Dr. Blumberg and his laboratory proposed the environmental “obesogen” hypothesis which holds that prenatal exposure to endocrine disrupting chemicals (EDCs) contributes to the burgeoning obesity epidemic. Obesity and obesity-related disorders such as type 2 diabetes and coronary artery disease have become a global problem; although, it is most severe in the U.S. Excessive consumption of calorie-dense food and diminished physical activity (the thermodynamic or “Couch Potato model”) are the generally accepted causal factors for obesity. They showed that certain EDCs could activate the nuclear hormone receptor, PPARγ and promote the development of fat cells. The Blumberg laboratory showed that chemical obesogens such as tributyltin (TBT) can perturb lipid homeostasis, adipocyte development, adipose tissue function and predispose exposed individuals to obesity. TBT binds very strongly (nanomolar affinity) and activates the nuclear receptors RXR and PPARγ which form a heterodimer and act as key regulators of fat cell development and lipid storage. TBT exposure promotes the development of fat cells in culture and prenatal exposure to TBT leads to increased fat storage early in life and significant increases in the amount of body fat later in life in animals fed a normal diet. Therefore, prenatal organotin exposure causes permanent physiological changes that predispose exposed individuals to obesity.
Dr. Blumberg and his colleagues made a major breakthrough in 2010 when they found that prenatal TBT exposure caused a permanent, epigenetic change in the multipotent stromal stem cell (MSC) compartment that predisposed MSCs to become adipocytes, at the expense of bone. They found that the obesogenic effects of TBT require PPARγ action, but that the commitment of MSCs to the adipocyte lineage required action of RXR. RXR activation by TBT or specific RXR activators lead to a genome-wide de-repression of genes important for adipogenic commitment which primed the cells to differentiate into adipocytes when PPARγ activators are present.
Perhaps the most important and exciting aspect of the work on obesogens was the finding published in 2013 that revealed the effects of prenatal TBT exposure are permanent and transgenerational. Exposure of pregnant F0 dams to environmentally relevant (nanomolar) levels of TBT via their drinking water leads to increases in adipose depot weight, adipocyte size, adipocyte number and the propensity of MSCs to differentiate along the adipogenic rather than the osteogenic pathways in F1, F2 and F3 offspring. Transgenerational increases in obesity have subsequently been reported with different chemicals in other laboratories, thus Dr. Blumberg and his colleagues established an important new paradigm in the field. More recently, Dr. Blumberg and his colleagues repeated the obesogen study and showed that the effects if early life obesogen exposure persist until at least the F4 generation. Put in human terms, the great-great-grandsons of the exposed mom still exhibited the effects of TBT exposure. Notably, these F4 male mice gained more fat than did control animals on a normal diet and rapidly became obese when dietary fat was increased. Moreover, they retained this increased fat even when switched back to a normal diet and did not lose this fat when fasted. Intriguingly, Dr. Blumberg and colleagues found that the effects of obesogen exposure are likely carried across the generations by large-scale changes in the structure and accessibility of chromatin. This is an exciting new paradigm for the field of transgenerational inheritance.
In addition to TBT, the Blumberg laboratory identified other chemicals as obesogens (triflumizole, dibutyltin) in animals. They showed that numerous other chemicals, many of which are fungicides can commit MSCs to the adipocyte lineage or cause them to differentiate into adipocytes in culture – these make the chemicals candidate obesogens that are likely to be bona fide obesogens, in vivo. This group of chemicals includes the commonly used fungicides zoxamide, quinoxyfen, fludioxonil, and flusilazole as well as the pesticides spirodiclofen, tebupirimfos, acetamiprid and pymetrozine the plant growth regulator forchlorfenuron, and the industrial chemical BADGE. Considering that there has been no systematic effort to identify candidate obesogens (or EDCs for that matter), this list is quite likely to increase in the future.
Work in the Blumberg laboratory and that of colleagues elsewhere has opened an entirely new field of inquiry in obesity research. Many laboratories around the world are now studying obesogens and it is likely that understanding the role of these environmental obesogens in regulating fat cell development will provide important insights into a novel contributing factor for obesity. The growing importance and acceptance of obesogen research was confirmed in a report issued by the White House Task Force on childhood obesity convened by then First Lady, Michelle Obama, highlighting obesogens as a priority area for future research.