Single-cell and metabolomic profiling reveals brain cellular and metabolic disruptions in pregnant mice exposed to micro- and nanoplastics.

Micro- and nanoplastics (MNPs) are emerging environmental contaminants that can cross biological barriers, but their direct effects on the developing brain remain poorly defined. We hypothesized that prenatal MNPs exposure impairs neurodevelopment by disrupting cerebral homeostasis. To test this hypothesis, we established a prenatal MNP exposure model in mice and integrated single-cell RNA sequencing (scRNA-seq) with untargeted metabolomics. Our results demonstrate that MNPs can cross both the placental and blood-brain barriers, accumulating in fetal brain tissue, particularly in grey matter. This transplacental passage may involve size-dependent endocytosis and transcytosis by placental trophoblasts, together with paracellular transport facilitated by oxidative stress-, inflammation-, and tight junction disruption-induced increases in placental permeability. scRNA-seq analysis revealed significant alterations in brain cellular composition following MNPs exposure, including increased proportions of microglia, macrophages, and monocytes, alongside marked reductions in excitatory neurons, pericytes, endothelial cells, fibroblasts, and oligodendrocytes. Further investigations indicated that MNPs disrupt intercellular communication among vascular cells, leading to compromised blood-brain barrier integrity and increased permeability. Additionally, MNPs exposure activated neuroinflammatory and neurodegenerative pathways, such as those associated with Alzheimer's and Huntington's diseases. Metabolomic profiling identified systemic reprogramming of key metabolic pathways, including disrupted lipid metabolism, amino acid metabolism, and glutathione metabolism, indicating adaptive responses to oxidative stress. Together, these findings reveal that prenatal MNP exposure induces coordinated vascular, cellular, inflammatory, and metabolic disturbances in the developing brain and may increase its susceptibility to the genotoxic effects of coexisting environmental contaminants, including plastic-derived monomers, dopants, additives, and other xenobiotic compounds. These results provide a mechanistic framework for understanding MNP-induced developmental neurotoxicity and underscore the potential neurological risks associated with maternal exposure during pregnancy.