DNMT1 as an environmental sensor: epigenetic pathways linking environmental exposures, sex hormone signaling, and vulnerability to neurodevelopmental and neurodegenerative diseases.

The developing and adult brain relies on a dynamic interplay between intrinsic genetic programs and extrinsic environmental signals to build and maintain complex neural circuits (). Epigenetic mechanisms provide a molecular interface for this dialogue by translating developmental cues, neuronal activity, and environmental exposures into stable yet plastic changes in gene expression (, ). Among these mechanisms, DNA methylation by DNA methyltransferases (DNMTs) plays a pivotal role in neuronal differentiation, synaptic function, and experience-dependent remodeling (). The three major DNMTs—DNMT1, DNMT3A, and DNMT3B—have distinct but partially overlapping functions, with DNMT3A and DNMT3B acting primarily as methyltransferases, and DNMT1 long regarded as the canonical maintenance enzyme that preserves methylation patterns during DNA replication (). Over the past decade, the traditional view of DNMT1 as merely a maintenance methyltransferase has been expanded. Emerging evidence indicates that DNMT1 participates in the integration of diverse environmental and cellular signals, including psychosocial stress, metabolic pathways, environmental toxicants, sex hormone signaling, and long non-coding RNAs that modulate its genomic targeting and subcellular localization (). Converging evidence from human genetics and postmortem studies further links DNMT1 dysregulation to a spectrum of neurodevelopmental, neuropsychiatric, and neurodegenerative conditions (). In this review, we propose that DNMT1 can be viewed as an environmentally responsive epigenetic hub. After providing a brief overview of DNMT1’s molecular identity and canonical brain properties, we examine how stress, nutrition, microbiome-derived metabolites, environmental toxicants, lncRNAs, and post-translational modifications tune DNMT1 activity. We next discuss how sex hormones introduce sex-specific dimensions to this regulation. Building on this framework, we review how DNMT1 dysregulation shapes vulnerability to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases, and discuss future directions and translational potential.