Methylomic changes in individuals exposed in utero to diethylstilbestrol

Abstract

Background In the Western world, more than 2 million people were exposed in utero to diethylstilbestrol. In exposed individuals and in their descendants, several adverse outcomes have been linked to such exposure, like cancers, genital malformations and, less consistently, psychiatric disorders. Disruption of epigenetic homeostasis was proposed as the molecular substratum of this environmental factor but was not fully proven. Methods We selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to diethylstilbestrol. We analyzed DNA methylation using Human Methylation 450 DNA Analysis BeadChip ® . We performed a methylome-wide association analysis searching for specific methylation changes in exposed versus unexposed individuals. Secondary, we compared exposed individuals with and without genital malformation, and with and without psychosis. Results No differentially methylated regions were identified between exposed and unexposed individuals. Yet, our analyses showed that exposed individuals with genital or psychotic abnormalities have several specific differentially methylated regions compared with exposed individuals without complication. These CpGs were located in genes relevant for cancer (ADAMTS9), genital abnormalities (HOOK2) and psychiatric diseases (ZFP57). Conclusions In utero exposure to diethylstilbestrol is not associated with changes in methylation profiles. In exposed individuals though, specific traits are associated with methylomic modifications encompassing genomic regions, mostly involved in cancer and neurodevelopment, leading to heterogeneous consequences.