GSE105051
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, adding a layer of complexity to long-standing attempts to clarify the relationships between genotypic and phenotypic variations. Transgenerational inheritance of environmental exposures has significant implications for understanding disease etiology. The environmental 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 TBT-dependent F4 obesity is consistent with a leptin resistant, "thrifty phenotype". We found that ancestral TBT exposure induced global changes in DNA methylation together with altered expression of metabolism-relevant genes when the animals were exposed to dietary challenges. Analysis of chromatin accessibility in sperm revealed significant differences between DMSO and TBT groups when guided by DNA sequence composition, a proxy for higher order chromatin organization. Taken together, these data establish an independent connection between ancestral TBT treatment and altered chromatin accessibility that may reflect changes in higher order chromatin organization transmissible through meiosis and mitosis. Overall design: We generated RNA-Seq data in gonadal adipose tissue from 33-week old F4 mice ancestrally exposed to DMSO (0.1%) or TBT (50 nM ) during in utero development and lactation. N=4 per treatment --> 8 RNA-seq samples in total We generated MBD-seq data in gonadal adipose tissue from 33-week old F4 mice ancestrally exposed to DMSO (0.1%) or TBT (50 nM ) during in utero development and lactation. N=4 per treatment --> 8 RNA-seq samples in total We generated ATAC-seq data in gonadal adipose tissue from F3 and F4 mice at 8 weeks of age ancestrally exposed to DMSO (0.1%) or TBT (50 nM ) during in utero development and lactation. N=6 per treatment --> 24 RNA-seq samples in total