Nuclear and Mitochondrial Epigenetic Mechanisms Underlying Neurodegeneration and Gut-Brain Axis Dysregulation Induced by Micro- and Nanoplastics.

The increasing and global distribution of microplastics and nanoplastics (MPs/NPs) in the environment has led to concern about their potential influence on human health, especially on the gastrointestinal tract, as well as the brain. MPs/NPs could traverse epithelial and endothelial barriers, disrupt the gut microbiota, and perturb the microbiota-gut-brain axis, leading to systemic inflammation and possibly extending neurodegenerative processes. Experimental models now demonstrate that MPs/NPs reprogram nuclear and mitochondrial epigenetics-DNA methylation, histone modifications, non-coding RNAs, and mitochondrial DNA regulation-in gut, immune, and neural cells with downstream effects on synaptic function, neuronal survival, and protein aggregation. This mechanistic narrative review integrates preclinical and emerging human evidence of how MPs/NPs compromise intestinal barrier integrity, modulate gut microbiota composition, affect the blood-brain barrier, and converge on oxidative stress, neuroinflammatory signaling, and cell death pathways within the central nervous system across key neurodegenerative diseases. Overall, the review offers an integrated model in which environmental exposure to chronic MPs/NPs disrupts the microbiota-gut-brain axis and drives concurrent nuclear and mitochondrial epigenetic remodeling, lowering the threshold for neurodegeneration in susceptible individuals, while outlining candidate mechanistic readouts that require exposure-specific validation in human-relevant models and longitudinal cohorts.