Cited by 116Epigenetics and DNA MethylationTryptophan and brain disordersMaternal Mental Health During Pregnancy and Postpartum

Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain

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Basil, P, Li, Q, Dempster, E L, Mill, J, Sham, P-C, Wong, C C Y, McAlonan, G M·2014·Translational Psychiatry

Abstract

Epigenetic processes such as DNA methylation have been implicated in the pathophysiology of neurodevelopmental disorders including schizophrenia and autism. Epigenetic changes can be induced by environmental exposures such as inflammation. Here we tested the hypothesis that prenatal inflammation, a recognized risk factor for schizophrenia and related neurodevelopmental conditions, alters DNA methylation in key brain regions linked to schizophrenia, namely the dopamine rich striatum and endocrine regulatory centre, the hypothalamus. DNA methylation across highly repetitive elements (long interspersed element 1 (LINE1) and intracisternal A-particles (IAPs)) were used to proxy global DNA methylation. We also investigated the Mecp2 gene because it regulates transcription of LINE1 and has a known association with neurodevelopmental disorders. Brain tissue was harvested from 6 week old offspring of mice exposed to the viral analog PolyI:C or saline on gestation day 9. We used Sequenom EpiTYPER assay to quantitatively analyze differences in DNA methylation at IAPs, LINE1 elements and the promoter region of Mecp2. In the hypothalamus, prenatal exposure to PolyI:C caused significant global DNA hypomethylation (t=2.44, P=0.019, PolyI:C mean 69.67%, saline mean 70.19%), especially in females, and significant hypomethylation of the promoter region of Mecp2, (t=3.32, P=0.002; PolyI:C mean 26.57%, saline mean 34.63%). IAP methylation was unaltered. DNA methylation in the striatum was not significantly altered. This study provides the first experimental evidence that exposure to inflammation during prenatal life is associated with epigenetic changes, including Mecp2 promoter hypomethylation. This suggests that environmental and genetic risk factors associated with neurodevelopmental disorders may act upon similar pathways. This is important because epigenetic changes are potentially modifiable and their investigation may open new avenues for treatment.

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  • Maternal immune activation models demonstrate global DNA methylation differences affecting genes involved in synaptic development and neural plasticity, suggesting inflammation-mediated signaling may influence fetal development.

    “Maternal immune activation models similarly demonstrate global DNA methylation differences affecting genes involved in synaptic development and neural plasticity, suggesting inflammation-mediated signaling may influence fetal development (50).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [50]

    The Results (LINE1 methylation in the hypothalamus) report reduced LINE1 methylation, used as a proxy for global DNA methylation, in adolescent mice exposed prenatally to maternal immune activation; the striatum showed no significant change. The Discussion (Mecp2 methylation) speculates that the observed Mecp2 change could influence developmental genes, but the study did not show methylation differences affecting genes involved in synaptic development or neural plasticity, nor measure fetal development directly. (LLM, conf=0.87)

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  • Inflammatory mediators such as cytokines induce alterations during neurodevelopment by histone modifications, methylation changes at the promoter of ASD-critical genes such as MECP2 or genes involved in synaptic functions, and global methylation changes.

    “Inflammatory mediators (e.g., cytokines) induce such alterations during neurodevelopment [138] by histone modifications [139], methylation changes at the promoter of ASD-critical genes (e.g., MECP2) [140] or genes involved in synaptic functions [141] and global methylation changes [136].”

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Authors
Basil, P., Li, Q., Dempster, E. L., Mill, J., Sham, P.-C., Wong, C. C. Y., & McAlonan, G. M.
Affiliations
  • University of Hong Kong (HK)
  • University of Exeter (GB)
  • King's College London (GB)
Corresponding author
McAlonan, G M
Venue
Translational Psychiatry
Published
2014-09-02
Volume
4
Issue
9
Pages
e434-e434
ISSN
2158-3188 (ISSN-L)
OpenAlex
W2020803237
Cited by
116
References
81
Citations by year
2026: 5 · 2025: 6 · 2024: 13 · 2023: 9 · 2022: 9 · 2021: 10 · 2020: 8 · 2019: 13 · 2018: 12 · 2017: 8 · 2016: 12 · 2015: 10 · 2014: 1
FWCI
4.23
Type
journal article
Language
en
Update notices
erratum (2014-09-30)
Open access
Locations
  • Translational Psychiatry (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by-nc-nd)
Funders
  • University of Hong Kong (GRF_HKU 774710M, 774710M)
  • Menzies Centre for Australian Studies, King's College London, University of London
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
Keywords
prenatal immune activation, maternal inflammation, DNA methylation, MeCP2, LINE-1, intracisternal A-particle, global DNA hypomethylation, hypothalamus, striatum, poly(I:C), schizophrenia, autism spectrum disorder, neurodevelopmental disorders, sex differences, adolescent brain
MeSH terms
Age Factors, Animals, Brain, Corpus Striatum, Disease Models, Animal, Female, Hypothalamus, Male, Mice, Inbred C57BL, Poly I-C, Pregnancy, Prenatal Exposure Delayed Effects, Reference Values, Sex Factors, DNA Methylation, Epigenesis, Genetic, Mice, Methyl-CpG-Binding Protein 2

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