Epigenetic Programming of Stress-Response Systems: A Systematic Review of How Early Life Stress Shapes Developmental...

Early life stress (ELS) is a critical environmental factor influencing developmental trajectories of behavioral and emotional regulation. Increasing evidence suggests that such experiences can alter biological systems during sensitive developmental periods through epigenetic processes. This systematic review aims to synthesize empirical human studies examining how ELS contributes to the developmental programming of mental health via epigenetic regulation of stress-response systems. This systematic review was conducted in accordance with PRISMA 2020 guidelines. A comprehensive search of PubMed/MEDLINE, Web of Science, Scopus, and PsycINFO databases was performed for studies published up to March 2026. Eligible studies included empirical human research investigating associations between ELS, epigenetic mechanisms (primarily DNA methylation), and mental health-related outcomes across developmental stages. A total of 14 studies met inclusion criteria and were synthesized using a qualitative approach. Findings indicate that ELS is associated with persistent epigenetic modifications in key genes regulating stress-response systems, particularly within the hypothalamic-pituitary-adrenal (HPA) axis. Altered DNA methylation patterns in genes such as NR3C1, FKBP5, SLC6A4, MAOA, and ANK3 were consistently linked to developmental alterations in emotional regulation and increased vulnerability to psychiatric conditions, including depression, anxiety disorders, and post-traumatic stress disorder. Importantly, evidence highlights early childhood as a sensitive developmental window during which environmental inputs exert stronger and more enduring biological effects. Some studies further suggest that epigenetic profiles may show partial plasticity in response to environmental or therapeutic changes across development. This review supports the concept that ELS contributes to the developmental programming of mental health through epigenetic mechanisms affecting stress-response systems. These findings underscore the importance of timing and environmental context in shaping long-term behavioral outcomes. However, the existing literature remains limited by methodological heterogeneity, including variability in developmental stages, tissue types, and measurement approaches. Future research should prioritize longitudinal and developmentally informed designs to better capture the dynamic interplay between environment, biology, and behavior across the lifespan.