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Neurotoxicity and Mechanisms of Microplastics and Nanoplastics Exposure in Terrestrial Mammals

Yuji Huang , Kailin Xu , Boxuan Liang , Yizhou Zhong , Maoyong Song , Zhenlie Huang

Progress in Chemistry ›› 2025, Vol. 37 ›› Issue (1) : 76 -88.

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Progress in Chemistry ›› 2025, Vol. 37 ›› Issue (1) : 76-88 DOI: 10.7536/PC240709
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Neurotoxicity and Mechanisms of Microplastics and Nanoplastics Exposure in Terrestrial Mammals
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Abstract

Microplastics and nanoplastics (MNPs) pollution has become a serious environmental issue. MNPs can enter the human body through inhalation, ingestion, and skin contact, raising significant concerns about their potential risks to the nervous system. This paper reviews the studies on the neurotoxic effects of MNPs in terrestrial mammals, focusing on their possible toxic mechanisms. Studies have shown that MNPs can cause damage to the nervous system by inducing oxidative stress, inflammatory responses, and mitochondrial dysfunction. Additionally, the impact of MNPs on the gut-brain axis is considered a crucial mechanism leading to neurotoxicity. Despite current progress, there are still insufficient data and incomplete understanding of the neurotoxic mechanisms involved. Future research should enhance epidemiological studies on MNP exposure, develop more suitable experimental models, investigate the health effects of different types of MNPs, explore their mechanisms in greater depth, and comprehensively assess various influencing factors. These efforts will provide essential insights for a more thorough understanding of the impact of MNPs on human health.

Contents

1 Introduction

2 Human exposure to MNPs

2.1 Routes of human exposure to MNPs

2.2 Detection of MNPs in human tissues and organs

3 Neurotoxic effects of MNPs

3.1 Cognitive impairment

3.2 Behavioral abnormalities

3.3 Neurodevelopmental toxicity

3.4 Alterations in brain structure

3.5 Combined neurotoxic effects of MNPs and other environmental pollutants

4 Mechanisms of toxicity

4.1 Oxidative stress

4.2 Neuroinflammation

4.3 Mitochondrial dysfunction

4.4 Synaptic function and neurotransmitter balance

4.5 Gut-brain axis mechanism

5 Conclusion and outlook

Graphical abstract

Keywords

microplastics and nanoplastics / nervous system / mammals / toxic mechanisms

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Yuji Huang, Kailin Xu, Boxuan Liang, Yizhou Zhong, Maoyong Song, Zhenlie Huang. Neurotoxicity and Mechanisms of Microplastics and Nanoplastics Exposure in Terrestrial Mammals. Progress in Chemistry, 2025, 37(1): 76-88 DOI:10.7536/PC240709

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1 Introduction

As the use of plastic products becomes more widespread, the problem of plastic pollution is becoming increasingly severe. Data shows that global plastic production reached 368 million metric tons in 2019, and it is projected to double by 2039[1]. During the COVID-19 pandemic, the extensive use of single-use plastic protective items (such as masks, gloves, etc.) further exacerbated global plastic pollution[2].
Abandoned plastics are difficult to degrade in the natural environment, but under the influence of various environmental factors such as photochemical reactions, physical shearing, and biological actions, they fragment into plastic particles[3]. Microplastics (MPs) refer to plastic particles with a diameter less than 5 mm, while nanoplastics (NPs) refer to plastic particles with a diameter less than 100 nm[4]. Microplastics and nanoplastics (MNPs) are now widely present in water bodies, soil, and air. In the coastal waters of China, the concentration of MNPs can reach up to 9,575.50 per m³; whereas in freshwater systems, the detectable concentrations range from tens to tens of thousands per m³[5]. In soils, especially agricultural soils, the concentration of MNPs can be between 1,430 and 3,410 per kg[6]. The concentration of MNPs in the air is also not negligible, with the number of MNP particles per cubic meter of air in eastern coastal cities of China being (224 ± 70)[7]. Humans have inevitably been exposed to MNPs, posing a potential threat to health[8-9].
As concerns about the health risks of MNPs to humans increase, the focus of toxicity studies is gradually shifting from aquatic organisms to higher terrestrial mammalian models, in order to further investigate their potential harm to human health. Currently, the target organs for MNP toxicity effect studies mainly include the gastrointestinal tract, nervous system, cardiovascular system, liver, kidneys, reproductive development system, and immune system, etc.[10]. However, research on the neurotoxic effects and molecular mechanisms of MNPs in terrestrial mammals is limited. Previous reviews on MNP neurotoxicity have primarily focused on summarizing neurotoxicity in non-mammals[11], and there is an urgent need for a systematic review of MNP neurotoxicity in terrestrial mammals. This paper aims to provide a comprehensive review of the neurotoxic effects and toxic mechanisms of MNPs in terrestrial mammals, in conjunction with human exposure scenarios, to offer references for further exploring the neurotoxic effects of MNPs on humans and to propose key scientific questions that future research should address.

2 Exposure Of Mnps To The Human Body

2.1 Exposure Ways Of Mnps To The Human Body

The main ways humans are exposed to MNPs include inhalation, ingestion, and dermal contact[12]. Although dermal contact accounts for a relatively small proportion of total human exposure to MNPs, skin exposure still occurs when the skin comes into contact with personal care products or water containing MNPs. In personal care products, the particle size of MPs typically detected is about 10-100 μm[13-14], while the pore size of human skin is approximately 40-80 μm[15]. Despite the protective barrier function of the skin, components in personal care products, such as oleic acid and ethanol, can increase the fluidity of intercellular lipids, thereby promoting the transdermal delivery of MNPs[16]. A survey in Iran found that the skin on the face and hands adsorbs more than 4,000 MNP particles in a day[17].
Oral ingestion and inhalation are considered the primary exposure routes for MNPs. Humans may be directly exposed to MNPs in drinking water, sea salt, and air, or indirectly through the food chain[18-19]. MNPs have been detected in the air in various regions, whether in urban areas with frequent human activity[20-21], or in remote areas (such as the Arctic, atmospheric boundary layer, etc.)[22-23]. It is estimated that adults inhale 1.9 × 103 to 1.0 × 105 MNPs annually from indoor air and 0 to 3.0 × 107 MNPs from outdoor air[24]. It should be noted that, in addition to entering the body via inhalation, airborne MNPs can also enter the body by being ingested after settling on food surfaces[25]. MNPs have been found in a wide range of meat and processed foods, including shellfish, fish, salt, beverages, dairy products, and meats[26⇓⇓⇓-30]; even many agricultural products such as carrots, apples, lettuce, watercress, and broad beans have tested positive for MNPs[31⇓-33]. Seafood, in particular, requires special attention because MNPs can accumulate through the food chain, leading to higher concentrations in these foods[34]. Another major source of oral intake is drinking water, where the concentration of MPs varies between 0 and 104 particles/L, and for smaller NPs, the particle count may be even higher[35].
Currently, due to the difficulties in sampling and analytical techniques for MNPs, especially NPs, accurately assessing the actual exposure levels in humans or organisms remains challenging. Researchers estimate that the annual MPs exposure per person is approximately 74,000 to 121,000 particles; however, this estimate does not take NPs into account, so the actual exposure may be higher[18]. Another higher estimate suggests that the average weekly intake of MNPs by humans is 0.1 to 5 g[36].

2.2 Detection Of Mnps In Human Tissue And Organs

Due to the small volume of MNPs, they can pass through physiological barriers in the human body and enter the interior of the organism. Once MNPs enter the circulatory system, they may diffuse and transfer in various tissues and organs[37-38] ( Figure 1). In human blood samples, MNPs have been detected at a concentration of about 1.6 μg/mL, confirming that MNPs can diffuse in the circulatory system[39]. Studies have also found the presence of MNPs in the liver, spleen, and kidneys, providing evidence for the aggregation of MNPs in peripheral organs through the circulatory system[40]. The concentrations of MNPs in other parts of the human body, such as hair, colon, lungs, and placenta, have also been reported[17,41⇓-43]. In addition, the presence of MNPs has been detected in the enclosed internal environment of the human vitreous humor[44]. The types of MNPs currently detected in the human body include polypropylene (Polypropylene, PP), polystyrene (Polystyrene, PS), polyvinyl chloride (Polyvinyl chloride, PVC), nylon-66 (Nylon 66, PA66), polyethylene terephthalate (Polyethylene terephthalate, PET), polymethyl methacrylate (Polymethyl methacrylate, PMMA), etc. ( Table 1).
Due to the difficulty in obtaining human brain tissue samples, there are currently no research reports on the detection of the distribution of MNPs in human brain tissue. However, a large amount of animal experimental data has already proven that MNPs can enter animal brain tissue. An in vivo experiment showed that after oral intake of MNPs for only 2 h, accumulation of MNPs could be detected in the brain tissue[45]. This suggests that MNPs (especially NPs) can enter the bloodstream through gastrointestinal absorption and cross the blood-brain barrier to enter the brain. In addition, MNPs can also directly enter the brain via the respiratory route (without passing through the bloodstream). One study pointed out that compared with MNPs injected into the blood via the tail vein, inhaled MNPs tend to accumulate more in the brain rather than in the liver[46]. Therefore, based on the results of ex vivo fluorescence imaging, researchers speculate that MNPs can be transported to the olfactory bulb and cerebral cortex of mice via the olfactory nerve pathway, as well as to the cerebellum and pons via the trigeminal nerve pathway[46].

3 The Neurotoxic Effects Of Mnps

The neurotoxic effects of MNPs are an important component in assessing their risk to human health. Early studies primarily focused on lower organisms and aquatic life[11]. In recent years, the impact of MNPs on the nervous systems of terrestrial mammals has gradually attracted significant attention. In one of the earliest studies evaluating the neurotoxicity of MNPs in mammals, researchers administered 1, 3, 6, and 10 mg/kg of polystyrene nanoplastics (PS-NPs) (25 and 50 nm) via oral gavage to adult male Wistar rats for 5 weeks, but no significant differences were observed in neurobehavioral tests[47]. Researchers speculated that this might be due to a small sample size or low exposure doses[47]. As research progresses, more and more evidence suggests that MNPs have neurotoxic effects on terrestrial mammals, manifesting as cognitive dysfunction, behavioral abnormalities, impaired neural development, and alterations in brain structure.

3.1 Cognitive Dysfunction

Cognitive function is the ability of the brain to process, store, and retrieve information, primarily manifested as learning and memory abilities. Long-term exposure to MNPs significantly affects the cognitive functions of mammals, leading to a decline in learning and memory capabilities. After male BALB/c mice continuously consumed water solutions containing 100 and 1000 μg/L polystyrene microplastics (PS-MPs) for 180 days, compared to the control group, the escape latency in the water maze test was significantly increased, and the discrimination rate in the novel object recognition experiment was also notably reduced, indicating cognitive deficits, and this defect was dose-dependent[48]. Although the study used PS-MPs of different sizes, such as 0.5, 4, and 10 μm, no significant size-dependent differences were observed[48]. In another chronic exposure experiment lasting 180 days, smaller-sized (25 nm) PS-NPs were used. The results showed that with the increase in exposure doses (0, 10, 25, and 50 mg/(kg·d)) of PS-NPs to male C57BL/6 J mice, there was a dose-dependent decline in spatial learning and memory abilities[49]. Studies with shorter exposure times have also found that MNPs affect the cognitive functions of the mouse brain. After 6 weeks of oral gavage with 80 nm PS-NPs (60 μg/d), neuronal damage in the hippocampus led to a decline in learning and memory abilities in male C57BL/6 J mice[50]. Similarly, another study found that after 7 weeks of oral gavage with 30-50 nm PS-NPs (10 and 20 mg/kg), male C57BL/6 J mice exhibited cognitive dysfunction, but their motor function and social behavior were not significantly affected[51]. Additionally, in a short-term exposure experiment lasting only 3 days, male Swiss mice, after intraperitoneal injection of 14.6 ng/(kg·d) 25 nm PS-NPs, also showed a decline in memory ability in the novel object recognition experiment[52]. Gender differences are also an important factor affecting the neurotoxicity of MNPs. In one study, after 8 weeks of oral gavage with 2 μm PS-MPs (8 and 16 mg/(kg·d)), male mice exhibited hippocampal-dependent learning and memory impairments, while female mice were not significantly affected[53]. This gender difference may be related to changes in estradiol, progesterone, or testosterone levels, which play crucial roles in regulating spatial and contextual memory. Further research is needed to clarify the specific mechanisms.
Cognitive dysfunction caused by MNPs may be associated with some common neurological diseases, such as Alzheimer’s disease (AD). In vitro studies have shown that after treating undifferentiated SH-SY5Y cells with 1 μg/cm² of aminated PS-NPs (50 nm) for 48 hours, there is an increase in the secretion of amyloid β (Aβ) and a decrease in neuronal differentiation[54]. Another study found that at concentrations as low as 100 pM, PS-NPs can significantly accelerate the formation of both Aβ40 and Aβ42 subtypes, promoting the accumulation of Aβ oligomers and thus inducing significant neurotoxicity[55]. However, whether MNPs promote the occurrence and development of AD still requires more epidemiological data from population studies and in-depth investigation through animal experiments.

3.2 Behavioral Abnormalities

Behavioral function is another core function of the brain, involving emotion regulation, social behavior, and motor behavior. Exposure of mammals to MNPs can lead to a variety of abnormal behaviors, among which anxiety- and depression-like behaviors are one of the most common emotional disorders induced by MNPs. Male C57BL/6 J mice that were orally gavaged with 0.5 mg/d of 100 nm and 1 μm PS-MPs, after being exposed for 30 days and 60 days respectively, exhibited a high degree of anxiety-like behavior[56]. Specifically, there was a significant reduction in the distance and time percentage of activity in the center area of the open field test, and the time percentage spent in the open arms of the elevated plus maze test was significantly lower than that of the control group[56]. Correlation analysis found that these anxiety-like behaviors were closely related to dysbiosis of the gut microbiota and changes in neurotransmitter metabolism in mice[56]. Another study showed that male C57BL/6 J mice, after being orally gavaged with 2 mg/(kg·d) of 480 nm PS-MPs, exhibited similar anxiety-like behaviors after just one week of exposure, possibly related to pro-inflammatory responses caused by microglial activation[57]. The causes of anxiety-like behaviors are diverse and may be related to the impact on multiple biological functions of the organism. In a six-month study, C57BL/6 J mice, after being orally gavaged with 25 nm PS-NPs at 50 mg/(kg·d), showed decreased sucrose preference and increased immobility time in the tail suspension test, indicating the induction of depression-like behaviors[58]. Additionally, a study explored the effects of PS-NPs (100 nm) with different surface modifications (native, —COOH, and —NH) on mice, and the results showed that these PS-NPs could all disrupt the blood-brain barrier and accumulate in the brain, leading to a series of neurobehavioral changes, including damage to anxiety, depression, and social behaviors[59]. However, another study found that adult male Swiss albino mice, after being orally gavaged with 50 nm PS-NPs (0.2 and 1 mg/(kg·d)) for eight weeks, exhibited anti-anxiety behaviors, a phenomenon that may be related to changes in the neurotransmitter system[60]. In summary, MNPs have a significant impact on the emotional function of mammals, and long-term exposure may trigger diseases related to emotional disorders.
In addition to emotional and social behaviors, MNPs also have a significant impact on motor behavior. After exposure to PS-NPs, the motor activity of mice is impaired[60]. In an oral exposure animal experiment, male C57BL/6 J mice were given 250 mg/(kg·d) of 50 nm PS-NPs by gavage. After 28 days of exposure, they exhibited a marked impairment in motor function. These mice showed decreased activity, reduced latency time in the rotarod test, and decreased grip strength, which are associated with damage to dopaminergic neurons[61]. The study suggests that this PS-NP-induced motor impairment may manifest as neurodegenerative damage similar to Parkinson's disease (PD). Further research has revealed that the toxic mechanism may be related to mitochondrial dysfunction in the brain, and melatonin intervention can mitigate the impact of MNPs on motor function to some extent[62]. The neuropathological characteristics of PD include pathological aggregation of α-synuclein (known as Lewy bodies)[63], which are closely associated with the degeneration of dopaminergic neurons[64]. Anionic NPs have a high affinity for α-synuclein. This interaction can slow down the degradation of α-synuclein, induce the formation of α-synuclein inclusions in dopaminergic neurons, and promote its spread across different regions of the brain[65]. In another study, using a Parkinson's disease model in Caenorhabditis elegans and human neuronal cells, it was found that 25 nm PS-NPs could increase the formation of α-synuclein aggregates, leading to the degeneration of dopaminergic neurons. A significant effect on the motor ability of Caenorhabditis elegans was observed even at a low concentration of 10 μg/L[66]. Although these findings reveal the link between MNP exposure and motor behavior impairment, further research is needed to confirm the correlation with the development of PD in humans.

3.3 Neurodevelopmental Toxicity

Neurodevelopment is a crucial foundation for the normal development and function of the mammalian nervous system, including key steps such as neurogenesis, migration, differentiation, synapse formation, and neural network establishment. Abnormalities at any stage can lead to serious neurological diseases and behavioral disorders[67]. Pregnant SD rats were orally administered PS-NPs of different sizes (25 and 50 nm) from day 1 to day 18 of pregnancy, with exposure doses of 0.5, 2.5, 10, and 50 mg/kg. The placental structural damage in the exposed groups showed a dose-dependent increase[68]. PS-NPs can penetrate the placental barrier, causing oxidative stress and inflammatory responses in various brain regions of the fetus, leading to neurotoxicity and affecting fetal growth and development[68]. Notably, smaller-sized and higher-dose PS-NP exposures have more significant neurotoxic effects on offspring[68]. Additionally, PS-NPs ingested by the mother can be transferred to the next generation through breast milk. When female mice were exposed to 50 nm fluorescent PS-NPs, fluorescence signals from PS-NPs could be detected in the brains of their offspring, which were fed with breast milk, leading to dysfunction of neural stem cells and ultimately resulting in neurodevelopmental defects[69]. Research has also found that there are sex-specific differences in the abnormal brain development of offspring caused by MNPs, which may be related to sex-specific synaptic development, function, and neurotransmitter activity in the hippocampus[70]. Using a 3D model of human forebrain cortical spheroids to simulate early human cortical development, it was found that exposure to 1 and 10 μm PS-MPs had adverse effects on cortical layer differentiation. Long-term exposure to PS-MPs reduced cell viability and downregulated the expression of markers of neuronal maturation[71].
Exposure to MNPs may be one of the risk factors for inducing autism spectrum disorder (ASD)-like behaviors. ASD is a type of neurodevelopmental disorder that occurs in infancy and early childhood, with core symptoms including persistent social deficits and repetitive, stereotyped behaviors and interests[72]. C57BL/6J mice, exposed indirectly through their mothers to 2 μm PS-MPs from the embryonic stage to 4 weeks of age, and then continuously given water containing 1 mg/L PS-MPs for 24 weeks after weaning, exhibited impaired social novelty preference, a form of social deficit, in the three-chamber social test[73]. A study comparing the effects of exposure to 10-20 μm polyethylene (PE) MPs at different life stages on C57BL/6J mice found that whether prenatally exposed (10 μg/d, 2 weeks) or post-weaning exposed (10 μg/d, 2 weeks), the mice showed more repetitive and compulsive behaviors in the Nestlet shredding test, along with decreased social novelty, revealing ASD-like characteristics[74]. These results suggest that exposure to MNPs may be an important cause of some adverse neurodevelopmental outcomes. Therefore, in addition to investigating the impact of MNPs on ASD, it is also worth exploring their effects on other neurodevelopmental disorders, such as intellectual disabilities, attention deficit, and hyperactivity disorders.

3.4 Alterations In Brain Structure

Cognitive dysfunction and behavioral abnormalities are external manifestations of internal damage to the nervous system, indicating that MNPs have caused a certain degree of structural damage to the brain. Among these, the disruption of the blood-brain barrier (BBB) is one of the most frequently reported types of brain structural damage. The BBB is a biological barrier composed of cerebral microvascular endothelial cells, the basement membrane, and surrounding astrocytes. Its primary function is to protect the brain from harmful external substances and maintain the stability of the internal environment of the brain[75]. MNPs can disrupt the BBB, increasing its permeability[48,61,76-77]. NPs can even enter the brain tissue, and this disruption of the BBB is considered an important prerequisite for the neurotoxicity caused by MNPs. For example, NPs penetrate the BBB and accumulate in the brain, leading to the activation of microglia in mice and causing neuronal degeneration[76]. The disruption of the BBB may allow toxic substances to more easily enter the brain tissue, thereby affecting the function and health of neurons[78].
MNPs can also affect the structure of brain neurons. After exposing mice to 500 nm PS-MPs for 4 weeks, Golgi staining revealed a disordered density of dendrites and dendritic spines in the prefrontal cortex neurons[79]. When Kunming mice were orally gavaged with 1 mg/d of 5.0~5.9 μm PS-MPs for 4 weeks, the neurons in the hippocampus showed signs of disorder and relaxation, with dispersed pyramidal neurons and a reduction or absence of main dendritic structures in the brain[80]. MNPs not only affect the morphology of neurons in the brain but also their numbers. There is evidence that PS-NPs may lead to the loss of dopaminergic neurons by causing mitochondrial dysfunction and energy metabolism disorders in the substantia nigra region of the mouse brain[61]. In C57BL/6 J mice exposed to PS-MPs, hematoxylin and eosin (H&E) staining of brain tissue showed darker nucleolar staining in neurons and a significant decrease in the number of neuronal cells in the hippocampus[48]. Similarly, after exposure to PS-MPs, the number of Nissl bodies in the hippocampus of Kunming mice was significantly reduced[80].

3.5 The Combined Neurotoxic Effects Of Mnps And Other Environmental Pollutants

In addition to the direct effects of MNPs, they often coexist with other chemical pollutants in water, soil, and air, forming a complex exposure environment. This environment allows MNPs and other pollutants to potentially produce combined toxic effects[81]. For example, when polystyrene microplastics (PS-MPs) and the plasticizer di(2-ethylhexyl) phthalate (DEHP) are co-exposed, they cause more severe damage to mitochondrial function in mouse neurons, leading to more pronounced apoptosis, indicating a synergistic toxic effect[82]. Furthermore, the co-exposure of DEHP and polypropylene microplastics (PP-MPs) also exhibits additive or synergistic toxic effects, inducing significant neurocognitive deficits in young mice[83].
The combined neurotoxic effects of MNPs and residual antibiotics in the environment have also attracted attention. The co-exposure to doxycycline (Dox) and PS-MPs disrupts the gut microbiota homeostasis in mice, mediates inflammatory damage in the brain, and leads to a decline in learning and memory abilities. Although the co-exposure to Dox and PS-MPs exhibits synergistic neurotoxic effects, Dox does not exacerbate the gut damage caused by PS-MPs[84]. Additionally, the combined toxic effects of MNPs and heavy metals are another research focus. Studies have found that 9-month-old male C57BL/6 J mice, after drinking water containing ammonium ferric citrate (5 g/L) and 5 μm PS-MPs (1000 μg/L) for three months, experienced an accumulation of iron in the brain due to the presence of PS-MPs, leading to iron homeostasis disruption, which in turn triggered ferroptosis-related lipid peroxidation and inflammation, further aggravating cognitive impairment[85].
It is noteworthy that in a 3-day short-term exposure experiment, male Swiss mice were intraperitoneally injected with 14.6 ng/kg of PS-NPs (25 nm) and zinc oxide nanoparticles (70 nm). Although individual exposures led to cognitive impairment in the mice, combined exposure did not exhibit additive or synergistic neurotoxic effects[52]. The increased joint toxic effect may be related to the high specific surface area of MNPs, which can physically or chemically adsorb other pollutants, thereby increasing the potential health risks associated with MNPs[86]. Although some studies have preliminarily explored the combined neurotoxic effects of MNPs with other pollutants, current research remains limited. Future studies should focus more on the impact of multiple exposures to MNPs and other pollutants in real environments on human neurological health.

4 Discussion On The Mechanism Of Toxic Action

4.1 Oxidative Stress

Oxidative stress is considered one of the important mechanisms by which MNPs exert neurotoxic effects[11]. Oxidative stress refers to a state where the redox balance in the body is disrupted, leading to the accumulation of reactive oxygen species (ROS) and causing damage to cells and tissues. ROS are reactive chemical species containing oxygen, including superoxide anion (Superoxide anion, O2•−), hydrogen peroxide (Hydrogen peroxide, H2O2), and hydroxyl radical (Hydroxyl radical, ·OH). The production of ROS induced by MNPs in organisms involves various biomolecular mechanisms. One key mechanism is the activation of NADPH oxidase (NADPH oxidase, NOX), which is a complex enzyme responsible for producing O2•−[87]. Mice exposed to MNPs can activate NADPH oxidase through multiple pathways, including the activation of Toll-like receptor 4 (Toll-like receptor 4, TLR4) and aryl hydrocarbon receptor (Aryl hydrocarbon receptor, AhR)[88]. Once activated, NOX produces O2•−, which is further converted into other ROS, such as H2O2 and ·OH.
In addition, MNPs can also exacerbate oxidative damage by disrupting the antioxidant defense system. Antioxidant enzymes, including peroxidase, catalase, superoxide dismutase, and glutathione peroxidase, play a crucial role in protecting tissues from ROS damage, and their activities are often used as biomarkers of oxidative stress. Studies have shown that exposure to PS-NPs significantly alters the activity of these antioxidant enzymes in mouse brain tissue, indicating a significant oxidative stress response[60,89]. In vitro experiments have also demonstrated that MNPs can induce the production of large amounts of ROS in mouse hippocampal neuronal HT22 cells, leading to cellular oxidative damage[90].
The central nervous system, due to its high oxygen demand and lower antioxidant capacity, is very sensitive to oxidative stress[91]. High levels of ROS can directly damage the biological macromolecules of neural cells, leading to cell death. For example, PS-NPs cause an increase in ROS levels, which promotes lipid peroxidation and induces ferroptosis in the mouse microglial cell line BV2[92]. PS-MPs induce apoptosis by increasing ROS production, and blocking ROS can alleviate this apoptosis[93]. Additionally, oxidative stress can also activate microglia and astrocytes, triggering a neuroinflammatory response that further exacerbates neural damage[94]. The neuroinflammatory response not only increases oxidative damage to neural cells but may also trigger inflammation of the blood-brain barrier, further aggravating the neurotoxic effects caused by MNPs. For instance, PS-NPs induce an inflammatory response in human brain microvascular endothelial cells (hCMEC/D3), which is associated with cellular oxidative stress[76]. Therefore, oxidative stress triggered by MNPs may lead to neuronal damage and death, thereby affecting the cognitive and behavioral functions of the nervous system.

4.2 Neuroinflammation

Neuroinflammation is a significant mechanism of neurotoxicity, often leading to neuronal damage and neurological dysfunction. It triggers a series of pathophysiological processes, including inflammatory cell infiltration, release of inflammatory cytokines, and activation of neurons and various glial cells[95]. As environmental pollutants, MNPs are closely associated with neuroinflammation and may cause neurotoxicity by triggering inflammatory responses. A study on PS-MPs showed that after exposure, the mRNA levels of TNF-α and IL-1β in the hippocampus of mice significantly increased, indicating an elevation in the level of neuroinflammation in mice[53]. The neuroinflammatory response caused by MNPs includes inflammatory cell infiltration around neurons and microglial activation[76]. Activated microglia can trigger a series of neuroinflammatory reactions and promote brain injury[96]. For example, microglia activated by PS-NPs release inflammatory factors that inhibit hippocampal neuronal activity, leading to cognitive impairment in mice[51]. Additionally, PS-MPs exacerbate neuroinflammation by inducing pyroptosis of microglia, further promoting the progression of cognitive impairment[97].
Astrocytes also play a crucial role in neuroinflammation. Studies have found that PS-NPs and PS-MPs can induce astrocyte activation in vitro and upregulate pathways related to neuroinflammation and immunity[98]. Aged MPs, compared to pristine MPs, significantly increase the activation of immune-related pathways[99]. In vitro experiments with HMC-3 cells revealed that the inflammatory response induced by aged MPs is more severe than that caused by pristine MPs[99]. This suggests that environmentally aged MNPs may have a higher potential for inducing neuroinflammation. Neuroinflammation can also lead to neuronal damage and neurotransmitter disorders, which in turn can cause abnormalities in nervous system function, such as cognitive impairment and decreased learning and memory abilities[100]. Additionally, neuroinflammation may exacerbate oxidative stress, further damaging neural cells. Oxidative stress and neuroinflammation promote each other, forming a vicious cycle that leads to further deterioration of neurological damage.

4.3 Mitochondrial Dysfunction

Mitochondria play a crucial role in cellular biological functions, including energy metabolism, redox balance, apoptosis, lipid metabolism, and calcium homeostasis. In the mechanisms of neurotoxicity, mitochondrial dysfunction is considered an important influencing factor. As an environmental pollutant, MNPs have been found to be closely related to mitochondrial dysfunction. Animal experiments have shown that NPs can enter neurons and accumulate within mitochondria, leading to mitochondrial dysfunction and reduced ATP production, which may be associated with abnormal animal behavior[59]. Similarly, the accumulation of PS-NPs in neurons also leads to mitochondrial dysfunction and increased energy consumption, thereby affecting neural development and cognitive function[101]. Research has also found that PS-NPs can induce significant mitochondrial damage in differentiated SH-SY5Y cells, mainly manifested as changes in mitochondrial structure, decreased mitochondrial membrane potential, and reduced ATP generation[62]. This reduction in ATP generation may lead to excessive mitophagy and ultimately result in the death of dopaminergic neurons[62]. Using single-cell nuclear RNA sequencing to analyze the brains of mice after exposure, it was found that PS-NPs cause mitochondrial dysfunction and energy metabolism disorders, particularly having the most significant impact on excitatory neurons[102]. The presence of MNPs disrupts the structural integrity of mitochondria, reduces mitochondrial membrane potential, and affects the integrity of the mitochondrial genome, leading to an imbalance in the dynamics between mitochondrial fission and fusion[102]. These changes directly affect critical functions such as mitochondrial energy production and apoptosis, thereby potentially impacting the normal structure and function of the nervous system. Therefore, mitochondrial dysfunction is one of the key mechanisms by which MNPs cause neurotoxicity. This process may lead to disordered cellular energy metabolism and exacerbated oxidative damage, further affecting the normal structure and function of the nervous system.

4.4 Synaptic Function And Neurotransmitter Balance

Synapses are key structures for signal transmission between neurons, and neurotransmitters play a crucial role in this process. Neurotransmitters such as glutamate, γ-aminobutyric acid, dopamine, and serotonin play a critical role in regulating the function and behavior of the nervous system. The balance of synaptic function and neurotransmitters is essential for the normal operation of the nervous system. Exposure to MNPs significantly affects the structure and function of synapses. For example, long-term exposure to PS-MPs in mouse models shows a decrease in dendritic spine density in hippocampal neurons, which is associated with memory impairment[48]. In cortical neurons, exposure to MNPs leads to a significant reduction in the length and number of neurites[88]. Additionally, MNPs can induce severe damage to synaptic function by affecting the expression of synapse-related genes in the brain, thereby impacting learning and memory abilities[49,53]. Changes in synaptic function directly affect the balance of neurotransmitters. Research has found that water-suspended plastic smoke particles can lower the membrane potential and synaptic vesicle acidification of neurites, weaken synaptic transporter proteins, leading to an excessive increase in glutamate concentration in the synaptic cleft, and thus overactivate ionotropic glutamate receptors, producing neurotoxic effects[103]. Moreover, exposure to MNPs can also lead to a decrease in acetylcholinesterase activity in the brain, which is closely related to their accumulation in the brain[52]. The inhibition of acetylcholinesterase activity is closely related to the activation of oxidative stress, which has been observed to cause impaired motor activity in mice[60]. In summary, the impact of MNPs on synaptic function and neurotransmitter balance may exist across different species, and these effects can lead to abnormalities in nervous system function, such as cognitive impairment and decreased learning and memory abilities.

4.5 Gut-Brain Axis Mechanism

The gut-brain axis plays a crucial role in maintaining the health and function of the nervous system. It is a complex physiological pathway connecting the digestive system with the central nervous system, playing an important role in regulating emotions, cognitive functions, and behaviors[104]. Exposure to MNPs may have negative effects on the gut-brain axis, leading to dysfunction of the nervous system and the occurrence of neurotoxic effects. Firstly, exposure to MNPs can cause dysbiosis of the gut microbiome[105]. Studies have shown that MNP exposure disrupts the balance of the gut microbiome, resulting in a decrease in beneficial bacteria and an increase in opportunistic pathogens, thus affecting intestinal function and immune regulation, and subsequently impacting the nervous system through the gut-brain axis[56,106]. Results from hippocampal transcriptomics, 16S rRNA sequencing of the gut microbiota, and plasma metabolomics indicate that circadian rhythm-related pathways mediated by the gut-brain axis are involved in the neurotoxicity of MNPs. Supplementation with probiotics significantly reduces intestinal damage and restores the expression of circadian rhythm-related genes and molecules related to neural plasticity[50]. Additionally, exposure to 50 μm MPs significantly reduces colonic mucin production and induces changes in the gut microbiota. Blocking the vagus nerve pathway improves these behavioral disorders, highlighting the critical role of the gut-brain axis in mediating neurobehavioral outcomes[77]. Secondly, MNPs can also induce gut microbiota dysbiosis and disrupt metabolic functions in both the brain and gut of mice. For example, PS-MPs lead to alterations in the Firmicutes and Bacteroidetes phyla in the gut, disrupting the metabolic processes in the mouse brain via the gut-brain axis[107]. Imbalance in the gut microbiota can alter the levels of neurotransmitters produced in the gut (such as serotonin), thereby affecting the neural functions and behaviors of the brain[105,108-109]. Moreover, disruption of the intestinal barrier and inflammatory responses can increase systemic inflammation, which in turn affects the immune response of the brain and leads to neuroinflammation[110]. In summary, exposure to MNPs may affect the function of the gut-brain axis through multiple pathways, thereby exerting toxic effects on the nervous system.

5 Conclusions and Prospects

The potential impact of MNPs on human health has attracted widespread attention, but current research still faces many uncertainties and challenges. Although some studies have initially explored the toxic effects of MNPs on the nervous systems of mammals, the following five aspects still require focused and in-depth investigation.
(1) Gaps and Needs in Epidemiological Studies: Although some studies have estimated human exposure to MNPs, the long-term effects on human health remain unclear. More large-scale, long-term epidemiological studies are needed, especially those conducted at different exposure levels and across various populations, to comprehensively assess their potential health impacts.
(2) Selection and Applicability of Animal Models: Currently, most studies rely on a single animal model, which may not fully represent the real exposure scenarios in humans. Future research should consider using animal models that more closely resemble human physiological and metabolic characteristics to investigate the differences in toxic responses to MNPs among different individuals and populations.
(3) Consideration of MNP aging and environmental risks: Most current studies use commercially available MNPs, while in the actual environment, MNPs that have undergone aging or weathering are present. There may be significant differences in their properties. Future research should strengthen the study of aged MNPs and their behavior and impact in the environment.
(4) Comprehensive evaluation of different types of MNPs: Currently, the main focus is on studying common materials such as PS for MNPs, with relatively little research on other types of MNPs, especially novel materials. Future studies should include the assessment of various novel materials to gain a comprehensive understanding of the potential health impacts of different chemical compositions and physical properties.
(5) In-depth exploration of toxicity mechanisms: There is currently insufficient understanding of the specific impact mechanisms of MNPs on the nervous system through pathways such as oxidative stress and inflammatory responses. More mechanistic studies need to be conducted in the future to uncover the toxicity mechanisms of MNPs on the nervous system and other critical physiological processes, providing a scientific basis for the development of preventive and intervention measures.
A comprehensive evaluation of the particle size, shape, chemical composition, exposure routes, and doses of MNPs is crucial for a full understanding of their health risks. To this end, interdisciplinary collaboration and the integrated use of research findings from fields such as materials science, environmental science, toxicology, and epidemiology are important directions and challenges for future studies.

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Funding

National Natural Science Foundation of China(82273656)

National Natural Science Foundation of China(82304177)

National Natural Science Foundation of China(22241604)

National Natural Science Foundation of China(82073519)

Guangdong Province University Student Innovation and Entrepreneurship Training Program projects(S202312121124)

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