Ancestral perinatal obesogen exposure results in a transgenerational thrifty phenotype in mice

Ancestral environmental exposures to non-mutagenic agents can exert effects in unexposed descendants. This transgenerational inheritance has significant implications for understanding disease etiology. The obesogen hypothesis proposes that exposure to obesogenic chemicals can lead to increased adiposity, in vivo. Here we show that exposure of F0 mice to the obesogen tributyltin (TBT) throughout pregnancy and lactation predisposes unexposed F4 male descendants to obesity when dietary fat is increased. Analyses of body fat, plasma hormone levels, and visceral white adipose tissue DNA methylome and transcriptome collectively indicate that the F4 obesity is consistent with a leptin resistant, \"thrifty phenotype\". Ancestral TBT exposure induces global changes in DNA methylation together with altered expression of metabolism-relevant genes when the F4 animals were exposed to dietary challenges. Analysis of chromatin accessibility in F3 and F4 sperm reveal significant differences between control and TBT groups and significant similarities between F3 and F4 TBT groups that overlap with areas of differential methylation in F4 adipose tissue. Taken together, our data suggest that ancestral TBT exposure induces changes in higher order chromatin organization transmissible through meiosis and mitosis.\n\nNon-technical summaryAncestral obesogen exposure in mice causes obesity in untreated F4 male descendants by inducing heritable changes in genome architecture that predispose these animals to become obese when dietary fat is increased modestly. This result is consistent with these animals having a leptin-resistant, \"thrifty\" phenotype