Plastamination: A Rising Concern for Parkinson's Disease

Parkinson's disease (PD) is the fastest growing neurological disorder with an estimated incidence far exceeding that expected based on increased life expectancy,1 suggesting a significant environmental contribution. The current massive increase in plastic production together with exceptionally low rates of recovery and recycling have led to the accumulation of over six gigatons of plastic waste in all environmental compartments, from the atmosphere to the sea to the soil, including the summit of Mount Everest,2 a phenomenon leading some authors to coin the term ‘plastamination’.3 This debris is broken down through several processes into secondary micro- and nanoplastics (MNPs), with particle sizes defined as <5 mm and <1 μm, respectively, which have been discovered widely in different organism specimens across the food chain.2, 3 Humans are constantly exposed to MNPs, mainly via ingestion and inhalation, intaking on average 0.1–5 g every week.4 Inevitably, MNPs have also been detected in several human specimens including the brain.2, 3 Therefore, MNPs represent a significant, but invisible, threat to human health, but their contribution to the development of PD has not yet been appreciated. The commonest route of exposure to MNPs is through diet, as demonstrated by their detection in gastrointestinal tissues and stools.2 However, their identification in other tissues has suggested their possible translocation across various barriers in the body, prompting further research to explore whether MNPs could accumulate at far distant sites including the brain. Indeed, after ingestion and absorption, MNPs can enter the brain through the blood–brain barrier (BBB).5, 6 Accordingly, it has been shown that orally consumed MNPs can accumulate in the brain of mice7 and fish8 models. In the real world, brain accumulation of MNPs has been documented in wild fish in a contaminated estuary.9 Conversely, in one study using the terrestrial model organism Drosophila melanogaster, MNPs were not found to accumulate in the brain after dietary exposure.10 It should be noted, however, that Drosophila has a distinct BBB structure compared with vertebrates, which among other reasons might explain this discrepant finding. Indeed, factors such as their shape, size, and concentration or the length of the exposure influence MNPs’ propagation into the brain.8, 11, 12 Beyond the oral route, accumulation of MNPs in the brain can occur after inhalation as demonstrated in mice models12, 13 and as suggested by a recent study which demonstrated the presence of MNPs in the olfactory bulb of human brains.14 Although the most likely hypothesis is that translocation might have occurred via lymphatic vessels that surround the olfactory axons at the level of the cribriform plate, other possibilities include systemic circulation, crossing the BBB, or via the respiratory pathway through the trigeminal nerve.14 Furthermore, MNPs can be absorbed percutaneously,15 although it is not known whether this route of exposure is relevant for subsequent brain translocation, and via placental transmission. Documentation of MNPs in several areas of offspring's brains including the striatum after maternal exposure throughout gestation16 is another source of concern in humans regarding the fact that exposure might start even before birth. Although some of the aforementioned studies (the methodological aspects of which are summarized in supplemental Table S1) used brain lysates suggesting the possibility that the detected MNPs originated from blood vessels, accumulation of MNPs in decedent human brains has been confirmed in an additional study.17 In the two available human studies,14, 17 multiple approaches for MNP detection were used: (1) the cryo-cuts method, which preserves the spatial context of MNPs within the tissue, allowing their proximity to anatomical structures such as blood vessels to be observed; and (2) the digestion method, which ensures that MNPs that are deeply embedded in the tissue are not overlooked. Therefore, it is very likely that the detected MNPs do not simply originate from blood vessels. Interestingly, MNP levels were 7–30 times greater in brain samples than in liver or kidney,17 which suggests, among other possibilities, that clearance mechanisms might be less efficacious in the brain. Of note, MNP levels were found to be significantly higher in 2024 than in 2016 brain samples,17 emphasizing their exponentially rising environmental presence. MNPs entering the brain via multiple routes can then propagate at different sites. Supporting evidence for this was found in one study showing that inhaled MNPs were transported from the olfactory bulb to the cerebrum, cerebellum, and basal forebrain.18 Given the ease of access through the oral route and the critical role of the gut−brain axis in brain functioning, the hypothesis that MNPs might further exert their neurotoxic effects indirectly via the gut−brain axis has been raised.19 Although there are no investigations that have explored directly the possible gut-mediated, neurotoxic effects of MNPs on PD pathophysiological pathways and/or in PD animal models, a group of studies have provided evidence of their detrimental results on the gut–brain axis in non-PD models, reporting outcomes including microbiota alterations, disrupted intestinal barrier permeability, oxidative stress, inflammation, neurotoxicity, neurotransmitter release alterations, and behavioral disturbances.19 In this section, we therefore briefly speculate about the possible mechanisms reconnecting these lines of evidence to PD. Although some inconsistencies exist about the spread of ⍺-synuclein (⍺-syn) from the gut to the brain, some evidence has supported the hypothesis that a yet unknown insult would first induce pathology in a peripheral organ, like the gut, to subsequently spread to the brain (eg, in ‘body-first PD’). Within this framework, cross-seeding by various amyloidogenic proteins has been demonstrated,20 certain amyloid-producing bacteria have been found enriched in the microbiome of PD patients,21 and gut microbial amyloids were shown to increase ⍺-syn accumulation in Caenorhabditis elegans.22 Moreover, ⍺-syn aggregation can be promoted by lipopolysaccharide,23 a major component of Gram-negative bacteria, and exposures to Enterobacteriaceae has been shown to exacerbate ⍺-syn pathology in both ⍺-syn- and toxic-based PD models.24-26 These lines of evidence support the concept that altered microbiota may trigger and/or exacerbate ⍺-syn misfolding, and given that MNPs have been demonstrated to alter microbiota composition,19 this might represent one mechanism linking MNPs’ exposure to PD through the gut–brain axis. An additional, not mutually exclusive, mechanism linking MNPs to PD is through inflammation. Indeed, MNPs have been shown to disrupt the intestinal barrier permeability and induce local and systemic inflammation.19 The latter can be driven by both direct effects on the mucosal cells as well as by change in the microbiota composition and both aspects seem relevant to PD. Indeed, gastrointestinal mucosal inflammatory damage has been estimated to confer a 76% greater risk of developing PD.27 The importance of co-occurrent disruption of the epithelial barrier, inflammation, and PD risk may be further supported by its possible association with inflammatory bowel diseases.28 Moreover, microbiota alterations, with a reduction of taxa with anti-inflammatory effects, have been reported in PD patients.29, 30 Local inflammation can therefore disrupt microbiota composition, triggering or fostering ⍺-syn misfolding; and subsequent systemic inflammation might further reverberate to the brain, priming microglial cells into an active state responsible for stronger responses dealing with an incipient neurodegenerative process.31 These processes are arguably intertwined and might be reasonably triggered by MNPs in subjects at risk for developing PD. Preliminary studies have demonstrated changes in social and motor behavior associated with alterations in dopaminergic circuits in rodent32 and fish33 models exposed to MNPs. In a 28-day oral toxicity study, MNPs induced gene expression alteration and cell-specific responses in mouse brains that were primarily linked with energy metabolism disorder and mitochondrial dysfunction in all brain cells, including those of the substantia nigra pars compacta (SNc) and striatum, and that were associated with diminished neurobehavioral and motor activity.34 Similarly, in another 28-day repeated oral gavage study in mice, the open-field test revealed a dose-dependent decrease in movement distances for exposed mice.35 The behavioral findings were associated with targets and toxicity mechanisms shared in PD-like neurodegeneration. In fact, staining experiments on nerve cells unveiled a dose-dependent reduction in Nissl bodies and TH-positive cells as well as a dose-dependent elevation in TUNEL-positive cells indicative of an increase of apoptotic cells in the SNc of mice exposed to MNPs.35 Further transcriptomic analysis revealed changes in differentially-expressed-genes associated with calcium ion homeostasis, which were upregulated, and with ATP metabolic processes, which were decreased.35 Accordingly, there was an elevation in mitochondrial calcium concentration and a reduction in tissue ATP content in the midbrain of exposed mice, which was not observed in the cortex, hippocampus, and striatum.35 Another study explored MNP-induced cytotoxicity, mitochondrial integrity and functioning, and ATP level alteration in dopaminergic-differentiated SH-SY5Y cells showing significant mitochondrial damage, characterized by altered morphology, reduced mitochondrial membrane potential, and decreased ATP production followed by excessive mitophagy and subsequent cell death.36 Notably, in vivo experiments demonstrated the potential of melatonin of mitigating dopaminergic neuron loss and motor impairments by restoring mitophagy regulation in mice.36 Although there are methodological differences across the aforementioned studies (Table S2), they provide converging evidence of the selective vulnerability of midbrain dopaminergic neurons mainly through mitochondrial dysfunction, linking these alterations to reduced motor activity. The molecular mechanisms whereby these alterations occur remain largely unknown, but in one study molecular docking analyses and dynamic simulations suggested that they might result from the interaction of MNPs with the mitochondrial complex I,36 and overwhelming evidence suggests that dopaminergic neurons are particularly vulnerable to mitochondrial stressors.37 Initial evidence has been produced that MNPs, especially anionic polystyrene particles, have high affinity with α-syn protein through a hydrophobic binding between the benzene ring and the amphipathic domain and the adjoining non-amyloid component (NAC) domain of α-syn.38-40 This interaction induces aromatic acid residue exposure and modifies α-syn secondary structure, promoting its fibrillization with a decrease in α-helices monomers and an increase in β-sheet oligomers, which have even higher affinity with MNPs.38-40 Furthermore, MNPs speed the aggregation kinetics of the NAC domain in a dose-dependent manner.39 Cell studies have further demonstrated co-localization of MNPs and α-syn aggregates at the lysosomal level and a mild lysosomal dysfunction that further slows down aggregated α-syn degradation and an increase in fibril-seeded pS129–α-syn inclusions.41 An increase in α-syn pathology was further observed in animal model studies.39, 40 Notably, α-syn pathology could be demonstrated across interconnected brain regions including dopaminergic neurons in the SNc and it was observed in about 30% of wild-type mice exposed to MNPs only (ie, without α-syn pre-fibrils), suggesting a ‘de-novo’ induction.40 The methodological details of these studies are available in Table S3. The evidence that MNPs can initiate and/or foster the pathophysiological mechanisms that are the basis of PD are only beginning to appear (Fig. 1) and, in the current viewpoint, we have collated existing research to suggest that MNPs might likely represent a major environmental culprit of this prevalent disorder, which has long been postulated to be a multifactor disease, despite the search for its environmental contributors having been mostly unsuccessful. Clearly, MNPs are appearing to contribute to other neurogenerative diseases, promoting β-amyloid aggregation peptides in Alzheimer's disease and increasing oxidative stress in amyotrophic lateral sclerosis (ALS), which emphasizes their more general neurotoxic effects.42 However, the evidence reviewed here would suggest a selective vulnerability of the dopaminergic system to MNPs as well as their promotion of α-syn oligomer emergence and fibrillization that would account for the motor deficits observed in animal models. It is therefore conceivable to speculate that MNP exposure might trigger PD pathophysiology in humans in predisposed subjects, according to a double- or multi-hit framework.43, 44 Since this research is still only in its early stages, there remain several knowledge gaps, especially in terms of methodology, which require immediate attention. First, while we have here collated evidence about MNPs on a broad scale, it has been demonstrated that their shape, size, and aging, among other factors, influence their neurotoxic properties.8, 11, 12 Second, future research should evaluate the neurotoxic effects of MNPs at environmentally realistic concentrations.42 Third, most research has explored the effects of single, specific MNPs, but humans are constantly exposed to a multitude of MNPs and other pollutants that are commonly bound to plastics and that exacerbate their neurotoxicity such as plasticizers, flame retardants, mechanical stabilizers, and persistent organic pollutants.42 Moreover, MNPs are well known for vector transport of heavy metals, which are arguably another environmental culprit of PD,45 and additional evidence is being generated concerning their combined neurotoxic effects.42, 46 All these gaps clearly add a layer of complexity, but one possible avenue of future research could be exploring the exposome, which is defined as the totality of environmental exposures throughout an individual's life.47 Exposomic science currently operates on an omics scale, enabling the simultaneous examination of various molecular components, including genomics, transcriptomics, proteomics, and metabolomics, and allowing for a holistic investigation of the intricate interplay between different environmental influences and biological responses.47 Environmental plastamination is predicted to double by 2040 and, given this increasing concern, global action is therefore needed, even based on the precautionary principle, to reduce emissions, whereas future resea should eventually identify measures to mitigate or counteract MNPs’ neurotoxicity. (1) Research Project: A. Design, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Design, B. Writing of the First Draft, C. Review and Editing the Final Manuscript. R.E.: 3A, 3B, 3C. C.S.: 3C. P.B.: 3C. Open access publishing facilitated by Universita degli Studi di Salerno, as part of the Wiley - CRUI-CARE agreement. Nothing to report. Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.