Transgenerational inheritance of BPA-induced obesity correlates with transmission of new CTCF sites in the Fto gene

The mechanisms by which epiphenotypes are transmitted transgenerationally through the parental germlines are poorly understood. Here we show that exposure of pregnant mouse F0 females during E7.5-E13.5 to bisphenol A results in obesity in the F2 progeny in the absence of additional exposure. This epiphenotype can be transmitted through the male and female germlines up to the F5 generation, decreases in F6, and disappears in F7. Analysis of chromatin changes in the sperm of the F1 generation reveals a widespread increase in chromatin accessibility at binding sites for CTCF and other transcription factors accompanied by alterations in 3D organization. Comparison of the transmission of obesity between F2 and F5 and its disappearance in F7 with alterations in the binding of these transcription factors points to the activation of an enhancer in an intron of the Fto gene as the cause of transgenerational inheritance. Activation of the Fto enhancer results in a decrease of m6A in sperm RNAs, which may result in alterations of gene expression in the embryo after fertilization. Given the established involvement of SNPs in FTO in human obesity, the results suggest that both genetic and epigenetic alterations of the same gene can lead to the same phenotypic outcomes on human health.