Epigenetics refers to the layer of molecular control that sits above the DNA sequence itself. Cells in the developing lung carry the same genome, yet an alveolar epithelial cell, a vascular endothelial cell and an airway smooth muscle cell behave in radically different ways because of chemical tags that switch genes on or off. The review centers on three principal mechanisms. DNA methylation, the addition of methyl groups to cytosine bases, typically silences genes when deposited in promoter regions. Histone modifications, including acetylation and methylation of the protein spools around which DNA winds, loosen or tighten chromatin and thereby control access of the transcriptional machinery. Finally, non-coding RNAs, including microRNAs and long non-coding RNAs, fine-tune gene expression after transcription. Together these systems form a regulatory network that orchestrates the precisely timed program of alveolarization, the formation of the millions of gas-exchange sacs that define a mature lung.

The problem for preterm infants is that this program is interrupted at its most sensitive stage. Alveolar development in humans largely unfolds during the third trimester, exactly the window in which many extremely preterm infants are instead exposed to mechanical ventilation, supplemental oxygen, infection and inflammation. The review synthesizes evidence that these exposures do not merely stall development; they inscribe lasting epigenetic changes that redirect it. Studies in newborn mice have shown that hyperoxia induces measurable epigenetic alterations in lung tissue, and single-cell transcriptomic analyses have mapped how oxygen-induced damage reshapes the developmental trajectories of individual lung cell populations. In human cohorts, epigenome-wide association studies, including the discovery-BPD program, have identified methylation signatures in preterm infants associated with the disease.

Hyperoxia receives particular attention as a mechanistic driver. Oxygen therapy is indispensable for survival, yet excess oxygen generates reactive oxygen species that overwhelm the immature lung’s antioxidant defenses. The review describes a field known as redox epigenetics, in which oxidative stress directly modifies the epigenetic landscape. Reactive species can alter histone post-translational modifications and influence DNA methylation patterns, linking the infant’s oxidative burden to long-term transcriptional states. Experimental work has shown that hyperoxia suppresses histone deacetylase activity in the neonatal lung, upregulates the cell cycle inhibitor p21 and drives cellular senescence, a state of permanent growth arrest that impairs alveolar formation. Other studies have documented hyperoxia-induced changes in redox-sensitive pathways, angiogenic signaling through vascular endothelial growth factor and hypoxia-inducible factors, and cell cycle control, all of which converge on impaired alveolar and vascular growth.

Inflammation adds a second, complementary layer of programming. Chorioamnionitis, postnatal sepsis and ventilator-induced injury all flood the immature lung with inflammatory cytokines, and the review argues that these stimuli can establish a form of epigenetic memory. In immune cells, inflammatory exposures can produce trained immunity, a state in which innate immune cells respond more vigorously to later challenges because of persistent chromatin remodeling. In the lung, cytokine-mediated epigenetic remodeling may explain why chronic inflammation and defective repair persist in bronchopulmonary dysplasia even after the inciting insult has resolved. Prenatal inflammatory exposures have been shown in animal models to program lung development by modulating mesenchymal fibroblasts in time- and dose-dependent patterns, suggesting that the epigenetic clock of the lung can be reset before birth.

Pharmacologic interventions occupy a more ambiguous position in this framework. Antenatal corticosteroids such as betamethasone are a cornerstone of modern perinatal care, accelerating lung maturation and reducing neonatal mortality. Yet the review highlights evidence that glucocorticoid exposure induces epigenetic changes that are both sex-specific and tissue-specific, acting on the placenta and on hypothalamic-pituitary-adrenal axis-related pathways. Studies have linked glucocorticoid exposure to alterations in epigenetic age in preterm infants and in human lung fibroblasts and neuronal cells. Postnatal steroids, while effective in facilitating extubation, carry well-documented risks for neurodevelopment, and the review situates these clinical trade-offs within the same programming logic: a drug that beneficially accelerates one developmental program may simultaneously leave epigenetic marks elsewhere in the body.

One of the most striking themes is sexual dimorphism. The epigenetic response to hyperoxia in the neonatal lung has been shown to differ between males and females, and sex-dependent transcriptomic changes have been documented in experimental models of the disease. This may help explain the well-recognized clinical observation that male preterm infants fare worse across many neonatal outcomes. The review also extends the framework beyond the lung itself, describing lung-brain-immune interactions in which perinatal hyperoxia and inflammation produce systemic effects, and pointing to epigenetic associations in stress-axis genes related to both bronchopulmonary dysplasia and antenatal steroid exposure. In this model, early-life exposures shape not only lifelong respiratory outcomes but extra-pulmonary ones as well.

The long-term consequences of this programming are increasingly documented. Adult survivors of bronchopulmonary dysplasia show reduced pulmonary reserve, accelerated lung aging and heightened vulnerability to respiratory illnesses across the lifespan, including airflow obstruction resembling early chronic obstructive pulmonary disease. The review proposes that these outcomes reflect epigenetically programmed lung phenotypes: lungs built with fewer alveoli, a simplified vasculature and senescent cell populations that age faster than they should. On the question of whether these marks can be transmitted to the next generation, the authors are careful. Evidence for transgenerational epigenetic inheritance in humans remains limited, and inherited susceptibility to respiratory disease is plausible but unproven. Animal studies demonstrate that such inheritance is mechanistically possible, but extrapolating to human clinical medicine would be premature.

The translational implications are where the review aims to change practice. If bronchopulmonary dysplasia is a disease of biological memory, then the epigenome becomes both a diagnostic target and a therapeutic one. The authors identify the validation of epigenetic biomarkers as a priority: methylation signatures measurable in cord blood or saliva could, in principle, identify high-risk infants within days of birth, enabling earlier and more individualized intervention. Epigenetic maturity scores derived from saliva have already been associated with gestational age at birth, and epigenetic maturity has been linked to respiratory morbidity in preterm infants, providing proof of concept. Longitudinal multi-omics cohort studies that follow infants from the neonatal period into adulthood are flagged as essential to connect early molecular signatures with lifelong outcomes.

Therapeutic possibilities are emerging but remain cautious. Experimental strategies that target the epigenetic machinery, including histone deacetylase inhibitors such as valproic acid, DNA methyltransferase inhibitors, and compounds that boost antioxidant pathways such as the Nrf2 activator dimethyl fumarate, have shown benefit in animal models of the disease. Yet the review emphasizes that the epigenome is not a simple switchboard: indiscriminate manipulation could disrupt developmental programs that are working correctly, and current methodological limitations, including tissue specificity and the difficulty of distinguishing cause from consequence in methylation studies, temper expectations. What the framework offers now is a unifying lens. By integrating hyperoxia, inflammation, pharmacologic exposures and microbiome alterations within a developmental-origins epigenetic model, the authors transform bronchopulmonary dysplasia from a static diagnosis defined by oxygen dependence at thirty-six weeks into a dynamic, mechanistically grounded account of how the first days of life can echo across decades of respiratory health.

Subject of Research: Epigenetic mechanisms linking early-life exposures to persistent lung disease in bronchopulmonary dysplasia

Article Title: Epigenetic programming in bronchopulmonary dysplasia: a framework linking early-life exposures to persistent lung disease—a narrative review

Article References: Rocha, G. M., Amaral, R. S., & Bhandari, V. (2026). Epigenetic programming in bronchopulmonary dysplasia: a framework linking early-life exposures to persistent lung disease—a narrative review. Pediatric Research. https://doi.org/10.1038/s41390-026-05417-2

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05417-2

Keywords: bronchopulmonary dysplasia, epigenetics, DNA methylation, histone modifications, non-coding RNAs, hyperoxia, prematurity, lung development, inflammation, trained immunity, corticosteroids, biomarkers