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

Abstract 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. Analyses of chromatin changes in the sperm of the F1 generation reveal 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 two enhancers located in intronic and intergenic regions of the Fto gene as the cause of transgenerational inheritance. These enhancers form an autoregulatory feedback loop that, in combination with a decrease of m6A in sperm RNAs, may cause 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.