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

Rivollier F1,2,3,4, Chaumette B1,2,3,4, Bendjemaa N1,2,3,4, Chayet M4, Millet B5, Jaafari N6, Barhdadi A7, Lemieux Perreault LP7, Provost S7, Dubé MP7, Gaillard R1,2,3,4, Krebs MO1,2,3,4, Kebir O1,2,3,4.

Author information

1  Université Paris Descartes, Université Paris Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.
2  INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.
3  CNRS, GDR3557-Institut de Psychiatrie, Paris, France.
4  Faculté de Médecine Paris Descartes, Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Paris, France.
5  Department of Adults Psychiatry, ICM-A-IHU, UPMC UMR S 975, Inserm U 1127, CNRS UMR 7225, GH Pitié-Salpêtrière, Paris, France.
6  Unité de Recherche Clinique en Psychiatrie Pierre Deniker, Centre Hospitalier Henri Laborit, INSERM CIC-P 1402, INSERM U 1084 Laboratoire Expérimental et Clinique en Neurosciences, Univ Poitiers, CHU Poitiers, Groupement De Recherche CNRS 3557, Poitiers, France.
7  Université de Montréal, Beaulieu-Saucier Pharmacogenomics Center, Montréal Heart Institute, Montréal, QC, Canada.

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.

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

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