Tributyltin exposure promotes obesity in following mice generations

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.

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.  

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.