Methylomic changes in individuals with psychosis, prenatally exposed to endocrine disrupting compounds: Lessons from diethylstilbestrol

PLoS One. 2017 Apr 13;12(4):e0174783. doi: 10.1371/journal.pone.0174783. eCollection 2017.

Abstract

Background: In the Western world, between 1940 and 1970, more than 2 million people were exposed in utero to diethylstilbestrol (DES). In exposed individuals, and in their descendants, adverse outcomes have been linked to such exposure, including cancers, genital malformations, and less consistently, psychiatric disorders. We aimed to explore whether prenatal DES exposure would be associated with DNA methylation changes, and whether these epigenetic modifications would be associated with increased risk of psychosis.

Methods: From 247 individuals born from mothers exposed to DES, we selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to DES. We performed a methylome-wide association study using HumanMethylation450 DNA Analysis BeadChip® in peripheral blood. We analyzed methylation changes at individual CpGs or regions in exposed (n = 37) versus unexposed individuals (n = 32). We also compared exposed individuals with (n = 7) and without psychosis (n = 30).

Results: There were more individuals with schizophrenia in the DES-exposed group. We found no significant differences between exposed and unexposed individuals with respect to differentially methylated CpGs or regions. The largest difference was in a region near the promoter of an ADAMTS proteoglycanase gene (ADAMTS9). Compared to exposed individuals without psychosis, exposed individuals with psychosis had differential methylation in the region encompassing the gene encoding the zinc finger protein 57 (ZFP57).

Conclusions: In utero exposure to DES was not associated with methylation changes at specific CpG or regions. In exposed individuals, however, psychosis was associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity.

Publication types

  • Clinical Trial
  • Comparative Study

MeSH terms

  • ADAMTS9 Protein / metabolism
  • Adult
  • CpG Islands
  • DNA Methylation*
  • DNA-Binding Proteins / metabolism
  • Diethylstilbestrol / toxicity*
  • Epigenesis, Genetic*
  • Female
  • Humans
  • Male
  • Maternal Exposure / adverse effects*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / metabolism*
  • Prenatal Exposure Delayed Effects / physiopathology
  • Promoter Regions, Genetic
  • Psychotic Disorders / etiology
  • Psychotic Disorders / metabolism*
  • Repressor Proteins
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • Repressor Proteins
  • Transcription Factors
  • ZFP57 protein, human
  • Diethylstilbestrol
  • ADAMTS9 Protein
  • ADAMTS9 protein, human

Grant support

This work was supported by the French Governement Agence Nationale pour la Recherche grant (ANR, 08-MNP-007) and by a competitive grant from Ile-de-France, Partenariat institutions-citoyens pour la recherche et l'innovation (PICRI 2007). The Institut National de la Santé et de la Recherche Médicale (INSERM) promoted the study. Additional financial support was obtained from Université Paris Descartes (recurrent funding), Fondation Deniker and Fonds Québécois de Recherche sur la Société et la Culture-INSERM joint grant (Marie-Odile KREBS, Oussama KEBIR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.