The plastic brain: neurotoxicity of micro‑ and nanoplastics

Given the global abundance and environmental persistence, exposure of humans and aquatic animals to micro- and nanoplastics is unavoidable. Current evidence indicates that micro- and nanoplastics can be taken up by aquatic organisms as well as by mammals. Upon uptake, micro- and nanoplastics can reach the brain, although there is limited information regarding the number of particles that reaches the brain and the potential neurotoxicity of these small plastic particles.

Earlier studies indicated that metal and metal-oxide nanoparticles, such as gold (Au) and titanium dioxide (TiO₂) nanoparticles, can also reach the brain to exert a range of neurotoxic effects. Given the similarities between these chemically inert metal(oxide) nanoparticles and plastic particles, this review provides an overview of the reported neurotoxic effects of micro- and nanoplastics in different species and in vitro.

The combined data, although fragmentary, indicate that exposure to micro- and nanoplastics can induce oxidative stress, potentially resulting in cellular damage and an increased vulnerability to develop neuronal disorders. Additionally, exposure can result in inhibition of acetylcholinesterase (AChE) activity and altered neurotransmitter levels, which both may contribute to the reported behavioral changes.

Background

Over the years, the environment has been contaminated with millions of tons of plastic. Annual production has grown from 250 million tons in 2009 to 335 million tons in 2016.¹Alimba CG, Faggio C (2019) Microplastics in the marine environment: current trends in environmental pollution. Environ Toxicol Pharmacol 68:61–74. Open → Approximately 10% of all annually produced plastic ends up as debris in the marine environment, and it is estimated that over 5 trillion pieces of plastic are afloat at sea alone.⁴Eriksen M et al. (2014) Plastic pollution in the world’s oceans: more than 5 trillion plastic pieces weighing over 250,000 tons afloat at sea. PLoS One. Open →

Breakdown of plastic fragments contributes to continuously increasing amounts of secondary microplastics (diameter 0.1 μm to 5 mm) and secondary nanoplastics (diameter below 100 nm). Micro- and nanoplastics are found in all aquatic ecosystems and can act as carriers for various contaminants, including metals, persistent organic pollutants, antibiotics, and pathogenic micro-organisms.^10–14Multiple studies on microplastic-mediated transport of contaminants, POPs, antibiotics, and pathogens. See references 10–14.

Humans are exposed to micro- and nanoplastics via consumption of contaminated food and consumer products, as well as through drinking water and inhalation of particles released from textiles, synthetic rubber tires, and plastic covers.^14,18,24,25Wright SL & Kelly FJ (2017) Plastic and human health: a micro issue? Environ Sci Technol 51(12):6634–47. Open → Uptake and subsequent translocation to the liver, spleen, and lymphatic systems of rodents has been reported, and in humans, micro-sized plastic fibers have been detected in lung tissue.^29–31Pauly JL et al. (1998) Inhaled cellulosic and plastic fibers found in human lung tissue. Cancer Epidemiol Biomarkers Prev 7(5):419–28.

Neurotoxicity of chemically inert metal(oxide) nanoparticles

In contrast to micro- and nanoplastics, metal(oxide) nanoparticles have been relatively well studied. Gold (Au) and titanium dioxide (TiO₂) nanoparticles approach the definition of chemically inert — an important characteristic for comparison with plastic particles.^23,28,51Bouwmeester H et al. (2015) Potential health impact of micro- and nanoplastics in the human food production chain. Environ Sci Technol 49(15):8932–47. Open →

Metal and metal-oxide nanoparticles can enter the brain by crossing the blood–brain barrier (BBB) or can bypass it via retrograde transport through olfactory nerve endings.^38,42–44Win-Shwe TT & Fujimaki H (2011) Nanoparticles and neurotoxicity. Int J Mol Sci 12(9):6267–80. Open →

Au-nanoparticles translocate to brain tissue of zebrafish and adult rats, where they induce oxidative stress, alterations in energy metabolism and AChE activity, and neurobehavioral effects.^52–54Truong L et al. (2012); Dedeh A et al. (2015); Ferreira GK et al. (2017). Effects of gold nanoparticles on zebrafish and rat brain biochemistry. TiO₂-nanoparticles similarly translocate to fish brains and, in rodents, cause oxidative stress, neuroinflammation, dysregulation of glutamatergic signaling, changes in AChE activity, impaired motor function, and impairment of learning and memory.^55–68Multiple studies (2006–2019) on TiO2 nanoparticle neurotoxicity in fish, rodents, and in vitro. See references 55–68.

Neurotoxic effects in marine invertebrates

Several studies investigated the neurotoxic effects of polystyrene and polyethylene micro- and nanoplastics in invertebrates such as nematodes, bivalves, and crustaceans.

Exposure of the nematode Caenorhabditis elegans to polystyrene microplastics (0.1 to 5 μm) resulted in excitatory toxicity on locomotor behavior, reduced survival rate, and impairment of cholinergic and GABAergic neurons with oxidative stress.⁶⁹Lei L et al. (2018) Polystyrene (nano)microplastics cause size-dependent neurotoxicity in C. elegans. Environmental Science: Nano. Open → In earthworms (Eisenia fetida), polyethylene microplastics induced signs of oxidative stress (increased catalase and malondialdehyde) and increased AChE activity.⁷⁰Chen Y et al. (2020) Defense responses in earthworms exposed to low-density polyethylene microplastics. Ecotoxicol Environ Saf. Open →

In freshwater zebra mussel (Dreissena polymorpha), polystyrene microbeads transferred into tissues and hemolymph and increased dopamine levels and catalase activity, suggesting cellular stress.⁷¹Magni S et al. (2018) Evaluation of uptake and chronic toxicity of virgin polystyrene microbeads in freshwater zebra mussel. Sci Total Environ. Open → In bivalves (Scrobicularia plana), polystyrene microplastics induced superoxide dismutase activity increases, GST activity changes, and AChE inhibition in the gills.⁷²Ribeiro F et al. (2017) Microplastics effects in Scrobicularia plana. Mar Pollut Bull. Open →

Mediterranean mussels (Mytilus galloprovincialis) exposed to polystyrene and polyethylene microplastics showed DNA damage, nuclear alterations, and reduction of AChE activity in gills.^73,74Avio CG et al. (2015) Pollutants bioavailability and toxicological risk from microplastics to marine mussels. Environ Pollut. Open → Asian freshwater clams (Corbicula fluminea) showed cholinesterase inhibition and increased lipid peroxidation levels suggestive of oxidative damage, effects that were only partly reversible following recovery.^75,76Guilhermino L et al. (2018); Oliveira P et al. (2018). Effects of microplastics on freshwater bivalves. See references 75–76.

Neurotoxic effects in fish

Fish were the most frequently studied organism group, with 17 separate investigations. Several studies confirmed that nanoplastics have the capacity to cross the blood–brain barrier in fish.

In adult Japanese rice fish (Oryzias latipes), fluorescent polystyrene nanoplastics (40 nm) were detected in the brain after 7 days of exposure, indicating that nanoplastics can cross the BBB.⁷⁹Kashiwada S (2006) Distribution of nanoparticles in the see-through medaka. Environ Health Perspect 114(11):1697–702. Open → In tilapia (Oreochromis niloticus), polystyrene microparticles accumulated in gut, gills, liver, and brain tissue with parallel inhibition of AChE activity and induction of SOD.⁸⁰Ding J et al. (2018) Accumulation and biochemical effects of polystyrene microplastics in the freshwater fish red tilapia. Environ Pollut. Open →

Perhaps most strikingly, in Crucian carp (Carassius carassius), polystyrene nanoparticles delivered through the food chain accumulated in the fish brain, coinciding with alterations in behavioral patterns, decreased brain mass, and morphological changes in the cerebral gyri. Nanoparticles had a higher presence in the brain than microparticles.²²Mattsson K et al. (2017) Brain damage and behavioural disorders in fish induced by plastic nanoparticles delivered through the food chain. Sci Rep. Open →

In adult zebrafish, high-density polyethylene microplastics (10–600 μm) resulted in changes in locomotory behavior and even induced seizures at the highest dose (1100 particles/L).⁸³Mak CW et al. (2019) Acute toxic effects of polyethylene microplastic on adult zebrafish. Ecotoxicol Environ Saf. Open → In adult zebrafish co-exposed with nanoplastics and Bisphenol A (BPA), nanoplastics increased the concentration of BPA in the brain, confirming that micro- and nanoplastics can act as carriers for environmental toxicants to the brain.⁸⁶Chen Q et al. (2017) Enhanced uptake of BPA in the presence of nanoplastics can lead to neurotoxic effects in adult zebrafish. Sci Total Environ. Open →

Neurotoxic effects in rodents

In striking contrast to the relative wealth of fish studies, only two studies have investigated the neurotoxicity of micro- and nanoplastics in rodents — a particularly notable gap given the observed neurotoxic effects in other species.

In the only published in vivo mouse study, adult mice were chronically exposed (30 days) to polystyrene microplastics (5 and 20 μm, 0.01–0.5 mg/day) via oral gavage. Exposure resulted in particle presence in the gut, liver, and kidneys, with dose-dependent changes in energy metabolism (decreased ATP, increased LDH) and oxidative stress (increased GSH-Px and SOD, decreased CAT). Interestingly, AChE activity in liver increased, and metabolomic alterations suggested potential changes in neurotransmitter levels. Unfortunately, brain tissue was not investigated.⁹⁴Deng Y et al. (2017) Tissue accumulation of microplastics in mice and biomarker responses suggest widespread health risks. Sci Rep. Open →

The other study involved chronic exposure (5 weeks) of male rats to polystyrene nanoplastics (40 nm, 1–10 mg/kg/day), but exposure did not result in behavioral alterations or changes in body weight gain. However, no proof of actual uptake was provided.⁹⁵Rafiee M et al. (2018) Neurobehavioral assessment of rats exposed to pristine polystyrene nanoplastics. Chemosphere 193:745–53. Open →

Neurotoxic effects in vitro

Only three studies have investigated the neurotoxicity of micro- and nanoplastics exposure in vitro, but the results are significant.

Human cerebral cells (T98G) showed increased production of reactive oxygen species (ROS) upon exposure to polystyrene microplastics, though only at the highest concentration tested (10 mg/L).⁹⁶Schirinzi GF et al. (2017) Cytotoxic effects of commonly used nanomaterials and microplastics on cerebral and epithelial human cells. Environ Res. Open →

Polystyrene nanoplastics (55 nm) affected mitochondrial activity of murine neuronal cells at high concentrations. Critically, microglial cells were able to internalize carboxylated polystyrene nanoparticles by phagocytosis, suggesting the potential for neuroinflammation — a response also observed with metal(oxide) nanoparticles. Toxicity increased for “aged” particles stored for over 6 months.⁹⁷Murali K et al. (2015) Uptake and bio-reactivity of polystyrene nanoparticles is affected by surface modifications. Nanoscale. Open →

Polyethylene nanoplastics (33 nm) were internalized by human dopaminergic neurons and developing neurospheres, coinciding with altered gene expression and increased malondialdehyde levels (oxidative stress). At high doses, exposure resulted in decreased cell viability.⁹⁸Hoelting L et al. (2013) A 3-dimensional human embryonic stem cell-derived model to detect developmental neurotoxicity of nanoparticles. Arch Toxicol. Open →

Discussion

Despite major limitations in the current evidence base, several consistent neurotoxic effects emerge across species. The review identifies three primary pathways of harm:

• Blood–brain barrier crossing and brain accumulation: Several studies reported accumulation of micro- and nanoplastics in brain tissue of fish, with confirmed BBB permeability for polystyrene nanoparticles in vivo and internalization in neuronal cells in vitro.^{22,79,80,86,110}Yang CS et al. (2004) Nanoparticle-based in vivo investigation on blood-brain barrier permeability. Anal Chem. Open →
• Oxidative stress and neuroinflammation: Increased lipid peroxidation (LPO) levels — a reliable indicator of oxidative stress — were demonstrated in marine invertebrates, in fish brain, and in neuronal cells in vitro. Uncontrolled ROS can lead to protein oxidation, DNA damage, cell membrane destabilization, mitochondrial damage, and cell death.
• Acetylcholinesterase (AChE) inhibition: Among the most consistently reported effects across bivalves, crustaceans, and fish. Inhibition of >30% is considered to disrupt cholinergic nervous system function and has been implicated in non-cholinergic functions related to neurite growth, synaptogenesis, and apoptosis.^115–117Lionetto MG et al. (2013) Acetylcholinesterase as a biomarker in environmental and occupational medicine. Biomed Res Int. Open →

Notably, oxidative stress and inflammation in the central nervous system have been linked to various neurodegenerative diseases, such as Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, and Amyotrophic Lateral Sclerosis, highlighting the possibility that exposure to micro- and nanoplastics may contribute to the onset or aggravation of neurodegenerative diseases.^113,114Tönnies E & Trushina E (2017) Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzheimers Dis; Radi E et al. (2014) Apoptosis and oxidative stress in neurodegenerative diseases.

The review identifies several critical gaps: most studies used manufactured spherical polystyrene particles, while real-world exposure involves irregularly shaped polypropylene, polyester, and polyamide particles. Exposure concentrations in experiments are often much higher than environmental levels. Most research has focused on aquatic species rather than mammals, and a systematic comparison of different particle types, shapes, and sizes at various concentrations is urgently needed.

Conclusions

Despite the ubiquitous presence of micro- and nanoplastics in the environment, there is a general scarcity of data regarding their uptake and neurotoxicity. The available studies indicate that plastic particles can:

• Induce oxidative stress across multiple species and cell types
• Inhibit AChE activity, disrupting cholinergic nervous system function
• Alter neurotransmitter levels, including dopamine and serotonin
• Produce behavioral changes in nematodes, crustaceans, and fish
• Cross the blood–brain barrier and accumulate in brain tissue

Whether these effects are related to human neurodevelopmental and/or neurodegenerative disorders remains to be determined. The authors call for standardized exposure protocols, testing with environmentally relevant particle types, and — crucially — far more research in mammalian models, including investigation of brain tissue. Regardless of the results of future hazard assessments, precautionary actions should be taken to minimize further contamination and spreading of macro-, micro-, and nanoplastics into our environment.

This article is an enhanced web presentation of the original open-access paper published in Particle and Fibre Toxicology under the Creative Commons Attribution License (CC BY 4.0). All text, data, and figures are from the original publication by Prüst, Meijer & Westerink (2020). Presented by DetoxBio for educational purposes.