Affiliation:
1. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Abstract
The mechanisms by which environmentally-induced epiphenotypes are transmitted transgenerationally in mammals are poorly understood. Here we show that exposure of pregnant mouse females to bisphenol A (BPA) results in obesity in the F2 progeny due to increased food intake. This epiphenotype can be transmitted up to the F6 generation. Analysis of chromatin accessibility in sperm of the F1–F6 generations reveals alterations at sites containing binding motifs for CCCTC-binding factor (CTCF) at two cis-regulatory elements (CREs) of the
Fto
gene that correlate with transmission of obesity. These CREs show increased interactions in sperm of obese mice with the
Irx3
and
Irx5
genes, which are involved in the differentiation of appetite-controlling neurons. Deletion of the CTCF site in
Fto
results in mice that have normal food intake and fail to become obese when ancestrally exposed to BPA. The results suggest that epigenetic alterations of
Fto
can lead to the same phenotypes as genetic variants.
Funder
HHS | NIH | National Institute of Environmental Health Sciences
HHS | NIH | National Institute of Neurological Disorders and Stroke
HHS | NIH | National Human Genome Research Institute
HHS | NIH | National Institute of Mental Health
HHS | NIH | National Institute of General Medical Sciences
Publisher
Proceedings of the National Academy of Sciences
Cited by
18 articles.
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