In yet another indictment of endocrine-disrupting chemicals, researchers have found a mechanism through which tributyltin (TBT) causes obesity and alters adipose lineage, according to an article recently published in Endocrinology.
The researchers, led by Bruce Blumberg, PhD, of the University of California, Irvine, point out that nearly 40 percent of American adults are now obese, as are 18.5 percent of American youth (age 2-19). Obesity carries with it a number of comorbidities and is an enormous burden on the U.S. economy. Although lifestyle modification is the first line of treatment for obese individuals, more and more research is showing that environmental factors in utero profoundly affect human health in adulthood. “In particular,” they write, “exposure to xenobiotic chemicals during early development has been implicated as an important contributor to the obesity epidemic.”
TBT is a potent obesogen. Animal models have shown that the chemical activates the peroxisome proliferator-activated receptor y (PPARy) and the retinoid X receptor (RXR). “The obesogenic effects of prenatal TBT exposure are propagated transgenerationally to unexposed generations, presumably via epigenetic modifications of the germline,” the authors write. “Undifferentiated MSCs [mesenchymal stem cells] from mice prenatally exposed to TBT have a proadipogenic, antiosteogenic gene expression profile, which led us to investigate how TBT influences early cell fate decisions in MSCs.”
To see exactly how TBT acts on these stem cells, the team developed an assay to distinguish the early commitment to adipose lineage from subsequent differentiation. They found that TBT and RXR activators had potent effects in committing MSCs to adipose lineage. They showed that “a [two]-day pretreatment with TBT or the rexinoid IRX4204 was as potent inducing adipogenesis as a 14-day cotreatment with induction cocktail (the standard assay).” The strong PPARy activator rosiglitazone was inactive.
The activation of RXR alters expression of enhancer of zeste homolog 2 (EZH2) and decreases genome-wide deposition of the repressive histone 3 lysine 27 trimethylation (H3K27me3 mark, thereby, derepressing genes that promote adipose commitment and programming subsequent differentiation. The authors write. “Here we report a role for RXR in the lineage commitment of MSCs and show that RXR activation in MSCs produces genome-wide reduction and redistribution of H3K27me3 marks to promote adipose lineage commitment,” they conclude. “These data identify RXR as an important interface between the environment and the epigenome that can influence the developmental programming of obesity.”