Pathogenic and protective effects of environmental factors in Parkinson’s disease: analysis of epidemiological data and molecular mechanisms

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Introduction

Parkinson’s disease (PD) is a chronic, slowly progressive multisystem neurological disorder characterized by gradual degeneration of dopaminergic neurons forming nigrostriatal projections in the brain. This neurodegenerative process leads to significant impairments in adaptation and loss of working capacity in patients. Furthermore, PD is considered the most common form of movement disorders [1].

The clinical presentation of PD comprises two main groups of manifestations: motor and non-motor symptoms. The disease is characterized by a prolonged prodromal period lasting 5–15 years, during which non-motor symptoms such as asthenia, apathy, cognitive disorders, hyposmia, sleep disturbances, constipation, depressive states, and sarcopenia often appear [2, 3]. The principal motor manifestations of PD typically include hypokinesia, resting tremor, and muscle rigidity. As the pathological process progresses with loss of 50–80% of dopaminergic neurons in the substantia nigra, patients develop gait and coordination disorders, postural instability, retropulsion, and propulsion [4].

The precise etiology of PD remains undetermined [5, 6]. From a pathophysiological perspective, PD is categorized into familial and sporadic subtypes. In familial PD cases, pathogenic mutations occur in specific genes: SNCA (alpha-synuclein) [7], LRRK2 (leucine-rich repeat kinase 2) [8], UCHL1 (ubiquitin carboxyl-terminal hydrolase L1) [1], VPS35 (vacuolar protein sorting-associated protein 35) [9], SPR (sepiapterin reductase) [10], HTRA2 (serine protease HTRA2) [11], GIGYF2 (GRB10-interacting GYF protein 2) [12], and EIF4G1 (eukaryotic translation initiation factor 4 gamma 1) [13]. These mutations exhibit complete penetrance with autosomal dominant inheritance patterns [1].

Current research focuses on sporadic PD, which demonstrates multifactorial pathogenesis requiring interaction between genetic susceptibility and environmental exposures [6]. In their pathogenesis, genetic mechanisms serve as predisposing rather than determinative factors: mutations establish susceptibility thresholds, while environmental factor exposures are required for penetrance and disease progression [6]. Predisposing genetic variants for sporadic PD include EPHB1 (EPH receptor B1) [14], DCC (DCC netrin 1 receptor) [14], and FMR1 (fragile X messenger ribonucleoprotein 1) [15]. Multifactorial disorders typically manifest unexpectedly at various ages following initial exposure to development-promoting environmental factors [6]. This underscores the critical importance of identifying environmental triggers for sporadic PD pathogenesis. Consequently, numerous epidemiological studies worldwide now evaluate both pathogenic and protective environmental factors [5, 6].

The aim of this review is to analyze and synthesize scientific data on the pathogenic and protective influences of environmental factors on the development and progression of sporadic PD.

This literature review incorporates domestic and international experimental and clinical studies from the past 20–25 years that evaluate the contribution of environmental factors to the pathogenesis of sporadic PD. The search was conducted in PubMed, Web of Science, Google Scholar, and eLIBRARY.RU databases using the following keywords: Parkinson disease, environmental factors, pathxogenic effect, protective effect, genetic predisposition.

Pesticides and Neurotoxins

Exogenous neurotoxins play a significant role among environmental factors contributing to PD [16]. Exposure to such substances, including pesticides, leads to disruption of neurotransmitter processes in the central nervous system (CNS) and increases the likelihood of abnormal (aberrant) protein formation [17]. Results of epidemiological studies conducted by Norwegian specialists showed that occupational exposure to pesticides carries a relative risk of PD at 1.67 (95% confidence interval (CI) 1.42–1.97). The authors noted that the risk magnitude did not depend on study type (case-control, cohort, or prospective) or participant gender, while any pesticide exposure increases disease probability by approximately 50% [18]. Researchers showed interest not only in agro-industrial toxicants but also in organophosphate pesticides widely used in households — utilized by up to 90% of U.S. households. A population study conducted by California scientists involved 366 PD patients and 424 healthy volunteers, enabling clarification of the relationship between household toxin exposure and disease risk [18]. To assess pesticide impact, trained research staff collected data on participant demographic characteristics and frequency of household chemical use. Analysis revealed that regular use of household pesticides increases PD risk by 47% (95% CI 1.13–1.92) [20]. For specific classes of chemical compounds where active ingredients were chlorpyrifos and diazinon, disease risk increased more substantially by 70–100% [19]. Modern epidemiological methods utilizing geographic information systems and satellite remote sensing allowed precise assessment of pesticide exposure at the county level in Nebraska [20]. The study demonstrated that exposure to certain pesticides, including alachlor and bromoxynil, shows significant positive association with PD prevalence [20]. These findings conclusively demonstrate a direct correlation between pesticide application frequency and PD risk.

PD research has identified neurotoxic compounds selectively targeting dopaminergic neurons in the midbrain substantia nigra. These substances include 6-hydroxydopamine (6-OHDA) and methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Due to their pronounced tropism and specificity for dopaminergic structures, these compounds are recommended as animal models of parkinsonism according to guidelines from the Scientific Center for Expert Evaluation of Medical Products. There is a hypothesis that such toxicants may enter the human body through contaminated food, water, or inhaled air [21].

Head Injury

Another significant factor contributing to neurodegenerative diseases, including PD, is traumatic brain injury. A meta-analysis involving 14 case-control studies and 1 cohort study established a significant association between mild traumatic brain injury and PD risk with the relative risk of 1.45 (95% CI 1.18–1.78) [21]. Results from another meta-analysis combining data from 22 original studies confirmed that at least one episode of traumatic brain injury of any severity accompanied by loss of consciousness is reliably associated with increased PD probability [22]. The pathogenetic mechanisms of this influence are considered from two perspectives. First, mechanical impact during trauma causes axonal damage and rotational injury to mesencephalic dopaminergic neurons. Second, trauma leads to disruption of the blood-brain barrier (BBB), initiating an immune response with neuroinflammation. Subsequent activation of acute-phase reactions, proliferation, alteration and exudation is accompanied by hyperexpression of proteins including α-synuclein, promoting further neurodegenerative processes [21].

Nicotine and Tobacco Use

Nevertheless, environmental factors can not only increase but also reduce the risk of PD. One of the most studied protective factors is tobacco smoking [6]. According to the latest meta-analysis combining 8 cohort and 61 case-control studies conducted over the past 55 years, the odds ratio (OR) for regular tobacco users was 0.59 (95% CI 0.56–0.62) compared to never-smokers [23]. A dose-dependent effect was also observed: smokers with a 30 pack-year index showed OR = 0.66 (95% CI 0.49–0.88), while those with lower cumulative tobacco exposure (less than 30 pack-years) had an even lower ratio of 0.39 (95% CI 0.29–0.53) [23]. It should be noted that tobacco consumption methods vary regionally. In Sweden, moist powdered tobacco for sublingual use (snus) is widely prevalent. Results from two large pooled cohort studies demonstrated that snus use is also associated with reduced PD risk, with OR ranging from 0.41 to 0.51, confirming the protective effect of tobacco products [23]. The main pharmacologically active component of tobacco is nicotine, which reaches the brain within 7 seconds after the start of tobacco smoke inhalation. When smoking one cigarette, 50–300 nmol of nicotine penetrates the BBB. In the structures of the cerebral cortex, striatum, limbic system, and midbrain, nicotine rapidly activates postsynaptic and presynaptic N-cholinergic receptors. A distinctive feature of nicotine is that it is not hydrolyzed by cholinesterase, which accounts for its prolonged action. As an agonist of presynaptic N-cholinergic receptors, nicotine enhances dopamine release in the ventral tegmental area and anterior striatum, while also increasing serotonin, glutamate, and β-endorphin levels in the CNS. The combination of these effects is considered a potential mechanism of nicotine neuroprotective action. Interestingly, nicotine — an alkaloid by chemical nature — is found not only in tobacco but also in plants of the nightshade family, such as peppers, tomatoes, potatoes, and eggplants. According to research data, the risk of PD inversely correlates with nightshade vegetable consumption: OR = 0.81 (95% CI 0.65–1.01). At the same time, consumption of vegetables not belonging to the nightshade family shows no significant effect on disease probability [24].

Caffeine

There is compelling evidence of an association between coffee consumption and reduced risk of PD. A meta-analysis of 26 studies, including 7 cohort studies, showed that coffee drinkers had an odds ratio (OR) of 0.75 (95% CI 0.68–0.82) [25]. Subsequent research has focused on investigating the dose-dependent nature of this protective effect. A meta-analysis of 16 studies involving 901,764 participants revealed that the greatest antiparkinsonian effect is observed with consumption of 3 cups of coffee per day (equivalent to 7–8 g of coffee per cup when calculated for espresso). At this dosage, the OR was 0.72 (95% CI 0.65–0.81) [26]. From a pharmacological perspective, the key component responsible for coffee psychostimulant effects is caffeine (1,3,7-trimethylxanthine). As a xanthine derivative, caffeine is well-absorbed orally and rapidly crosses all histohematic barriers, including the BBB. In the CNS, it enhances cholinergic transmission in the cerebral cortex and hippocampus, improving cognitive function; stimulates the respiratory center of the medulla oblongata; and increases adrenergic transmission activity in the hypothalamus, toning the vasomotor center. Furthermore, caffeine enhances dopaminergic neurotransmission in the limbic system and reticular formation, producing a psychostimulant effect [25, 27]. The anti-parkinsonian effects of caffeine are associated with its ability to block A1 adenosine receptors. This disruption of intracellular signaling through the secondary messenger system leads to accumulation of cyclic adenosine monophosphate (cAMP). Elevated cAMP levels reduce membrane permeability to potassium ions, promoting the release of neurotransmitters, primarily dopamine, as well as norepinephrine, serotonin, acetylcholine, and glutamate in the CNS. Additional confirmation of caffeine’s anti-parkinsonian effects has been demonstrated through tea consumption, where caffeine is also the primary chemical component. At least two meta-analyses encompassing 8 studies on tea consumption showed an odds ratio (OR) of 0.63 (95% CI 0.49–0.81) [28]. From a cultural perspective, black tea is consumed both in Eastern and Western countries, while green tea is more prevalent in Eastern regions. Black tea undergoes complete fermentation, resulting in higher caffeine content but reduced antioxidant levels. Green tea is minimally oxidized, containing more antioxidants but lower quantities of caffeine. The question of which tea provides more effective protection against PD was investigated in a prospective cohort study conducted in Singapore. The study revealed that black tea consumption was associated with reduced PD risk, while green tea showed no such association [27]. Particular interest surrounds mate tea — an infusion made from dried, roasted, and crushed leaves/stems of Ilex paraguariensis, widely consumed in South America and the Middle East. A case-control study in Argentina demonstrated that mate consumption reduces PD risk comparably to regular tea, with an OR of 0.64 (95% CI 0.54–0.76) [28].

Physical Activity

Recent studies show that physical activity is also a factor reducing the risk of PD. A meta-analysis evaluating 6 cohort studies with a total of 43,368 participants followed for an average of 12.6 years found that regular physical exercise exerts neuroprotective effects on the nigrostriatal dopaminergic system. The pooled risk estimate was 0.66 (95% CI 0.57–0.78) [29]. The relationship between physical activity and PD was also investigated by Chinese researchers in a cohort of 5,932 individuals. Multivariate conditional logistic regression analysis showed that both physical exercise and high social activity are significantly associated with reduced probability of PD [30].

Body Mass Index

When studying environmental risk factors for PD, the role of some factors remains unclear due to discrepancies in results from various research groups. Research on the influence of body mass index (BMI) shows contradictory findings. Elevated BMI is a well-established risk factor for many metabolic and vascular diseases such as type 2 diabetes mellitus, ischemic heart disease, and stroke, some of which may serve as contributing or precipitating factors for PD [31]. The relationship between BMI and PD risk has been examined in 2 meta-analyses. The first meta-analysis evaluated 10 prospective studies and found no increased PD risk, demonstrating a pooled odds ratio of 1.00 (95% CI 0.89–1.12). Moreover, no significant association was found between overweight (25 kg/m² ≤ BMI ≤ 29.9 kg/m²), obesity (BMI ≥ 30 kg/m²), or general overweight (BMI ≥ 25 kg/m²) and PD risk [31]. Another meta-analysis employing different methodology assessed 12 case-control studies involving a total of 871 PD patients in the comparison group and 736 control subjects. Meta-analysis revealed that patients with PD exhibited significantly lower body mass index (BMI) compared to controls: OR = 1.73 (95% CI 1.11–2.35) [32]. Additionally, a large 2017 multicenter randomized study conducted across European research centers and one facility in the Philippines demonstrated that higher BMI was associated with reduced PD risk (OR = 0.82; 95% CI 0.69–0.98) [32]. This study uniquely employed Mendelian randomization, an analytical method using genetic variants as instrumental variables to assess causal relationships between risk factors and disease onset/progression [33].

Uric Acid

Oxidative stress is considered a potential mechanism underlying the selective loss of dopaminergic neurons in PD [34]. Uric acid is a potent antioxidant [35] that may exert neuroprotective effects. Several studies have investigated the association between uric acid levels and PD risk. A meta-analysis of 3 prospective cohort studies and 1 case-control study conducted in the United States demonstrated a pooled odds ratio of 0.63 (95% CI 0.42–0.95). Higher serum uric acid concentrations were found to protect against PD risk in men but not women [36]. Similar results were observed in an earlier meta-analysis of 4 cohort studies from the Netherlands and US, along with 2 US case-control studies, showing an odds ratio of 0.67 (95% CI 0.50–0.91), with subgroup analyses indicating protective effects of uric acid specifically in males [37]. Gout is a systemic chronic metabolic disorder characterized by deposition of monosodium urate or uric acid crystals in various tissues. This disease typically occurs in individuals with elevated serum uric acid levels, though other risk factors contribute. A UK case-control study examining the gout-PD association [38] revealed comparable effect sizes consistent with uric acid-PD research. Individuals with prior gout history showed reduced PD risk (OR = 0.69; 95% CI 0.48–0.99). This protective association remained significant in men (OR = 0.60; 95% CI 0.40–0.91) but not in women (OR = 1.26; 95% CI 0.57–2.81) [38]. A meta-analysis using analytical epidemiology compared Eastern (Asia/Africa) and Western (Americas/Europe/Australia) populations across 13 case-control studies. PD patients exhibited significantly lower serum uric acid levels compared to controls, with no observed differences between Eastern and Western cohorts [39].

Dietary Components

Epidemiological data indicate that dietary components may contribute to PD. The influence of diet on PD risk may be mediated through oxidative stress, which can lead to degeneration of dopaminergic neurons. Cells of the substantia nigra are particularly susceptible to high levels of oxidative stress, partly due to dopamine metabolism and subsequent generation of hydroxyl radicals via the Fenton reaction (a chemical reaction between hydrogen peroxide and iron ions that degrades organic compounds). Dietary fats, including cholesterol, have been implicated in PD pathogenesis in some studies and are thought to promote oxidative stress, though findings remain inconsistent. Three prospective cohort studies from the Netherlands and United States found no association between plasma cholesterol levels and PD risk. Two U.S. case-control studies produced conflicting evidence: one reported reduced PD risk with elevated cholesterol [40], while another showed increased risk [41]. A Singaporean prospective cohort study demonstrated that highest-quartile cholesterol levels were associated with decreased PD risk, though this effect was gender-specific (OR = 0.53; 95% CI 0.33–0.84 in males) [42]. Conversely, a Japanese case-control study of 249 PD patients and 368 controls found elevated plasma cholesterol correlated with increased PD risk [43].

The role of alcohol consumption in PD remains controversial. A meta-analysis of 32 studies (8 prospective cohort, 17 matched case-control, and 7 unmatched case-control studies) showed that alcohol may be associated with a moderate reduction in PD risk, with more pronounced effects in European studies compared to North American and Asian research [44]. A prospective cohort study from Singapore revealed a non-significant risk reduction in weekly alcohol consumers compared to non-drinkers or those drinking less than weekly (OR = 0.6; 95% CI 0.31–1.16). Other meta-analyses more frequently identified weak protective associations in case-control studies than in prospective cohort studies, suggesting potential methodological limitations in case-control designs [45]. Conversely, a Swedish prospective study demonstrated that excessive alcohol consumption was associated with increased PD risk (OR = 1.38; 95% CI 1.25–1.53) [46]. Notably, an original Japanese case-control study found no significant association between overall alcohol consumption and PD risk [47].

Furthermore, conflicting data exist regarding milk and dairy product consumption’s impact on PD. A meta-analysis examining the association between dairy consumption and PD evaluated 5 prospective studies. The pooled PD risk for highest versus lowest dairy consumption levels was 1.40 (95% CI 1.20–1.63) overall, with 1.66 (95% CI 1.29–2.14) for men and 1.15 (95% CI 0.85–1.56) for women. Linear dose-response analysis showed a 17% increased PD risk (95% CI 1.06–1.30) per 200g milk intake increment and 13% increased risk (95% CI 0.91–1.40) per 10 g cheese intake increment [48]. This study received considerable commentary suggesting these dairy effects might be associated with pesticide contamination in milk [48]. This hypothesis is supported by a Japanese study that rigorously analyzed milk for toxins, including pesticides, finding no association between milk consumption and PD risk [49].

Conclusion

Thus, the multifactorial nature of sporadic PD appears indisputable. This disease form can develop only through the combination of genetic predisposition and exposure to adverse environmental factors. None of these components alone can trigger sporadic PD. Modern data convincingly demonstrate that pesticides, neurotoxic substances, and traumatic brain injury are among the most significant provoking factors for PD, highlighting the need to minimize contact with them. At the same time, alongside pathogenic influences, there exist protective factors that can reduce the risk of disease onset or progression. These include consumption of coffee and plants from the Solanaceae family, as well as regular physical activity. These measures can be considered as elements of preventive medicine for individuals at high risk of developing PD, as well as additional non-pharmacological approaches for patients with an established diagnosis, contributing to improved disease course and prognosis. Controversial data regarding BMI, dairy product consumption, plasma uric acid, and cholesterol levels require further methodologically refined and standardized studies in larger patient cohorts.

 

The review analyzes pathogenic and protective environmental factors in PD, along with factors of uncertain significance

Environmental factor	Impact on PD	Reference
Pesticides	Increased risk	16–20
Specific neurotoxins	Increased risk	21
Head injury	Increased risk	21–22
Nicotine	Decreased risk	23–24
Caffeine (coffee and black tea consumption)	Decreased risk	25–28
Physical activity	Decreased risk	29–30
Alcohol and alcohol-containing drink consumption	Contradictory data	44–47
Plasma cholesterol	Contradictory data	40–43
Milk and dairy product consumption	Contradictory data	48–49
Body Mass Index	Contradictory data	31–33
Plasma urea acid	Contradictory data (in men — decreased risk, in women — no impact)	34–39

About the authors

Natalia G. Zhukova

Siberian State Medical University

Email: znatali@yandex.ru
ORCID iD: 0000-0001-6547-6622

Dr. Sci. (Med.), Professor, Professor, Department of neurology and neurosurgery

Russian Federation, Tomsk

Zainutdinkhuzha F. Sayfitdinkhuzhaev

Siberian State Medical University

Author for correspondence.
Email: sayfutdinxodjaev2002@gmail.com
ORCID iD: 0009-0007-2184-2708

research assistant, Scientific and educational laboratory of cognitive neurophysiology of psychosomatic relationships

Russian Federation, Tomsk

Dilorom A. Nurmatova

City Children’s Clinical Hospital No. 1

Email: okhunbaev@gmail.com
ORCID iD: 0009-0002-2031-8940

Cand. Sci. (Med.), Assistant professor, Head, Department of neurology of older children

Uzbekistan, Tashkent

Irina A. Zhukova

City Children’s Clinical Hospital No. 1

Email: zhukova.ia@ssmu.ru
ORCID iD: 0000-0001-5679-1698

Cand. Sci. (Med.), Assistant Professor, Expert, Clinical Research Center

Uzbekistan, Tashkent

Jakhongir M. Okhunboev

City Children’s Clinical Hospital No. 1

Email: okhunbaev@gmail.com
ORCID iD: 0009-0002-7312-7750

neurologist, Department of neurology of elderly children

Uzbekistan, Tashkent

Alexandra Ya. Masenko

Siberian State Medical University

Email: masenkosasha@yandex.ru
ORCID iD: 0009-0003-4583-5407

postgraduate student, Department of neurology and neurosurgery

Russian Federation, Tomsk

Olesya V. Gaponova

Siberian State Medical University

Email: masenkosasha@yandex.ru
ORCID iD: 0009-0009-6061-0314

postgraduate student, Department of neurology and neurosurgery

Russian Federation, Tomsk

References

Supplementary files