Neurodegeneration in Parkinson’s Disease: The Role of Environmental Toxins

Abstract

Parkinson’s disease (PD) is a rapidly growing global health challenge, with prevalence projected to reach 13–14 million cases by 2040. While aging and improved diagnostic awareness partly explain this trend, mounting evidence implicates environmental factors as critical contributors. This review synthesizes current literature on exposures such as pesticides, solvents, heavy metals, air pollutants, and infectious agents, emphasizing their mechanistic links to neurodegeneration. These factors interact with genetic susceptibility and aging, supporting the “multiple-hit” hypothesis, which posits that PD arises from cumulative insults rather than a single cause. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired protein clearance emerge as convergent pathways underlying dopaminergic vulnerability. Recent findings highlight viral infections—particularly SARS-CoV-2—as potential triggers or amplifiers of PD pathogenesis, raising concerns about long-term neurological sequelae following pandemics. Beyond individual toxins, the exposome concept underscores the lifelong interplay of physical, chemical, and social exposures in shaping disease risk. Climate-related changes, including increased air pollution and wildfire frequency, further compound these risks, suggesting a systemic dimension to PD etiology. Understanding these complex interactions is essential for developing preventive strategies, refining experimental models, and informing public health policies aimed at mitigating environmental contributions to neurodegeneration. This multifactorial perspective offers a foundation for future research targeting modifiable risk factors and resilience mechanisms in PD.

Plain Language Summary

Parkinson’s disease (PD) is a brain disorder that affects movement and is becoming more common worldwide. While aging and genetics play a role, research shows that environmental factors—such as pesticides, air pollution, industrial chemicals, and even certain infections—may also increase the risk of developing PD. This article explains how these factors can damage brain cells over time. For example, pesticides and solvents can harm the parts of the brain that control movement. Air pollution and heavy metals may also contribute to brain inflammation and stress. Infections like influenza and COVID-19 could act as “triggers,” making the brain more vulnerable to damage later in life. Scientists call this the “multiple-hit” theory, meaning PD often results from a combination of aging, genes, and environmental exposures rather than a single cause. The review also introduces the concept of the “exposome,” which looks at all the things we are exposed to throughout life—chemicals, air quality, diet, and even stress—and how they interact with our biology. Understanding these links can help researchers find ways to prevent PD, improve treatments, and guide public health policies. In short, Parkinson’s disease is not just about getting older or having certain genes. It may also be influenced by what we breathe, eat, and encounter in our environment. By studying these factors, we can work toward reducing risks and protecting brain health.

Introduction

Parkinson’s disease (PD) is experiencing unprecedented global growth, now outpacing even Alzheimer’s Disease (AD) in prevalence and impact. Between 1990 and 2015, the number of individuals affected more than doubled, and projections estimate that this figure will reach nearly 13 to 14 million by 2040. ¹ This surge is driven by a combination of factors, including global population aging, increased life expectancy, increased awareness, declining smoking rates (a known protective factor), widespread underdiagnosis and, perhaps, environmental/biological risk factors (Table 1).^2-4

Table 1.

Environmental and Biological Risk Factors Associated With Parkinson’s Disease

Category	Examples	Pathophysiology
Pesticides	Paraquat, rotenone, dieldrin, heptachlor, permethrin, maneb, chlorpyrifos, organochlorines, pyrethroids, organophosphates	Excitotoxicity, dopamine oxidation and metabolism, microglial activation, mitochondrial dysfunction, inflammasome, endolysosomal and proteasome dysfunction, α-synuclein accumulation and insolubility
Halogenated solvents	Trichloroethylene, tetrachloroethylene, methylene chloride	Mitochondrial dysfunction, endolysosomal and proteasome dysfunction, α-synuclein accumulation and insolubility
Heavy metals	Manganese, lead, iron, mercury	Excitotoxicity, astrocyte activation, α-synuclein accumulation and insolubility
Air pollution	PM2.5 (fine particulate matter), NO2 (nitrogen dioxide), PM10 (coarse particulate matter), SO2 (sulfur dioxide)	Dopamine uptake and transmission, α-synuclein accumulation and insolubility
Pathogens	H1N1, gut microbiota, other viruses or LPS-producing bacteria	Astrocyte activation, microglial activation
Head trauma	Repeated episodes of unconsciousness	Excitotoxicity, astrocyte activation, microglial activation

The initial “first hit” in PD pathogenesis may stem from aging or early environmental exposures, yet this alone does not significantly alter the trajectory of dopaminergic neuron degeneration in the substantia nigra for an extended period. ⁵ Under typical conditions, individuals may cross the threshold of symptomatic dopamine loss between the ages of 64 and 70. ⁶ However, additional “hits” accumulated throughout life—such as exposure to environmental toxins or viral infections—can modify the slope of neurodegeneration, accelerating the onset of motor symptoms and contributing to early involvement of non-motor systems, including gastrointestinal dysfunction. Importantly, the sequence and nature of these hits vary across different models, underscoring the heterogeneity of disease progression and the multifactorial nature of PD.

Accordingly, the aim of this narrative review isto integrate current evidence on environmental toxicants, infectious exposures, and the broader exposome in Parkinson’s disease, with a focus on shared pathophysiological mechanisms rather than isolated risk factors. By synthesizing recent epidemiological and experimental findings, we address the gap between mechanistic insights and clinical observations, emphasizing mitochondrial dysfunction, neuroinflammation, and gene–environment interactions. This integrative perspective is intended to generate testable hypotheses, clarify disease susceptibility, and inform translational and preventive strategies.

Toxins and Other Pollutants as Risk Factors for Parkinsonism

There are many ways of studying toxins related to neurodegeneration, such as genetic versus environmental causes of diseases, single agent versus mixed longitudinal exposure, current versus life course exposure to risk factors, patients versus healthy high-risk groups. ⁷ Noteworthy, neurodegeneration develops over years, but the current technology is only able to evaluate current exposure. The literature is divergent regarding the main cause of PD, some authors believe that it is predominantly environmental ⁸ and others a genetic ⁹ condition. It is possible that the answer is something between these two hypotheses because suggesting one way or another likely represents only a small portion of the PD population. Whether we are talking about specific environmental factors leading to environmental PD or specific genes leading to genetic PD, we are missing the majority of cases that are composed of an interaction.

There is a significant interplay among the aging process, genetic predisposition, and environmental toxins. ¹⁰ Aging is the strongest risk factor, with age-related cellular impairments—such as mitochondrial dysfunction, oxidative stress, impaired autophagy, and neuroinflammation—creating a pre-parkinsonian state, particularly in the ventral substantia nigra. ¹¹ However, aging alone is insufficient, as most elderly individuals do not develop PD. ¹² In addition, there have been reports of increased rates of early onset parkinsonism. ¹³ Genetic contributions include rare high-penetrance mutations (e.g., SNCA, LRRK2, GBA) and common low-risk variants, with overall heritability estimated at approximately 30%. ¹⁴ Environmental factors like pesticide exposure, head trauma, and smoking show variable associations; smoking consistently correlates with reduced PD risk, though causality remains debated. ¹⁵ Experimental models demonstrate that genetic mutations (e.g., LRRK2, Parkin) increase vulnerability to environmental toxins, and aging exacerbates these effects, supporting a “multiple-hit” hypothesis (Figure 1).

Figure 1.

Likelihood of diagnosing Parkinson’s Disease (PD). The probability of a PD diagnosis increases as the cumulative burden of risk factors rises. Key contributors include aging, chronic inflammation, and exposure to environmental toxins and pollutants. These factors interact with genetic susceptibility—particularly high-penetrance mutations—to elevate disease risk. The synergistic effect of these elements underscores the multifactorial nature of PD pathogenesis

The first reports about toxins-related to PD was with MPTP, a synthetic version of heroin. In 1985, Journalist Jon Palfreman produced a documentary for the PBS series “NOVA” titled “The Case of the Frozen Addict” describing the story of six young California drug users that developed clinical manifestations similar to PD symptoms. ¹⁶ Langston et al., later on, identified the scientific foundation of these cases, ¹⁷ which was the replacement of heroin by the MPTP. ¹⁸ It was a translational breakthrough in PD study due to the MPTP model being low cost and promoting the understanding of the pathophysiological pathways for developing the disease (Table 2).^19-27

Table 2.

Toxic Models of Parkinson’s Disease

Model	Features	Drawbacks	References
6-OHDA	- Stable, permanent depletion of TH-positive nigral neurons	- Unilateral	Deumens et al. (2002)
	- Variable PD manifestations depending on injection parameters	- Does not replicate full PD pathology
		- Risk of mechanical damage
		- Bilateral models need intensive care
BSSG	- Found in cycad plants	- Less commonly used	Van Kampen et al. (2017)
	- Chronic exposure induces progressive PD-like symptoms and α-synuclein aggregation	- Requires long-term exposure
DSP-4	- Selectively targets noradrenergic neurons	- Does not replicate core DA pathology	Iannitelli et al. (2023)
	- Used to study non-DA contributions to PD
Iron	- Iron accumulation observed in PD brains	- Non-specific neurotoxicity	Gerlach et al. (2008)
	- Promotes oxidative stress and DA neuron damage	- Limited behavioral phenotype
LPS	- Induces neuroinflammation	- Does not directly cause DA neuron death	Dutta et al. (2008)
	- Mimics inflammatory aspects of PD	- Inflammatory model, not neurotoxic
	- Can be administered systemically or intracerebrally
Manganese	- Chronic exposure leads to motor deficits and DA dysfunction	- Does not cause selective DA neuron loss	Lucchini et al. (2009)
	- Mimics parkinsonism-like symptoms	- More relevant to manganism than PD
MPTP	- Affects humans and various animals (e.g., primates, mice)	- Transient striatal damage in young mice	Smeyne et al. (2005)
	- Mimics different PD stages via dosing	- Limited behavioral deficits in mice
	- Useful for mechanistic studies	- Strain-dependent effects
Paraquat	- Induces DA neuron damage	- Severe systemic toxicity	Berry et al. (2010)
Rotenone	- Chronic exposure mimics PD features	- High mortality	Radad et al. (2019)
	- Causes nigrostriatal degeneration	- Inconsistent results
	- Cytoplasmic inclusions in DA neurons	- No inclusion bodies in some cases

Abbreviations: 6-OHDA, 6-hydroxydopamine; BSSG, β-sitosterol-D-glucoside; DA, dopamine; DSP-4, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson’s disease; TH, Tyrosine hydroxylase.

Pesticides

Occupational exposure to pesticides has been associated with a 2.5-fold increased risk of PD, while household use—particularly of organophosphates—has been linked to a 1.7-fold increase. ²⁸ A large pan-Indian study revealed an OR 1.67 to develop PD with exposure to insecticides, pesticides, or fungicides. ²⁹

Living within a certain distance of a golf course has been associated with an increased risk of Parkinson’s in a dose dependent relationship. ³⁰ This is likely related to water contamination in the pesticides and other chemicals used to maintain the golf courses. There is a doubled amount of risk when living in the same watershed area as a golf course when compared to areas without a golf course. There’s is greatest risk living within 1-3 miles of the course, the risk diminishing with further distance.

Leveraging California’s unique Pesticide Use Reporting (PUR) system, researchers were able to precisely map long-term ambient exposures based on residential proximity to agricultural applications. This enabled the identification of pesticide clusters commonly applied together, complicating efforts to isolate individual chemical effects. Recognizing that most PD cases cannot be explained by genetics or environmental factors alone, researchers have explored gene-environment (GxE) interactions to explain the heterogeneity in PD risk. In a large population-based case-control study in Central California, three exposure pathways—ambient, household, and occupational—were assessed alongside genetic variants involved in pesticide metabolism (PON1), blood-brain barrier transport (ABCB1), dopamine transport and metabolism (DAT, ALDH2), mitochondrial function (NOS1, SKP1), and immune regulation (HLA-DR). ³¹

Many epidemiological studies worldwide have investigated the association between pesticide exposure and PD. For instance, Tanner et al. reported a significant correlation between exposure to paraquat and rotenone and increased PD risk. ³² However, while epidemiological data provide valuable insights, they require validation through laboratory-based research—a process known as reverse translation. Supporting this, Salama et al. demonstrated the neurotoxicity of rotenone through its impact on L-thyroxin function, which is closely linked to dopaminergic signaling, ³³ and its inhibitory effects on umbilical cord matrix cell regeneration. ³⁴

Samareh et al. demonstrated that PD patients exhibited significantly elevated serum levels of organochlorine pesticides and reduced activity of key antioxidant enzymes such as paraoxonase-1 (PON1), catalase, and superoxide dismutase, alongside increased oxidative stress markers, suggesting a mechanistic link between pesticide exposure and neurodegeneration. ³⁵ Complementing this, Mulcahy et al. developed a refined rotenone-based PD model in rats, showing that direct intra-striatal infusion of the pesticide induced motor deficits and selective dopaminergic neuron loss without systemic toxicity, thereby validating the neurotoxic potential of pesticides in vivo. ³⁶ Genetic susceptibility also plays a critical role, as shown by Manthripragada et al., who found that individuals carrying the PON1-55 MM genotype had a more than twofold increased risk of PD when exposed to organophosphates like diazinon and chlorpyrifos. ³⁷ Further, Paul et al. identified significant gene-environment interactions between NOS1 gene variants and organophosphate exposure, with certain genotypes amplifying PD risk nearly threefold in exposed individuals, underscoring the importance of oxidative stress pathways in mediating pesticide-related neurotoxicity. ³⁸

Trichloroethylene (TCE) is a common volatile organic solvent that has been widely used in industrial applications and consumer or commercial products such as cleaning and degreasing agents in ink and varnishes. It is a common environmental pollutant usually found in air, soil, and water. Some authors have referred to this agent as the urban equivalent of agricultural pesticides in the context of PD pathogenesis. In a 2012 twin study, TCE exposure was associated with a sixfold higher PD risk (OR 6.1), with perchloroethylene (PERC) and carbon tetrachloride (CCl₄) showing suggestive associations. ³⁹ A 2023 cohort study of over 340,000 veterans showed higher PD incidence (OR 1.68) among those stationed at Camp Lejeune, where water was contaminated with TCE and other VOCs, compared to Camp Pendleton. ⁴⁰ Prodromal PD features were also more common in the exposed group, reinforcing TCE’s role as a key environmental risk factor. Noteworthy, chronic exposure to TCE at 200 mg/kg in aged rats activated wildtype LRRK2 kinase in the brain, induced dopaminergic neurodegeneration in the nigrostriatal pathway, increased oxidative stress, disrupted endolysosomal function, and led to α-synuclein accumulation. ⁴¹

Arellano et al. revealed that carbaryl, carbofuran, copper hydroxide, and copper sulfate are not only associated with dopaminergic toxicity, but they are also associated with abnormalities in alpha-synuclein. ⁴² Gong et al. revealed that the copper pesticides exposure leads to abnormal methylation of regions of the COL11A2 gene, UBE3C, MAGI2, and chromosome 1. ⁴³

Air Pollution

Recent epidemiological investigations have increasingly linked ambient air pollution to elevated PD risk, particularly in urban and metropolitan settings. Long-term exposure to fine particulate matter (PM2.5) showed a modest pooled relative risk (RR) of 1.06 per 10 μg/m³ increase, while nitrogen dioxide (NO₂) and ozone (O₃) exposures yielded RRs of 1.01 and 1.01 respectively, though with high heterogeneity across studies. Notably, short-term PM2.5 exposure was associated with increased hospital admissions for PD (RR = 1.03 per 10 μg/m³). ⁴⁴ In a large cohort study of over 78,000 individuals, NO₂ exposure was significantly associated with PD incidence (HR = 1.41 for highest vs. lowest quartile), whereas other pollutants showed no significant associations. ⁴⁵ Subgroup analyses revealed stronger associations among women and never-smokers, with PM10 and PM2.5 exposures linked to increased PD risk, particularly in female never-smokers (ORs up to 2.34). ⁴⁶ Another case-control study found that individuals in metropolitan cores exposed to high levels of PM2.5 and NO₂ had elevated PD risk (ORs = 1.23 and 1.13, respectively), and PM2.5 exposure was further associated with increased risk of akinetic-rigid PD presentation and dyskinesia. ⁴⁷ Additionally, traffic-related NO₂ exposure was linked to a 9% higher PD risk per interquartile range increase, with stronger effects observed in long-term urban residents. ⁴⁸ In the Health Professionals Follow-Up Study (HPFS), cumulative exposure to various PM fractions up to two years before PD onset was modeled, ⁴⁹ reinforcing the association between particulate pollution and PD development.

Long-term exposure to traffic-related air pollutants, particularly carbon monoxide (CO) and fine particulate matter (PM2.5), has been associated with an increased risk of PD in central California, based on residential and occupational location modeling. ⁵⁰ Notably, even PM2.5 levels below current European Union air quality standards have been linked to elevated PD mortality, suggesting that existing regulatory thresholds may not adequately protect vulnerable populations. ⁵¹ Advances in environmental monitoring technologies have enabled more precise exposure assessments, including the use of remote sensing data to track particulate matter concentrations across geographic locations over time. This cumulative exposure mapping, based on both current and historical residential addresses, offers unprecedented resolution in identifying environmental risk factors for PD. ⁵²

Climate Change and Neurodegenerative Disorders

Climate change exerts a complex and multifactorial influence on global health through a cascade of environmental, biological, and social pathways. Alterations in temperature, precipitation patterns, and hydrological cycles—exacerbated by glacial melt and extreme thermal events—lead to physical changes such as droughts, inland and coastal flooding, and reduced agricultural productivity. These environmental stressors increase water scarcity and create favorable conditions for the proliferation of disease vectors. As a result, vulnerable populations face heightened risks of undernutrition, waterborne illnesses (e.g., diarrhea), and vector-borne diseases (e.g., malaria and dengue). ⁵³

Air pollution, particularly exposure to fine particulate matter (PM2.5), coarse particulate matter (PM10), nitrogen dioxide (NO₂), sulfur dioxide (SO₂), and ozone (O₃), has been increasingly recognized as a significant environmental risk factor for a range of neurological and cerebrovascular conditions. There has been an increase in wildfire season length, frequency, and burned area (accessed on December 1st, 2025, https://www.epa.gov/climate-indicators/climate-change-indicators-wildfires). Wildfires have accounted for 25% of PM2.5 in the US. ⁵⁴ Chronic exposure to these pollutants is associated with elevated risks of cognitive decline, stroke, transient ischemic attacks (TIAs), and various forms of dementia, including vascular dementia and Alzheimer’s disease. Neuroimaging studies have linked air pollution to white matter disease and increased amyloid deposition, both of which are biomarkers of neurodegeneration. Additionally, there is growing evidence that air pollution contributes to brain atrophy, exacerbates migraine frequency, increases the risk of PD, and may trigger relapses in individuals with multiple sclerosis. ⁵⁵

Epigenetic mechanisms are emerging as key mediators in this interaction, with studies in animal and cellular models demonstrating how environmental exposures can alter gene regulation in disease-relevant cell types. ⁵⁶ Although human studies remain limited, they underscore the potential of epigenetic research to uncover novel pathogenic pathways. Aravindan et al. found that occupational exposures, especially to industrial toxins such as dyes (OR 25.33) and methylene chloride (OR 16.5), were associated with the highest risk of PD, while residential and general exposures also showed elevated odds. ⁵⁷ Notably, consumption of fatty whale meat, rich in persistent bioaccumulative toxicants, was linked to a tenfold increase in PD risk. However, global research efforts remain uneven, with significant data gaps in South America, Africa, and much of Asia. Complementing this, Rojas-Rueda (2021) identified air pollution, heavy metals, and chemicals—including pesticides—as major environmental risk factors across a broad spectrum of diseases, reinforcing the need for integrated environmental health policies. ⁵⁸

The Epidemiological Paradox of Neurodegenerative Disorders

AD and other neurodegenerative disorders represent a growing global health challenge, with recent data from the GBD Study 2021 highlighting their significant impact. Neurological conditions are now the leading cause of disease burden worldwide, affecting approximately 3.4 billion individuals in 2021 and contributing to over 443 million DALYs. ⁵⁹ The lifetime risk of developing a chronic non-communicable disease (NCD) is substantial, with recent WHO data indicating that NCDs—such as cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes—account for 71% of all global deaths (accessed on December 1st, 2025, https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases). In the WHO European Region alone, 1 in 5 men and 1 in 10 women die before the age of 70 due to NCDs. ⁶⁰ These conditions are not only the leading cause of death but also a major contributor to disability and economic burden, with an estimated 1.8 million avoidable deaths and over $514 billion in productivity losses annually in Europe (accessed on December 1st, 2025, https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases). The high lifetime risk is driven by modifiable risk factors such as tobacco use, unhealthy diets, physical inactivity, and high blood pressure, which remain prevalent despite being largely preventable.

A notable epidemiological paradox, known as the competing risk phenomenon, emerges when evaluating the lifetime risk of neurodegenerative diseases. Surprisingly, individuals without major comorbidities—often considered “healthy”—face a 20.2% lifetime risk of developing neurodegenerative conditions (accessed on December 1st, 2025, https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases). In contrast, those with cardiovascular risk factors exhibit a significantly lower risk of 3.7%, likely because they are more prone to earlier mortality from cardiovascular events, thereby reducing the window of time in which neurodegenerative diseases could manifest (accessed on December 1st, 2025, https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases).

Pathophysiological Mechanism

The value of also understanding environmental contribution is to understand pathways and one of the challenges whether we have a common pathway or not. There is evidence of mitochondrial damage as an important component of all of those risk factors. ⁶¹ It is considered the mitochondrial complex one inhibition as the hallmark of the environmental risk for developing PD.

Some genetic variations already found to be more likely prone to develop PD according to pesticide levels were K-variant BCHE, ⁶² PON1 L55M, ⁶³ and cytochrome P450 2D6. ⁶⁴ These examples were single agents and single genes. These studies were done with a control population, in which evaluation of levels of toxic agents were evaluated as well as SNPs.

In a study assessing biomarkers for neurodegeneration in PD in patients exposed to pesticide, ⁶⁵ the authors found approximately 50 chemical substances that were related to neurotoxicity. ⁶⁶ To be more specific, all the pesticides tested were found in the individuals with PD. The combined effect of environmental pollutants in PD pathogenesis is not necessarily additive; in some cases, interactions may be multiplicative or even exponential, leading to disproportionately greater neurotoxic outcomes. And, this can be explained by the fact that mixture behaviors are purely different from their individual behavior.

Human exposure to toxic substances goes beyond pesticides, and it includes lifestyle, exogenous exposure, and socioeconomic status. Also, the individual’s unique characteristics such as endogenous exposures, epigenetic and genetic changes, and physiology.

Exposome Concept

Everything that we are exposed to contributes to the development of neurodegeneration (Figure 2). Ibanez et al. emphasizes that both physical (e.g., air pollution, heavy metals, microplastics) and social (e.g., socioeconomic disparities, chronic stress) components of the exposome significantly influence neurodevelopment, cognitive aging, and vulnerability to neuropsychiatric and neurodegenerative disorders. The authors highlight how these exposures interact with internal biological factors, including the microbiome and epigenetic mechanisms, to modulate brain function and disease risk. ⁶⁷

Figure 2.

Role of exposome in Parkinson’s Disease. Exposure to environmental factors through an individual’s life-time plays a role in pathogenesis of Parkinson’s disease. (A) Heavy metals (Iron, Zinc, Mercury, Lead, Copper) exposure through paint, tools and drinking water. (B) Air pollution and environmental toxins containing PM2.5, NO2, O3 and other particles. (C) Pesticide and fungicide exposure to 2,4-dichlorodiphenyldichloroethylene, Rotenone, diquat, paraquat and others. (D) Helicobacter pylori infection and other gut microbiomes exert influence. (E) Exercise and physical activity. (F) Exposure to nicotine, intravenous drugs and toxins such as MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). (G) Diet and understanding of macro and micronutrients

A study in Cairo is trying to propose a protocol for the study of exposome in patients with PD. First, the authors included the environmental contribution. It is challenging because the exposure that is being observed needs to be up to twenty data for neurodegeneration. It is worth mentioning that the current environmental pollutants measurement is not associated with risk factors. For avoiding recall bias, remote sensing and wristbands for environmental exposure are being used to assess risk factors. Most countries have cumulative data that can be obtained based on the patient’s address. In the second phase, the genetic data is collected as well as metabolomics. Environmental exposure does not only increase the risk of neurodegeneration but also will affect the metabolic interaction in our body. ⁶⁸

Natural Toxins

Natural toxins are important to explain the development of neurodegeneration before the industrial revolution and accumulation of pesticides and the air pollution. Several natural toxins have been identified as relevant agents for modeling PD due to their ability to replicate key pathological features of the disorder in experimental systems. ⁶⁹ These include sterol glucosides derived from cycad plants, epoxomicin produced by Actinomycetes bacteria, Nocardia asteroides and Streptomyces venezuelae—both bacterial sources known to induce neurodegenerative changes, annonacin from plants of the Annonaceae family, and DOPAL, an endogenous metabolite of dopamine. ⁷⁰ Each of these agents has been studied for its neurotoxic potential, particularly in relation to mitochondrial dysfunction, oxidative stress, and α-synuclein aggregation, making them valuable tools for investigating PD pathogenesis and testing therapeutic strategies.

The selection of specific natural toxins for modeling PD requires adherence to defined criteria, as proposed by Shaw and colleagues. ⁷¹ Several essential properties must be met for an agent to be considered a suitable candidate for toxic PD models. These include: (1) the agent must be of natural origin; (2) it must be globally available to account for the widespread prevalence of PD across diverse geographic regions; and (3) it must reliably reproduce PD-like pathology in experimental animals. ⁷²

The Interaction Between Infections and Neurodegeneration

The Genesis

The hypothesis that an infectious agent could trigger PD gained traction following the 1918 H1N1 “Spanish” influenza pandemic, which infected approximately 500 million people and caused 20–40 million deaths. In the aftermath, a global outbreak of encephalitis lethargica emerged around 1926, affecting an estimated 15 million individuals, of whom 5 million died. By 1940, nearly half of the survivors—around 5 million—developed early-onset post-encephalitic parkinsonism. ⁷³ Although H1N1 is classified as a non-neurotropic virus, its widespread impact and temporal association with parkinsonian syndromes raised concerns about viral contributions to neurodegeneration. ⁷⁴ Importantly, the clinical presentation of post-encephalitic parkinsonism did not fully align with idiopathic PD, as it encompassed a broader spectrum of neurological disturbances. Nonetheless, many features overlapped with PD, supporting the notion that viral infections may act as environmental “hits” capable of initiating or accelerating dopaminergic neurodegeneration in susceptible individuals.

The study by Henry et al. provides a comprehensive historical review of the neurological manifestations of influenza, with a particular focus on parkinsonism, across the 20th and 21st centuries. ⁷⁵ The authors examined literature from 1889 to the present, identifying at least twelve major influenza pandemics and numerous reports of neurological complications, including encephalitis, seizures, myelopathy, Guillain-Barré syndrome, and encephalopathy. Notably, the 1918 H1N1 “Spanish flu” pandemic was temporally associated with an epidemic of encephalitis lethargica, a condition that often progressed to post-encephalitic parkinsonism, although a direct viral etiology remains unconfirmed. The review highlights that while influenza-related parkinsonism has been rarely reported since 1918, recent animal studies—particularly those involving H5N1—demonstrate that influenza viruses can enter the CNS, induce neuroinflammation, and cause dopaminergic neuron loss and α-synuclein aggregation. These findings support a “two-hit” hypothesis, where early viral exposure primes the CNS for later neurodegeneration. Noteworthy, these infections do not have to only be degenerative, but they can also be associated with psychiatric effects.

After a long interregnum, the role of viruses as a causative agent for neurodegeneration has reentered our consciousness. More recently bird flu, long-term COVID, West Nile virus, Eastern Equine Encephalitis. ⁷⁶ But, this is not new, viral infections have been associated with a number of neurodegenerative disorders, including PD.

A growing body of research has demonstrated that influenza viruses, particularly neurotropic strains like H5N1, can induce persistent neuropathological changes relevant to PD. Jang et al. showed that H5N1 travels from the peripheral nervous system into the CNS, where it triggers sustained microglial activation, α-synuclein phosphorylation and aggregation, and significant dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) 60 days post-infection. ⁷⁷ Bantle et al. expanded this concept using a two-hit model, demonstrating that juvenile manganese exposure sensitizes glial cells to exaggerated neuroimmune responses following adult H1N1 infection, marked by altered histone acetylation and transcriptomic changes in genes linked to mitophagy and neurodegeneration. ⁷⁸ Sadasivan et al. found that although the CA/09 H1N1 strain is not neurotropic, it still induces robust microglial activation in the SN and hippocampus, with downregulation of neurotrophic factors and upregulation of inflammatory markers, implying that even non-neurotropic viruses may contribute to neurodegenerative processes. ⁷⁹

Influenza Virus

In experimental models using C57BL/6J mice, animals are anesthetized with isoflurane before intranasal administration of 20 microliters of influenza virus at the LD₅₀ dose. ⁸⁰ Due to the absence of a gag reflex in mice, the entire volume is either inhaled into the lungs or swallowed if retained in the nasal passages. At designated time points post-infection, mice are sacrificed and tissue biopsies are collected to assess viral presence and associated neuropathology.

Influenza viruses produce several proteins that help them infect cells and evade the immune system. The two main surface proteins are hemagglutinin (HA), which allows the virus to attach to and enter host cells, and neuraminidase (NA), which helps new virus particles exit infected cells. Inside the virus, proteins like the matrix protein (M1) and nucleoprotein (NP) help package the viral RNA, while polymerase proteins (PB1, PB2, and PA) are responsible for copying the viral genome. Some influenza strains also produce non-structural proteins (NS1 and NS2) that interfere with the host’s immune response. ⁸¹

Jang et al. have demonstrated that the highly pathogenic avian influenza virus H5N1 (A/Vietnam/1203/04 strain) can invade the CNS of C57BL/6J mice via peripheral routes, leading to persistent neuroinflammation and neurodegenerative changes. In their 2009 study, they reported sustained microglial activation, alpha-synuclein phosphorylation and aggregation (pSer129), and significant dopaminergic neuron loss in the substantia nigra pars compacta 60 days post-infection, suggesting that H5N1 may initiate protein aggregation disorders such as Parkinson’s and Alzheimer’s disease. ⁷⁷ H5N1 influenza virus exhibits a striking cellular specificity within the central nervous system, selectively infecting neurons and microglia while sparing astrocytes entirely. Although viral presence in the brain is typically cleared by 10 to 15 days post-infection, microglial activation begins around day 10 and persists for at least 90 days. This prolonged microglial activation, in the absence of ongoing viral replication, suggests a sustained inflammatory state that may contribute to the long-term progression of neurodegenerative processes associated with H5N1 infection. Follow-up work in 2012 revealed that although the dopaminergic phenotype and monoamine levels in the basal ganglia recovered by 90 days, microglial activation and elevated expression of multiple cytokines and chemokines persisted across brain regions including the brainstem, striatum, and cortex. These findings support the hypothesis that H5N1 infection induces a long-lasting inflammatory response in the brain, which may contribute to the development or progression of neurodegenerative disorders. ⁸² H5N1 influenza virus has been shown to infect the gastrointestinal tract and subsequently access the central nervous system by traveling along the vagus nerve, effectively bypassing the blood-brain barrier. This neuroinvasive route allows the virus to reach brainstem structures such as the dorsal motor nucleus of the vagus and the solitary nucleus, which are primary targets of vagal innervation. ⁷⁵ Notably, H5N1 infection does not appear to involve the cerebellum, ⁷⁷ a pattern that seems consistent across various viral etiologies. The current strain of H5N1 (Eurasian lineage goose/Guangdong clade 2.3.4.4b) seems to be infecting mammals both at a greater rate and with more extensive regions affected than a previous strain (A/Vietnam/1203/04 strain). ⁸³

Crowther et al. investigated whether the G2019S mutation in the LRRK2 gene, a common genetic variant linked to PD, interacts synergistically with non-neurotropic H1N1 influenza to exacerbate neurodegeneration. Using a mouse model, the authors found that H1N1 infection in G2019S LRRK2 mice led to increased mortality, higher pulmonary viral loads, and a 20% indirect loss of dopaminergic neurons, accompanied by persistent neuroinflammation. Notably, selective deletion of mutant LRRK2 in Cx3Cr1+ peripheral monocytes mitigated neuronal loss. ⁸⁴ Interestingly, although infection with H1N1 is not neurotropic nor does it induce dopamine neuron loss directly, it does initiate an increase in activated microglia. Like H5N1, H1N1 infection induces long-term alteration in the level of cytokines in the substantia nigra following influenza infection. ⁸⁵

Both neurotropic H5N1 and non-neurotropic H1N1 influenza viruses have been shown to activate microglia, the brain’s innate immune cells, suggesting that virus-induced neuroinflammation may play a central role in initiating or exacerbating neurodegenerative processes.^85,86 This persistent inflammatory response, even in the absence of direct viral invasion of the brain, supports the idea that influenza infection could act as one of the environmental “hits” in a multiple-hit model of PD etiology. When combined with genetic susceptibility—such as mutations in LRRK2—this immune activation may sensitize the brain to subsequent insults, contributing to the progressive loss of dopaminergic neurons characteristic of PD.

Smeyne et al. further demonstrated that prior SARS-CoV-2 infection increases susceptibility to MPTP-induced dopaminergic neuron loss and microglial activation, reinforcing the idea that viral priming can exacerbate neurotoxic insults. ⁸⁷ Finally, Sadasivan et al. showed that H1N1 infection synergizes with MPTP to produce a 20% greater loss of SNpc dopaminergic neurons than either insult alone, an effect preventable by vaccination or antiviral treatment, underscoring the importance of mitigating viral exposure to reduce PD risk. ⁸⁸ Therefore, exposure and recovery from H1N1 leads to increased sensitivity to the parkinsonian MPTP, but not paraquat. ⁸⁹ Noteworthy, MPTP is a mitochondrial toxin, and paraquat generates oxygen species through membrane effects.

Bantle et al. investigating gene–environment interactions in PD, G2019S LRRK2 knock-in mice were intranasally infected with the CA/09 H1N1 influenza virus and evaluated 30 days post-infection. Stereological analysis of the substantia nigra pars compacta revealed a 30% reduction in tyrosine hydroxylase-positive dopaminergic neurons in mutant mice, indicating that the G2019S mutation may act as a primary genetic “hit” that enhances the neurodegenerative effects of influenza infection. ⁹⁰

Cocoros et al. found that individuals hospitalized for influenza had a 73% increased risk of developing PD more than a decade later. ⁹¹ This long-term association supports preclinical evidence suggesting that severe influenza infections may contribute to the pathogenesis of PD, potentially acting as an early environmental trigger in susceptible individuals.

Coronavirus (SARS-CoV-2)

Crunfli et al. demonstrated that even mild COVID-19 cases can lead to orbitofrontal cortical atrophy, neurocognitive deficits, fatigue, and anxiety, while severe cases showed direct viral presence and replication in astrocytes, leading to metabolic disruption and reduced neuronal viability. Their findings suggest a noncanonical spike-NRP1-mediated entry mechanism into astrocytes, which may underlie the observed neurodegeneration. ⁹² Complementing this, Stein et al. conducted comprehensive autopsies and found widespread SARS-CoV-2 RNA across multiple organs, including the brain, with persistence up to 230 days post-infection. Despite this extensive viral presence, they observed minimal inflammation or cytopathology outside the lungs, indicating that viral persistence rather than acute inflammation may drive long-term symptoms. ⁹³

Emerging preclinical evidence suggests that prior SARS-CoV-2 infection may increase susceptibility to parkinsonian neurotoxins. ⁹⁴ In a mouse model, animals infected intranasally with the USA-1 strain of SARS-CoV-2 exhibited a 20% increase in dopaminergic neuron loss in the substantia nigra pars compacta following exposure to subtoxic doses of MPTP, compared to non-infected controls. This effect was not observed with paraquat, indicating a possible toxin-specific interaction. ⁹⁵ Additionally, in a separate study involving mice carrying the LRRK2-G2019S mutation—a known genetic risk factor for PD—prior SARS-CoV-2 infection led to a 40% increase in mortality and a 20% increase in nigral degeneration. Notably, these effects were consistent across both the ancestral USA-1 and Omicron variants, suggesting that the exacerbation of neurodegeneration may be independent of viral strain. ⁹⁶ Mice immunized with the CORAVAX vaccine—but not those receiving an mRNA-based vaccine—were fully protected from dopaminergic neuron loss in the substantia nigra pars compacta, a degeneration clearly observed in sham-vaccinated controls. ⁹⁵

Limitations

Several limitations of this review should be acknowledged. As a narrative synthesis, the conclusions drawn are inherently dependent on the quality, scope, and heterogeneity of the available literature, which includes a wide range of epidemiological studies, experimental models, and translational investigations with differing methodologies and assumptions. Exposure assessment in environmental and infectious studies remains variable and often indirect, limiting causal inference and comparability across populations. In addition, mechanistic insights are frequently derived from animal or cellular models that may not fully capture the complexity of human Parkinson’s disease, particularly with respect to cumulative exposures, gene–environment interactions, and long latency periods. While this review emphasizes integrative pathophysiological frameworks, some proposed interactions remain hypothesis-generating and require longitudinal human studies and experimental validation. Finally, as this work was not designed as a systematic review or meta-analysis, formal quantitative synthesis and risk-of-bias assessment were beyond its scope. These limitations underscore the need for well-designed prospective studies that integrate exposome-level data with mechanistic and clinical outcomes.

Future Perspectives

Future studies should prioritize the development of a coordinated research agenda that addresses the multifactorial and systemic nature of climate-related health impacts, particularly in the context of neurological diseases. Given the growing evidence linking air pollution to dementia and specific pollutants to PD, research must move beyond isolated exposure-outcome models and adopt systems-based approaches that account for cumulative and interacting environmental stressors. Methodological innovation is essential to overcome challenges such as exposure misclassification, long latency periods, and population heterogeneity. Additionally, future investigations should integrate resilience and coping frameworks to better understand how individuals and communities adapt to climate-related neurological risks. This includes identifying protective factors, evaluating the effectiveness of mitigation strategies, and ensuring that research designs are inclusive, geographically diverse, and sensitive to vulnerable populations disproportionately affected by both climate change and neurological disease burden.

There are a lot of challenges to understand environmental components and their contribution to the development of the disease. There is the need for specific targets avoiding the noise caused by other factors. For the study of neuro-exposome, two main features should be met. The first is the collaboration between clinical and non-clinical scientists and the need for focus of high-incidence disease, whether or not strict cluster criteria are met. ⁹⁷ Other factors are the deep investigation with community-based studies to understand the historical background of the individual, and the investigation of external and internal variables across the individual’s life.

Understanding how environmental toxicants contribute to PD requires deeper investigation into the mechanisms underlying selective dopaminergic vulnerability. Mitochondrial dysfunction remains a central pathway, but other cellular processes disrupted by toxicant exposure—such as oxidative stress, endolysosomal impairment, and protein aggregation—must also be delineated. Gene-environment interactions, particularly involving PD-associated genes like LRRK2, should be systematically explored to identify susceptibility profiles. Advancing experimental models that replicate human exposure scenarios and disease-relevant biology will be essential for uncovering targetable mechanisms and informing strategies for risk reduction and neuroprotection.

Conclusions

In conclusion, the findings support a multifactorial model of PD etiology, where viral infections such as SARS-CoV-2 may serve as a critical “hit” in the multiple-hit hypothesis. Notably, the neurotropism of the virus does not appear essential for triggering central nervous system effects, suggesting that systemic or immune-mediated mechanisms may be at play. The interaction between SARS-CoV-2 and environmental toxins is selective, with only certain agents like MPTP showing synergistic neurodegenerative effects, likely through mitochondrial pathways. There is also substantial evidence that pesticide exposure, environmental factors, and air pollution serve as additional “hits.” Genetic predisposition also plays a significant role, as animals carrying the G2019S LRRK2 mutation exhibited heightened vulnerability to SARS-CoV-2, including increased mortality following emotional stress. Importantly, vaccination with CORAVAX provided complete protection against dopaminergic neuron loss in the substantia nigra pars compacta in wild-type mice, a benefit not observed with mRNA-based vaccines. These findings underscore the complex interplay between viral infection, genetic susceptibility, environmental exposures, and vaccine type in shaping neurodegenerative outcomes.

Appendix.

Abbreviation List

AD

Alzheimer’s disease

CNS

Central nervous system

DALY

Disability-adjusted life years

GBD

Global burden of disease

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NCD

Noncommunicable disease

PD

Parkinson’s disease

TCE

Trichloroethylene.

ORCID iD

Jamir Pitton Rissardo https://orcid.org/0000-0001-6179-2177

Ethical Considerations

We have read the Journal’s position on issues involving ethical publication and affirm that this report is consistent with those guidelines.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated and/or analyzed during the current study.*