DNA methylation mediates the effect of exposure to prenatal maternal stress on cytokine production in children at age 13½ years: Project Ice Storm

Clin Epigenetics. 2016 May 12;8:54. doi: 10.1186/s13148-016-0219-0. eCollection 2016.


Background: Prenatal maternal stress (PNMS) is an important programming factor of postnatal immunity. We tested here the hypothesis that DNA methylation of genes in the NF-κB signaling pathway in T cells mediates the effect of objective PNMS on Th1 and Th2 cytokine production in blood from 13½ year olds who were exposed in utero to the 1998 Quebec ice storm.

Results: Bootstrapping analyses were performed with 47 CpGs across a selection of 20 genes for Th1-type cytokines (IFN-γ and IL-2) and Th2-type cytokines (IL-4 and IL-13). Six CpGs in six different NF-κB signaling genes (PIK3CD, PIK3R2, NFKBIA, TRAF5, TNFRSF1B, and LTBR) remained as significant negative mediators of objective PNMS on IFN-γ secretion after correcting for multiple comparisons. However, no mediation effects on IL-2, IL-4 and IL-13 survived Bonferroni correction.

Conclusions: The present study provides preliminary evidence supporting the mediating role of DNA methylation in the association between objective aspects of PNMS and child immune states, favoring a Th2 shift.

Keywords: Cytokines; DNA methylation; IFN-γ; Mediation effect; NF-κB signaling; Prenatal maternal stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Cohort Studies
  • CpG Islands
  • Cytokines / genetics*
  • DNA Methylation*
  • Epigenesis, Genetic
  • Female
  • Humans
  • Maternal Exposure
  • Pregnancy
  • Prenatal Exposure Delayed Effects / etiology
  • Prenatal Exposure Delayed Effects / genetics*
  • Prenatal Exposure Delayed Effects / immunology
  • Signal Transduction
  • Stress, Psychological / psychology*


  • Cytokines