Tributyltin promotes obesity in mice generations

According to a study by researchers from the University of California, Irvine, prenatal exposure to tributyltin (TBT) may promote obesity in mice generations after the exposure by permanently altering how fat and liver cells develop, mature and store fat. The mice had more fat deposits in tissues and livers, more and bigger fat cells, and more liver disease than unexposed mice. The authors believe the changes were passed on to future generations through epigenetic programming, although the researchers did not measure such changes in this study. 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 exposure to certain environmental chemicals while in the womb may permanently change the regulation of fat cells and liver function and lead to weight gain. TBT is a persistent pollutant best known as an antifouling agent used in the paints applied to ships to keep hulls free of barnacles and other marine organisms. Because of toxic effects on oysters, snails and other marine life, an international convention has restricted its use by member countries. 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 food supply. People can be exposed at work and through contaminated food and water. Obesity is so widespread it is considered a global health epidemic. The World Health Organization estimates obesity has doubled worldwide since 1980 and affects 40 million children younger than 5. Obesity is a major health issue because it is related to other serious illnesses such as metabolic disease, diabetes and cardiovascular disease. Why obesity rates have climbed quickly in just a couple of generations is not clear. Experts point to personal habits (overeating, lack of exercise), genetics and even environmental chemicals – called obesogens – as possible factors. Obesogens can promote obesity by increasing fat cell size or fat cell number, by altering metabolism or by interfering with appetite and satiety. Prior studies by the same group of Irvine researchers show TBT can act as an environmental obesogen, altering epigenetic instructions that push stem cells to become fat cells. This study takes those findings a step further by showing those and other cell changes persist from generation to generation. The authors suggest these developmental changes could explain some of the population-wide increases in obesity that has occurred in a relatively short amount of time. In this study, pregnant mice drank water spiked with one of three doses of TBT throughout their pregnancies. The lowest dose was five times below the level of TBT measured in human blood, the middle dose was about half of the human detected level and the highest dose was 20 times higher. The children of the pregnant mice were bred and had the grandchildren, which were bred, and produced the great-grandchildren. The first generation children were directly exposed to TBT during their development. The grandchildren were 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 the adult children, grandchildren and great-grandchildren, the researchers analysed 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 three doses, 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. More research is needed to verify these results. The researchers have taken important first steps to understand the mechanism of how TBT can increase the risk for obesity and non-alcoholic fatty liver disease in mice. But further studies of its effects in people are needed to confirm these findings.