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. Here we show that exposure of F0 mice to the obesogen tributyltin (TBT) throughout pregnancy and l...

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Bibliographic Details
Published in:Nature communications 2017-12, Vol.8 (1), p.2012-13, Article 2012
Main Authors: Chamorro-Garcia, Raquel, Diaz-Castillo, Carlos, Shoucri, Bassem M., Käch, Heidi, Leavitt, Ron, Shioda, Toshi, Blumberg, Bruce
Format: Article
Language:English
Subjects:
631/208/176/1988
692/163/2743/393
Adipose tissue
Adipose Tissue - metabolism
Animals
Antifouling substances
Body fat
Chromatin
Deoxyribonucleic acid
DNA
DNA Methylation
Etiology
Exposure
Female
Gene expression
Heredity
Humanities and Social Sciences
Inheritance Patterns - genetics
Lactation
Leptin
Male
Meiosis
Metabolism
Mice
Mice, Inbred C57BL
Mitosis
multidisciplinary
Obesity
Obesity - genetics
Perinatal exposure
Phenotype
Pregnancy
Prenatal Exposure Delayed Effects - chemically induced
Prenatal Exposure Delayed Effects - genetics
Science
Science (multidisciplinary)
Transcriptome
Trialkyltin Compounds - toxicity
Tributyltin
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Summary:Ancestral environmental exposures to non-mutagenic agents can exert effects in unexposed descendants. This transgenerational inheritance has significant implications for understanding disease etiology. 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 and altered expression of metabolism-relevant genes. Analysis of chromatin accessibility in F3 and F4 sperm reveals 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. Our data suggest that ancestral TBT exposure induces changes in chromatin organization transmissible through meiosis and mitosis. Early life exposure to endocrine disrupting chemicals has been linked to increased adiposity during adulthood. Here Chamorro-García et al. show that ancestral exposure to the obesogen tributyltin causes obesity in untreated F4 generation male descendants by inducing heritable changes in genome architecture that promote a thrifty phenotype.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-017-01944-z