Obesity is commonly ascribed to an imbalance between caloric intake and energy expenditure, but a growing body of evidence underscores the contributions of other factors in the obesity epidemic. We found that exposure of F0 animals to TBT throughout pregnancy and lactation predisposed male 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 and elevated serum leptin levels. Limited fat mobilization and elevated leptin levels suggest 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 show that ancestral, in utero exposure to TBT alters chromatin structure to modulate expression of genes important for fat storage and mobilization. We propose that altered chromatin structure is a novel method for transgenerational transmission of the effects of obesogen exposure.
18 - 21 May 2019
European Society of Endocrinology