## 5 Neurodegenerative Diseases and Environmental Factors
Studies on organisms, including mammals, have demonstrated that ingested plastic particles can diffuse throughout the organism, exerting harmful effects on numerous organs at the macroscopic, histological, and metabolic levels [98; 99]. These particles tend to accumulate in tissues, particularly in the liver and intestine, leading to cytotoxicity, inflammation, alteration of genetic expression profiles, and metabolic changes [100]. The digestive tract, renowned for its absorptive function, offers an efficient route for orally ingested particles to enter the body, much akin to the mechanisms observed in many oral delivery formulations based on polymeric nanoparticles designed to withstand degradation by enzymes and acids during transit [101]. To gain entry into the body, both MPs and NPs acquire a biomolecular corona composed of proteins and other biomolecules that accumulate on their surface [102]. Consequently, factors such as the size, negative charge, hydrophilicity, and Van del Waals' forces of MPs and NPs facilitate their passage through the mucus layer of the gastrointestinal epithelium and trans-intestinal transport, primarily reliant on endocytosis, wherein the particles traverse through the cell and are released at the basolateral membrane. In vitro experiments have underscored the ability of PS-plastic particles to traverse biological plasma membranes, with various sizes (50-500 nm) internalized through diverse mechanisms such as passive diffusion, endocytosis, and macropinocytosis, as evidenced by studies on cultured cells [103]. PS-NPs (50 nm) follow a water-phospholipid partition system and are internalized through endocytosis via the clathrin-and caveolin-mediated pathways and through micropinocytosis. The lysosomes represent the main accumulation site, where the plastic particles are transported through an energy-dependent mechanism. Interestingly, the same authors analyzed the mechanism of NPs release for the first time, which relies on both lysosomal exocytosis by energy consumption and an energy-free penetration mechanism [103]. MPs and NPs induce an imbalance in the gut microbiome, characterized by an increase in harmful bacteria and a reduction in beneficial bacteria, which could compromise the intestinal barrier. Consequently, certain bacterial products or species may breach into the bloodstream, potentially causing damage to other tissues and organs [104]. The gut microbiota may significantly influence the effects of foreign environmental pollutants on the nervous system. A recent study hypothesizes that NPs ingested through the digestive tract could alter the composition of the gut microbiota, subsequently impacting the host's rhythmic function and causing damage to the nervous system [105]. Additionally, enteric neurons, situated in the gut wall, are likely the initial neurons exposed to MPs and NPs, given their location and involvement in regulating gastrointestinal functions. It is suggested that central neurodegeneration might originate peripherally, with growing evidence implicating the enteric nervous system in various neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases, possibly mediated by interactions with the gut microbiome [106, 107, 108, 109]. The intestinal absorption pathway serves as a conduit for plastic particle uptake, potentially leading to their dissemination into non-target organs and tissues via the bloodstream and systemic circulation, including the CNS. Thus, the involuntary intake of plastic particles may be a crucial aspect triggering the initial development of neurodegenerative diseases or accelerating the illness' progression. The effects of MNPs on enteric neurons' morphology and functionality have been hypothesized [110, 111]. However, even though these features have not been extensively studied yet, an important advancement in this field has been made by studying bigger sizes of plastic particles (namely, PET-MPs), and the effects on the enteric nervous system in animal models have now been demonstrated [112].