014). Exposure levels were lower in these babies than in the animal studies described below.

Animal Studies

What are obesogens?

"Obesogens are chemicals that directly or indirectly lead to increased fat accumulation and obesity."

- Janesick and Blumberg, 2012.
An early study found that TBT caused effects in male mice, after 24 hours of exposure, that promoted fat cell development (Grün et al. 2006). Additional studies have shown that exposure to low doses of TBT (comparable to estimated human intake) promotes fat formation in adult mice of both genders (Penza et al. 2011).

Male mice exposed to low doses of TBT after puberty for 45 days show excess weight gain, high insulin levels, and fatty liver. These finding suggest that TBT exposure may lead to obesity, insulin resistance, and fatty liver disease over time (Zuo et al. 2011).

Rats exposed to TBT had higher cholesterol and triglyceride levels. Males had higher body weight and fat mass, while females ate more food (He et al. 2014). A different study found that rats exposed to TBT developed higher body weights and higher glucose, insulin, and adiponectin levels, and lower glucagon levels. After the exposure was removed, the animals recovered, except they had lower glucagon and adiponectin levels than controls (Li et al. 2017).

TBT also affects the hypothalamic-pituitary-gonadal axis in rats, in conjunction with higher weight gain, abnormal glucose tolerance and insulin sensitivity, and high insulin and leptin levels (Sena et al. 2017).

In fact, TBT is an obesogen even in non-vertebrate species, including one crustacean (Jordão et al. 2015). For an article on this study, see A Closer Look at Obesogens: Lipid Homeostasis Disruption in Daphnia, published in Environmental Health Perspectives (Konkel 2015). TBT also disrupts metabolism and alters body weight in zebrafish, an animal model used to text toxic chemicals (Lyssimachou et al. 2015). In fact, within hours, zebrafish larvae exposed to very low levels of TBT show a remarkable increase in fat tissue (Ouadah-Boussouf and Babin, 2016).

Exposure During Development

Evidence is growing that exposure to pollution during critical developmental periods, such as in utero or during childhood, may have effects later in life.

Prenatal exposure to obesogenic endocrine disrupting chemicals such as TBT can predispose an organism to store more fat from the beginning of its life. One way these chemicals do this is via epigenetic changes that predispose exposed individuals to subsequent weight gain and obesity. The laboratory evidence suggests that humans exposed to obesogenic chemicals during development might be susceptible to storing increased amounts of fat, resulting in a lifelong struggle to maintain a healthy weight and exacerbating the effects of poor diet and inadequate exercise (Janesick and Blumberg, 2012).

When pregnant mice were injected with TBT, their offspring already showed effects at birth, including excess fat in the liver and higher fat accumulation. At 10 weeks of age, male offspring had more fat mass (although total body weight was not different) from controls. Tadpoles treated during development also showed higher fat cell formation in certain areas(Grün et al. 2006).

Stem cells from mice exposed to TBT in the womb showed increased capacity to develop into fat cells (instead of bone cells) and accumulated more fat than untreated controls. This effect could cause weight gain over time (Kirchner et al. 2010). Other studies have also found that cells exposed to TBT fail to develop into bone cells-- TBT acts similarly to the pharmaceutical drug rosiglitazone (Avandia) (used to treat type 2 diabetes) which increases the risk of bone fractures and weight gain (Baker et al. 2015).  
Dr. Bruce Blumberg

Dr. Bruce Blumberg coined the term "obesogen." He directs a lab at UC Irvine where he studies how TBT affects the development and function of fatty tissue.

Transgenerational Effects

When Dr. Blumberg exposed pregnant mice to very low doses of TBT, and fed them a regular diet (not a high-fat diet), their offspring had more fat cells, larger fat cells, and more fatty tissue than unexposed controls. Their stem cells were reprogrammed to develop into fat cells instead of bone cells. They had more fat in their liver, and the genes that controlled fat production and the burning of fat were affected as well via changes in gene expression. These effects were present in the children, grandchildren, and great-grandchildren of the exposed mice-- into the third generation (Chamorro-García et al. 2013).

For two articles describing this important study, see Tributyltin promotes obesity in mice generations, published by Environmental Health News, and An obesogen over time: transgenerational impact of tributyltin, published by Environmental Health Perspectives (Nicole 2013).

Dr. Blumberg notes that these transgenerational effects make regulation of endocrine disrupting compounds even more important. The effects are not only long lasting but potentially permanent (Chamorro-García and Blumberg, 2014).

Cell Culture Studies

In mouse pre-fat cells, TBT increased the number of fat cells that matured by about 7-fold, as compared to untreated controls (Grün et al. 2006). TBT causes stem cells taken from human and mouse fatty tissue to develop into more fat cells, and absorb more fat than untreated controls (Kirchner et al. 2010).

Researchers used cell and gene expression tools to identify the mechanisms involved in TBT's ability to promote obesity, showing effects of gene expression and PPARγ signalling pathways (Pereria-Fernandes et al. 2013a). We have known for a long time that organotins activate the PPARγ receptor and thereby promote fat cell development (Kanayama et al. 2005). It turns out that the fat cells that are induced by TBT are functionally different and more dysfunctional than other fat cells (Regnier et al. 2015). There are also additional mechanisms taking place that do not involve PPARγ, depending on when the cells were exposed. In any case, whatever mechanisms are involved, the bottom line is that TBT turns stem cells into fat cells (Biemann et al. 2014a).

Other chemicals also activate PPARγ, including the organotins tributyltin and triphenyltin, a phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). A study showed that all of these increased fat accumulation and suppressed bone formation in mouse bone marrow cell cultures, but to different extents. The organotins were the most effective in suppressing bone formation (Watt and Schlezinger 2015).

A mixture of organotins, phthalates, and BPA increased the development of fat cells from stem cells-- the effects of organotins and phthalates were more important than that of BPA (Biemann et al. 2014b).

Screening Obesogens

Based on the above studies, TBT is now seen as a "model obesogen," a chemical that can predispose to weight gain. Using TBT and the diabetes drug rosiglitazone, researchers are developing screening tools that could be used to identify other obesogens. The screening model involves evaluating a chemical's ability to affect gene expression in fat cells and influence PPARγ signalling. Using this model, the researchers tested a variety of chemicals used in personal and household care products, including parabens, musks, phthalates, and bisphenol A (BPA). The found that all of these had the potential to promote obesity (Pereira-Fernandes et al. 2013b).

The Obesogen Hypothesis


Watch Dr. Bruce Blumberg explain his findings on how TBT promotes obesity:

Transgenerational Inheritance of Prenatal Obesogen Exposure

Courtesy of the Michigan Green Chemistry Clearinghouse YouTube Channel

Courtesy of Advancing Green Chemistry, Environmental Health Sciences, and UC Irvine.


Another screening model uses tadpoles to screen chemicals for PPARγ signalling effects. These screens could be used for pharmaceutical drugs as well as chemicals, to see how they affect PPARγ receptors (Punzon et al. 2013).

Diabetes, Types 1 and 2

In the laboratory, mice chronically exposed to TBT experienced beta cell death, lower insulin levels, and high blood glucose levels (Zuo et al. 2014). While this is not an autoimmune attack, the results look a lot like type 1 diabetes to me-- beta cell death and high blood sugar.

Another animal study shows that TBT causes insulin resistance, increased insulin and glucose levels, and glucose intolerance, which sounds a lot like type 2 diabetes. The same study also found that TBT affected beta cells by increasing insulin secretion (which is the opposite effect of what some other studies have found-- perhaps it depends on dose, route of exposure, age, sex, any number of things are possible) (Chen et al. 2017).

In a cell culture study, dibutyltin (DBT) was found to block glucocorticoid receptors and thereby may have the potential to disturb both the metabolic system (e.g., type 2 diabetes) as well as the immune system (e.g., type 1 diabetes) (Gumy et al. 2008). Other cell culture studies have found that TBT and DBT can affect the secretion of cytokines (linked to inflammation) from human immune cells (Brown and Whalen 2014Lawrence et al. 2013). TBT also increases oxidative stress in conjunction with having immune system effects in zebrafish, an animal model used to identify the effects of toxic chemcials (Zhang et al. 2016).

A review of these and other studies of TBT's effects on the immune system effects concludes that the immune system may be a target of TBT, especially during development (Graceli et al. 2013). 

Curiously, a study of female rats found that while TBT increased weight gain, liver inflammation, and fat accumulation, it also resulted in increased glucose tolerance and insulin sensitivity, along with more pancreatic islet cells and higher insulin levels (Bertuloso et al. 2015). What this means for type 2 diabetes is unclear to me.

Another organotin, triphenyltin chloride (TPT), can damage the function beta cells of hamsters transiently, but does not cause more serious damage (Ogino et al. 1996). Instead, it inhibits insulin secretion (Miura et al. 2012Miura and Matsui, 2006; Miura et al. 1997).

References

To download or see a list of all the references cited on this page, see the collection Organotins and diabetes/obesity in PubMed.