Brain single-nucleus transcriptomics highlights that polystyrene nanoplastics potentially induce Parkinson’s disease-like neurodegeneration by causing energy metabolism disorders in mice

With the prevalence of nanoplastics in daily life, human exposure is inevitable. However, whether and how nanoplastics cause neurotoxicity in humans remains obscure. Herein, we conducted a 28-day repeated dose oral toxicity study in C57BL/6 J mice exposed to 0.25-250 mg/kg body weight (BW) polystyrene nanoplastics (PS-NPs, 50 nm). We revealed that PS-NP-caused Parkinson's disease (PD)-like neurodegeneration in mice by multiple approaches. Furthermore, a single-nucleus RNA sequencing of 62,843 brain nuclei unearthed PS-NP-induced cell-specific responses in the mouse brains. These disturbed responses among various brain cells were primarily linked with energy metabolism disorder and mitochondrial dysfunction in all brain cells, and especially in excitatory neurons, accompanied by inflammatory turbulence in astrocytes and microglia, dysfunction of proteostasis and synaptic-function regulation in astrocytes, oligodendrocytes, and endotheliocytes. These responses may synergize in PS-NP-motivated PD-like neurodegeneration pathogenesis. Moreover, we verified these single-nucleus transcriptomics findings on different brain regions and found that PS-NPs potentially caused PD-like neurodegeneration primarily by causing energy metabolism disorder in the substantia nigra pars compacta (SNc) and striatum. This manifested as decreases in adenosine triphosphate (ATP) content and expression levels of ATP-associated genes and proteins. Given nanoplastics' inevitable and growing exposure risks to humans, the neurological health risks of nanoplastic exposure warrant serious consideration.