## 7 Molecular Effects of Nanoplastics in Processes of Neurotoxicity
### Nanoplastics Affect the Transcriptomics and Epigenomic in Neuronal Models  
Transcriptomic analysis serves as a powerful tool for unraveling the intricate regulatory networks within cells and identifying specific altered pathways and deregulated genes. This method enables the simultaneous detection of gene regulation on a large scale, offering mechanistic insights. Such an approach has been instrumental in understanding the deregulatory effects of NPs at the gene expression level. From this perspective, the alterations of gene regulation by NPs in biological in vivo and in vitro models suitable for neurological studies are described to achieve a deeper insight into the molecular mechanisms involved in neurotoxicity processes, which could lead to or could interplay with other factors in neurodegenerative processes caused by these environmental contaminants. Nearly a decade ago, [PERSON] et al. [140] published one of the pioneering papers describing the effects of PE-NPs with an average particle size of 33 nm on transcripts in a neural model characterized by a 3D neuroscience system. PE-NPs were found to reduce the transcript levels of _NOTCH_ pathway genes, including _NOTCH1_ and _HESS5_, as well as downstream neuronal precursor genes (_NEURODI_, _ASCL1_, _FOXG1_). The dysfunction of these genes results in severe nervous system impairments in mice, particularly affecting neurodevelopmentalments. More recently, [PERSON] et al. [141] demonstrated that an imbalance in _NOTCH1_ signaling might be implicated in AD, where _NOTCH1_ plays a role in regulating the proteolytic processing of amyloid precursor protein (APP). In studies focusing on gene expression and exposure to NPs in animal models, [PERSON] et al. [142] provided transcriptomics data on isolated nuclei from frozen brains of adult male C57 BL/6 J mice, commonly used in neurobiology studies, which were exposed to 50 nm pristine PS-NPs. The analysis revealed evidence of [PERSON]'s disease-associated genes among differentially expressed genes (DEGs). Astrocytes exhibited the highest number of DEGs (597 genes), followed by oligodendrocyte, neurons, and endotheliocytes, with 486, 326, and 280 DEGs, respectively. PS-NPs were found to inhibit multiple biological processes in a cell-specific manner, including mitochondrial function, proteostasis, ATP metabolism, and synaptic function regulation. Notably, ATP metabolism was the most enriched biological process in neurons, while mitochondrial and proteostasis functions were most enriched in neurons, oligodendrocytes, astrocytes, and endotheliocytes. Furthermore, synaptic function regulation was enriched in astrocytes and endotheliocytes. Overall, the genes and pathways analyzed by these authors provide a comprehensive understanding that PS-NPs induce PD-like neurodegeneration through cell-specific pathways in mouse brains. In the same mouse model, exposure to NPs through the diet revealed neurotoxic effects by reprogramming circadian rhythm-related genes involving the gut-brain axis [105]. Key genes involved in PS-NPs neurotoxicity include _Camk2g_, which encodes a calcium/calmodulin-dependent protein; _Adcyap1_, encoding key mediators of neuroendocrine stress responses; and _Per1_, a critical gene in circadian rhythms. Thus, the ingestion of PS-NPs could affect the expression of genes related to circadian rhythms in the hippocampus through dietary intake, affecting the gut-brain axis, reducing neuroplasticity, and further causing nerve damage in mice. These findings in mice offer a distinct perspective on the potential effects of exposure to NPs through ingestion via contaminated food and water consumption, and further support the role of the \"gut-brain axis\" described in Section 6. Recent studies have examined the gene expression profiles following exposure to NPs using in vitro neuronal cell models. In one study, different metabolic pathways were identified in human neural stem cells (hNS1) exposed to 0.5, 2.5, and 10 ug/mL of PS-NPs for 4 days.