Organotins

The Details

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. TBT also affects other hormone receptors, such as RXR (Shoucri et al. 2018) and the thyroid (Santos-Silva et al. 2018). In fact, many mechanisms may play a role in the promotion of obesity by organotins (Tinkov et al. 2019). In part due to their ability to induce obesity, organotins are considered an endocrine disruptor (Marques et al. 2018).

TBT has other related effects as well. TBT 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). TBT also affects the gut microbiome in mice, in conjunction with weight gain, visceral fat accumulation, and worse cholesterol levels (Guo et al. 2018). TBT also appears to interfere with areas of the brain that control food intake (Farinetti et al. 2018). In adult mice, chronic long term exposure to TBT, BPA, and DES altered the hypothalamic circuits that control food intake and energy metabolism (Marraudino et al. 2021).

Rats exposed to TBT and a high-carb diet had increased weight gain, abnormal triglyceride and glucose levels, and reproductive disorders (Zanol et al. 2021). Also in rats, TBT injured the liver and affected cholesterol and triglyceride levels (Ren et al. 2023).

In adult male rats, low dose chronic TBT exposure lowered body temperature and increased fat accumulation in brown fatty tissue via inflammation and oxidative stress (Merlo et al. 2023).

The gut microbiota are involved in the effects of TBT. In mice, TBT exposure significantly increased body weight, affected cholesterol, glucose, and insulin levels, and changed gut microbiota composition. Untreated mice that received gut microbiota from the TBT-treated mice had similar changes as the donor mice, including significant body weight, and changes to glucose and insulin levels (Zhan et al. 2020). TBT caused impaired gut barrier function, inflammation, oxidative stress, and affected the gut microbiota in mice (Chen et al. 2024).

Stem cells in bone marrow can develop into fat cells or bone cells. Exposure to TBT causes them to favor the development into fat cells instead of bone cells, and leads to lower bone density in lab rats (Yao et al. 2019).

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). Tributyltin has metabolic effects even in tiny little microscopic aquatic organisms (Lee et al. 2019), as well as in fish, molluscs, arthropods, rotifers, and echinoderms (Capitão et al. 2020; Chen et al. 2021).

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). Other fish also show effects from TBT, effects that include increased lipids, total cholesterol, and triglycerides, as well as oxidative stress (Zhang et al. 2017). 

Chemicals in combination

TBT may interact with other chemicals to increase its obesogenic effects. In fish, separate exposure to TBT or the perfluoroalkyl substance PFOS elevated fatty tissues areas at low doses, but not at the highest doses. Combined exposure significantly promoted fat accumulation in newly hatched larvae, even when the doses of TBT and PFOS were both at the levels that did not show obesogenic effects (Qui et al. 2018).

Of eight organotins, three affected the differentiation of fat cells, especially TBT. In combination, DBT and TPT interfered with TBT's effects on fat cell differentiation (Ticiani et al. 2023). 

Chemicals (TBT and pesticides) that activate different receptors (CAR and RXR) can act synergistically in animals (as is seen in vitro) to increase cholesterol/triglyceride levels (Dauwe et al. 2023). 

Cell Studies

Pancreatic Islets

TBT affected oxidative stress levels, insulin secretion, cell death, and cell viability in pancreatic islets (Ghaemmaleki et al. 2020).

TMT increased blood glucose levels in mice, and impaired beta cell function (Zhang et al. 2023).  

Fat Cells

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; Shoucri et al. 2017). TBT also does not seem to show the same health-promoting effects as some pharmaceuticals that also bind with PPARγ receptors (Kim et al. 2018).

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 cells, but to different extents. The organotins were the most effective in suppressing bone formation (Watt and Schlezinger 2015). Dibutyltin compounds also promote fat formation via PPARγ (Milton et al. 2017).

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).

Other Cells

TBT increases fat (lipid) levels in human liver cells (Stossi et al. 2019). 

TBT affects the glucose metabolism of Sertoli cells, which play an important role in male fertility (Cardoso et al. 2018).

TBT also affects immune system cells (Jie et al. 2020).

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 BPA. The found that all of these had the potential to promote obesity (Pereira-Fernandes et al. 2013b).

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). Tools using zebrafish can also show the obesogenic effects of TBT, diet, and other chemicals during development (den Broeder et al. 2017). Fish liver cells can also be used to screen obesogens like TBT (Marqueño et al. 2020).

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), even at low doses (Huang et al. 2018). 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).

Another found that TBT-treated mice had higher fasting blood glucose and insulin levels, glucose intolerance, lower glucagon levels, and less pancreatic beta cell mass (Xu et al. 2019). 

In a cell study, 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 in vitro studies of cells have found that TBT and DBT can affect the secretion of cytokines (linked to inflammation) from human immune cells (Brown and Whalen 2015; Lawrence et al. 2015). 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. 2017).

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 islets 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. 2012, Miura and Matsui, 2006; Miura et al. 1997).

TBT can also affect pancreatic alpha cells (Dos Santos et al. 2022).

Triorganotins may also be able to affect vitamin D receptors in the lab (Toporova et al. 2018); vitamin D levels are linked to type 1 diabetes development (see the Vitamin D Deficiency page).

Diabetes Complications and Control

Organotins can affects the kidney (reviewed by Barbosa et al. 2018), which could be significant for people with diabetes.