Prenatal exposure to the pesticide tributyltin increased obesity in mice for several generations by permanently changing how fat cells develop, mature and store fat, according to a new study. The children, grandchildren and great-grandchildren of pregnant mice exposed to the chemical in their diet had bigger fat cells, more fat deposits and the start of liver disease.
Organotin compounds (OTs) are very effective biocides. Tributyltin (TBT) is a highly persistent pollutant best known as an antifouling agent. Anti-fouling paints are used to coat the bottoms of boat and ship vessels to prevent sea life such as algae and mollusks from attaching themselves to the hull, which would slow the ship and increase fuel consumption.The new study
Unfortunately OTs are also very toxic to aquatic organisms such as mollusks (oysters, mussels, snails, etc.) acting as endocrine disruptors. Because of its toxic effects resulting in "imposex", an international convention has restricted its use by member countries. However, TBT is still used to kill fungus or other microbes in some building materials, wood coatings, textiles and other products.
TBT is absorbed into fat and passes up the food chain where it can get into the human food supply. People can be exposed at work and through contaminated food and water.
In this study from the University of California, Irvine, pregnant mice drank water spiked with one of three concentration levels of TBT throughout their pregnancies. The chosen concentration levels deliver approximately 50-fold lower, 5-fold lower, and 2-fold higher doses, respectively, compared with the established no observable adverse effect level (NOAEL) of 25 µg/kg/day.
The children of the pregnant mice were bred and had the grand-children, which were bred, and produced the great-grandchildren. While the first generation was directly exposed to TBT during development, the second generation was exposed as germ cells – the egg and sperm that were developing in their parents when they were exposed in the womb. The original study
Changes in the grandchildren are considered multigenerational effects and may not be inherited. The great-grandchildren, however, were never exposed to TBT. Effects in these mice indicate the changes are permanent and inherited across multiple generations.
In all three generations of mice, the researchers analyzed the number and size of fat deposits and the number and size of fat cells in fat tissue. They measured gene expression and fat accumulation that might indicate non-alcoholic fatty liver disease. They also examined effects on developing stem cells. All three generations of TBT-exposed lineages were compared to the respective generation of control mice.
In each generation and at all TBT concentration levels, the number and size of white fat cells increased and more white fat deposits were found in TBT mice. Males were more affected than females. Surprisingly, the great grandchildren had the largest increases in white fat deposits.
TBT-mouse livers at all doses/generations had more fat deposits and gene markers related to non-alcoholic fatty liver disease. Females tended to have stronger changes in their livers than the males. Non-alcoholic fatty liver disease threatens health because it is associated with diabetes and cardiovascular disease.
Finally, the researchers report that more stem cells developed into fat cells, even at the expense of developing bone cells. This suggests that exposure to TBT can reprogram developing cells to become fat cells. The authors believe that such changes were passed on to future generations through epigenetic programming, although such effects were not studied in more detail.
This is the first study that shows changes to fat cells brought on by prenatal exposure to TBT persist, influencing obesity and liver disease for at least three generations. The findings suggest that prenatal exposure to certain environmental chemicals may permanently change the regulation of fat cells and liver function and lead to weight gain. The authors suggest these developmental changes could explain some of the population-wide increases in obesity that have occurred in a relatively short amount of time.
R. Chamorro-García, M. Sahu, R.J. Abbey, J. Laude, N. Pham, B. Blumberg, Transgenerational inheritance of increased fat depot size, stem cell reprogramming and hepatic steatosis elicited by prenatal obesogen tributyltin in mice
, Environ. Health Perspect., 121 (2013) 359-366. doi: 10.1289/ehp.1205701. Related studies:
X. Li, J. Ycaza, B. Blumberg, The environmental obesogen tributyltin chloride acts via peroxisome proliferator activated receptor gamma to induce adipogenesis in murine 3T3-L1 preadipocytes
, J. Steroid Biochem. Mol. Biol., 127 (2011) 9–15. doi: 10.1016/j.jsbmb.2011.03.012
Zhenghong Zuo, Shuzhen Chen, Tian Wu, Jiliang Zhang, Ying Su, Yixin Chen, Chonggang Wang, Tributyltin causes obesity and hepatic steatosis in male mice
, Environ. Toxicol., 26/1 (2011) 79–85. DOI: 10.1002/tox.20531
S. Kirchner, T. Kieu, C. Chow, S. Casey, B. Blumberg, Prenatal exposure to the environmental obesogen tributyltin predisposes multipotent stem cells to become adipocytes
, Mol. Endocrinol. 24 (2010) 526–539. DOI: 10.1210/me.2009-0261
F. Grün, H. Watanabe, Z. Zamanian, L. Maeda, K. Arima, R. Cubacha, D.M. Gardiner, J. Kanno, T. Iguchi, D. Blumberg, Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates
, Mol. Endocrinol. 20 (2006) 2141–2155. DOI: 10.1210/me.2005-0367
T. Kanayama, N. Kobayashi, S. Mamiya, T. Nakanishi, J. Nishikawa, Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator-activated receptor
gamma/retinoid X receptor pathway
, Mol. Pharmacol., 67 (2005) 766–774. doi: 10.1124/mol.104.008409
K. Kannan, K. Senthilkumar, J.P. Giesy, Occurrence of butyltin compounds in human blood
, Environ. Sci. Technol., 33 (1999) 1776–1779. DOI: 10.1021/es990011w Related EVISA Resources
EVISA Link Database: Industrial use of organotin compounds
EVISA Link Database: Toxicity of organotin compounds
EVISA Link Database: All about organotin compounds
Related EVISA News June 5, 2009: EU bans certain organotin compounds
November 12, 2008: Mechanism of immuno toxicity of dibutyltin clarified
November 5, 2008: Tributyltin added to U.N. trade watch list
September 18, 2008: Tributyltin canned
June 21, 2008: TBT and other Persistent Man-Made Chemical Pollutants Found in Deep-Sea Octopods and Squids
June 5, 2008: Organotin ban in hull paint begins in September
April 30,2008 Human exposure to organotin compounds via consumption of fish
September 20, 2007: TBT-ban convention ratified October 11, 2006: TBT from antifouling paint is still endangering marine life, says WWF November 11, 2004: Source for butyltin compounds in wine
December 11, 2003: No degradation of TBT in seafood during cooking
last time modified: March 25, 2013