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Single-nucleus transcriptomics reveals cell-type-resolved brain responses to concurrent exposure to polyethylene nanoplastics and butyl benzyl phthalate
Summary
Mice exposed to both nanoplastics and a common plastic softener (BBP, found in some vinyl products and packaging) together showed worse brain damage, memory problems, and movement issues than mice exposed to either one alone, suggesting these two plastic pollutants can team up to cause more harm than either does by itself. The study found this combo exposure disrupted brain cells, weakened the protective blood-brain barrier, and triggered inflammation, highlighting that real-world exposure to multiple plastic-related chemicals at once (as happens in everyday life) may pose greater risks to brain health than scientists previously realized from stud
The co-occurrence of plastic-derived particles and plastic-associated chemicals represents an emerging toxicological concern, yet their combined neurotoxicity remains insufficiently understood. Here, we evaluated whether repeated oral concurrent exposure to polyethylene nanoplastics (PE-NPs) and butyl benzyl phthalate (BBP) aggravates neurotoxic outcomes and characterized associated cell-type-resolved brain responses. In HT-22 neuronal cells, concentration-response matrix analysis revealed a positive interaction pattern between PE-NPs and BBP. A 90-day oral exposure model was then established in mice using pristine 50 nm PE-NPs, BBP, and their combination. Compared with single exposures, concurrent exposure caused more pronounced impairment in locomotor/exploratory behavior and spatial learning, accompanied by aggravated hippocampal neuronal and synaptic injury, neurotransmitter disturbance, enhanced glial reactivity, and reduced tight-junction-associated markers. Whole-brain single-nucleus RNA sequencing of control and co-exposure groups identified co-exposure-associated transcriptional alterations across neuronal, glial, and endothelial populations, involving synaptic organization, mitochondrial bioenergetics, glial/complement responses, and neurovascular barrier-related processes. Cell-cell communication analysis further suggested contraction of neuronal adhesion/trophic and vascular-associated signaling networks under the co-exposure condition. Targeted qRT-PCR validation using all four exposure groups supported representative snRNA-seq-derived candidates, including decreased Rbfox3, Rims1, Erbb4, Nrg1, Ptprm, and Cldn5 and increased Apoe and C1qa, with significant PE-NP × BBP interactions detected for Apoe, C1qa, and Cldn5. Overall, these findings show that concurrent PE-NP and BBP exposure aggravated neurotoxic outcomes and highlight the need to consider mixed plastic-derived contaminants in neurotoxicity assessment.