Heritable changes in chromatin contacts associated with transgenerational susceptibility to diet-induced insulin dysregulation and obesity

Effects of prenatal environmental exposures can be transmitted across generations through the germline without DNA mutations, an example of transgenerational epigenetic inheritance. Understanding how such inheritance occurs remains a central unanswered question in biology. Here we show that gestational exposure of mice to the environmental obesogen tributyltin produces heritable changes in chromatin interactions within the Ide gene encoding insulin-degrading enzyme in male primordial germ cells. These altered contacts persist through the F3 generation and are accompanied by reduced hepatic Ide expression, hyperinsulinemia, hyperglycemia and hyperleptinemia, resembling the phenotype of Ide-deficient mice that are predisposed to adult-onset, diet-induced obesity. The formation of new chromatin contacts, suppression of Ide expression, and associated metabolic phenotypes occurs only in males. These findings reveal a plausible molecular mechanism by which environmental exposures induce location-specific, three-dimensional changes in chromatin structure that transmit susceptibility to metabolic disorders to subsequent unexposed generations in mammals.