title: Prenatal antidepressant exposure associated with CYP2E1 DNA methylation change in neonates.
abstract: Some but not all neonates are affected by prenatal exposure to serotonin reuptake inhibitor antidepressants (SRI) and maternal mood disturbances. Distinguishing the impact of these 2 exposures is challenging and raises critical questions about whether pharmacological, genetic, or epigenetic factors can explain the spectrum of reported outcomes. Using unbiased DNA methylation array measurements followed by a detailed candidate gene approach, we examined whether prenatal SRI exposure was associated with neonatal DNA methylation changes and whether such changes were associated with differences in birth outcomes. Prenatal SRI exposure was first associated with increased DNA methylation status primarily at CYP2E1(β(Non-exposed) = 0.06, β(SRI-exposed) = 0.30, FDR = 0); however, this finding could not be distinguished from the potential impact of prenatal maternal depressed mood. Then, using pyrosequencing of CYP2E1 regulatory regions in an expanded cohort, higher DNA methylation status--both the mean across 16 CpG sites (P < 0.01) and at each specific CpG site (P < 0.05)--was associated with exposure to lower 3rd trimester maternal depressed mood symptoms only in the SRI-exposed neonates, indicating a maternal mood x SRI exposure interaction. In addition, higher DNA methylation levels at CpG2 (P = 0.04), CpG9 (P = 0.04) and CpG10 (P = 0.02), in the interrogated CYP2E1 region, were associated with increased birth weight independently of prenatal maternal mood, SRI drug exposure, or gestational age at birth. Prenatal SRI antidepressant exposure and maternal depressed mood were associated with altered neonatal CYP2E1 DNA methylation status, which, in turn, appeared to be associated with birth weight.
authors.affiliation: a Center for Brain Science; Department of Molecular Cellular Biology; Harvard University ; Cambridge , MA , USA.
authors.forename: Cécile
authors.initials: C
authors.lastname: Gurnot
authors.forename: Ignacio
authors.initials: I
authors.lastname: Martin-Subero
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Mah
authors.forename: Whitney
authors.initials: W
authors.lastname: Weikum
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Goodman
authors.forename: Ursula
authors.initials: U
authors.lastname: Brain
authors.forename: Janet F
authors.initials: JF
authors.lastname: Werker
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kobor
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Tim F
authors.initials: TF
authors.lastname: Oberlander
authors.forename: Takao K
authors.initials: TK
authors.lastname: Hensch
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000009:adverse effects*; D015331:Cohort Studies; D018899:CpG Islands; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D019964:Mood Disorders / Q000188:drug therapy / Q000378:metabolism; D036801:Parturition / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects*; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D019392:Cytochrome P-450 CYP2E1; D017367:Selective Serotonin Reuptake Inhibitors
keywords: CNV, copy number variation; CYP2E1; HAMD, Hamilton Rating Scale for Depression; HR, heart rate; SRI, serotonin reuptake inhibitor; depression; neonatal health; pregnancy; serotonin reuptake inhibitor (SRI) antidepressants