Yoon Hee Jung^a,1, Hsiao-Lin V. Wang^a, Daniel Ruiz^a, Brianna J. Bixler^a, Hannah Linsenbaum^a, Jian-Feng Xiang^a, Samantha Forestier^a, Andrew M. Shafik^a, Peng Jin^a, and Victor G. Corces^a,2

^aDepartment of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
¹Present  address:  Department  of  Physiology,  Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
²To  whom  correspondence  may  be  addressed : Victor G. Corcesa

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.