Perinatal morphine exposure induces chromatin and transcriptomic remodeling to alter immune and metabolic function.

Overview

1. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
2. Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, CA, United States
3. Department of Chemical Engineering, Virginia Tech, Blacksburg, VA, United States
4. Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, United States

Abstract

Introduction: Infants exposed to opioids in utero are at risk of developing Neonatal Opioid Withdrawal Syndrome (NOWS). Rodent models of perinatal opioid exposure can reliably recapitulate the acute withdrawal and developmental deficits exhibited in clinical NOWS, but few persisting phenotypes are consistently observed between studies, limiting mechanistic insight into the long-lasting effects of early-life opioid exposure.

Methods: To investigate the enduring impact of perinatal opioid exposure, we employed a multi-region, multi-omic approach. We combined RNA sequencing (RNA-seq) and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) from NeuN+ neuronal nuclei in a mouse model of NOWS. Additionally, cytokine levels were measured in the brain and spleen, and physiological responses were assessed under both basal and immune-challenged conditions.

Results: Analysis revealed differentially expressed genes and H3K27ac modifications were enriched for immune and metabolic pathways in hypothalamic neurons. Transcription factor network inference identified state-dependent rewiring of immune and metabolic regulatory circuits, with Transcription factor 4 (TCF4) emerging as a convergent epigenomic and transcriptional hub under immune-challenged conditions. Consistent with molecular signatures, cytokine levels were suppressed in morphine-exposed mice both in adulthood, both at baseline and under immune-challenged conditions. Several metabolic properties, including changes in weight and basal body temperature, were also altered.

Discussion: Our findings suggest that perinatal opioid exposure creates a lasting enhancer imprint in hypothalamic neurons, leading to suppressed baseline immune gene expression and altered regulatory responses to subsequent inflammatory challenges. These epigenomic and transcriptional changes may underlie the long-term physiological impacts of early-life opioid exposure, offering new insights into the enduring consequences of NOWS.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE332794, at NCBI GEO; found in “Data availability statement”

Data availability statement

ChIP-seq and RNA-seq data have been submitted to GEO under accessions GSE332794 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE332794) (H3K27ac ChIP-seq) and GSE332798 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE332798) (RNA-seq). All other data are available in the main text or the Supplementary Materials.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 7 authors, 8 keywords, 14 MeSH terms, 1 funder, 54 references.

Cite

This paper

Ferrante, J. R., Du, Y., Zhang, X., Neice, J. D., Wang, W., Lu, C., & Blendy, J. A. (2026). Perinatal morphine exposure induces chromatin and transcriptomic remodeling to alter immune and metabolic function. Frontiers in immunology, 17, 1835359. https://doi.org/10.3389/fimmu.2026.1835359

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