BME Seminar Series: How Does Prenatal Obesogen Exposure Lead to a Transgenerational Predisposition to Obesity?

Professor Blumberg is standing in front of Langston Library at the UCI campus. He is wearing a dark blue button up shirt and is smiling softly.
McDonnell Douglas Auditorium (MDEA)
Bruce Blumberg, Ph.D.

Professor
Department of Developmental and Cell Biology
School of Biological Sciences
School of Pharmaceutical Sciences
UC Irvine
Blumberg Laboratory

Abstract: Obesity is commonly ascribed to a simple imbalance between caloric intake and energy expenditure, but a growing body of evidence underscores the contributions of other factors in the obesity pandemic. We found that exposure of pregnant F0 mice to the obesogen tributyltin (TBT) throughout pregnancy, or throughout pregnancy and lactation, predisposed male F3 and F4 descendants of TBT-treated animals to obesity when challenged with a higher fat diet. The TBT group showed impaired ability to mobilize fat during fasting together with elevated serum leptin levels. Limited fat mobilization and elevated leptin levels suggested that fat accumulation results, in part, from leptin resistance. Integrated methylome and transcriptome analysis from fat and liver of F4 animals revealed that ancestral TBT exposure led to changes in global DNA methylation consistent with architectural changes in chromatin structure. Our results showed that ancestral, in utero exposure to TBT alters chromatin structure to modulate expression of genes important for fat storage and mobilization, and we propose that altered chromatin structure is a novel method for transgenerational transmission of the effects of obesogen exposure. Two repeated experiments revealed that TBT elicited transgenerational effects in the plasma and hepatic metabolomes that are diagnostic for TBT exposure and changes in higher order chromatin structure in primordial germ cells that modulate expression of gene(s) important for the transgenerational predisposition to obesity.

Bio: The Blumberg laboratory studies the biology of nuclear hormone receptors in development, physiology and disease. They proposed the obesogen hypothesis, which holds that exposure to chemical "obesogens" predisposes individuals to weight gain and obesity. His laboratory showed that maternal obesogen exposure led to increased adiposity, in vivo and elicited epigenomic changes in chromatin structure that were transgenerationally inherited through at least four subsequent generations, predisposing descendants of exposed individuals to obesity and modifying individual responses to diet. These findings have led to a deeper understanding of how the effects of environmental exposures can be transmitted to future generations.