Pesticides and Parkinson’s disease: A potential hazard in agricultural communities
Smathorn Thakolwiboon MD, Parunyou Julayanont MD, Doungporn Ruthirago MD
Corresponding author: Smathorn Thakolwiboon
Contact Information: firstname.lastname@example.org
Parkinson’s disease (PD) is a prevalent neurodegenerative disorder. Its pathogenesis is related to both genetic and environmental factors. Current evidence suggests that pesticide exposure is one of the risk factors of PD. In this review, we summarize four molecular mechanisms of pesticide-induced PD with supportive evidences from both laboratory and epidemiological studies. Rotenone is the first pesticide reported to be associated with PD by inhibiting complex I of mitochondrial electron transport chain. Paraquat, a commonly-used herbicide in some countries, is an oxidative stressor causing dopaminergic neuronal loss which contributes to the pathogenesis of PD. The ubiquitin-proteasome system (UPS) and aldehyde dehydrogenase (ALDH) inhibitors cause unwanted proteins (especially alpha-synuclein) and 3,4-dihydroxyphenylacetaldehyde (DOPAL) accumulation leading to dopaminergic neuronal apoptosis. In addition, exposure to different pesticides affecting different mechanisms may have synergistic effects in increasing risk of PD. Protective glove use, the amount of fat intake, and neuroprotective agents are reported to have disease modification effects for pesticide-associated PD.
Keywords: pesticides, Parkinson, Parkinsonism, agriculture
Parkinson’s disease (PD) is a common neurodegenerative disorder which affects millions of people worldwide. The crude prevalence of PD is 315 per 100,000.1 The overall annual incidence is approximately 37.55 per 100,000. The incidence of disease correlates with age and increases from 3.26 per 100,000 in the fifth decade to 103.48 per 100,000 in the ninth decade.2
The etiology of PD appears to include interactions between genetic and environmental factors. Hypothetically, there is a dual-hit caused by a genetic predisposition and subsequent environmental exposure(s) interacting to cause the cellular pathology leading to PD. Braak and colleagues have demonstrated that the pathology of PD appears to begin outside the central nervous system in the olfactory bulbs, the enteric nervous system, and the dorsal motor nucleus of vagus nerve. It eventually spreads to the brainstem and cerebral cortices in a sequential fashion.3,4 Recent studies have suggested that environmental factors have a crucial role in triggering and/or propagating the pathological changes in PD.5 The olfactory bulbs and the enteric nervous system are the gateways to the environment, which may be one of the mechanisms of PD related to environmental risks. Several studies have reported the association between PD and exposures to environmental factors, such as 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), pesticides, solvents, and metals.6-9 Pesticide use is an important risk factor which raises a special concern, since agricultural fields account for 37.7% of land area worldwide. In this review, we focus on the association between pesticide exposure and PD.
PESTICIDES AND PARKINSON’S DISEASE: EPIDEMIOLOGY
Pesticides are chemical or biological agents that have brought a lot of benefits to mankind not only in the agricultural field but also in industrial and health areas. However, toxicity from pesticides is a major concern in public health and is associated with many health problems, including, for example, cancers, neurodegenerative diseases, asthma, infertility, and birth defects.10
The association between pesticide use and PD was first reported in 1987 by Barbeau and colleagues.11 A recent meta-analysis reported by Breckenridge and colleagues showed a significant association between pesticide use and PD (relative risk (RR) = 1.56; 95% confidence interval (CI) =1.37-1.77).8 People exposed to pesticides at workplaces have a higher risk of PD than people exposed at home, and exposure at both workplaces and residences has the highest PD risk.12
The pathophysiology of PD is a combination of neurodegenerative processes that are broadly classified as cell-autonomous and non-cell-autonomous processes. Cell-autonomous processes take place in the degenerating dopaminergic neurons. These mechanisms include mitochondrial dysfunction, oxidative stress, protein aggregation, impairment of ubiquitin-proteasome process, and autophagy. Currently, a number of genetic mutations and environmental exposures are known as contributing factors to these mechanisms. However, dopaminergic neurons of the nigrostriatal pathways do not function in isolation. These neurons receive a variety of afferent inputs and are surrounded by non-dopaminergic neurons and non-neuronal cells. The non-cell-autonomous processes, which occur outside the degenerative neurons, were also hypothesized as the contributing mechanisms of PD. These mechanisms include a spreading of pathology (especially alpha-synuclein) and inflammatory processes.13
Recently, a number of laboratory and epidemiological studies have suggested several molecular mechanisms to explain pesticide association with PD. These molecular mechanisms are cell-autonomous. To the best of our knowledge, the roles of pesticides in non-cell-autonomous processes are still poorly understood. In this review, we will focus on the four major mechanisms (Figure) that have strong evidence in both laboratory and epidemiological studies.
Figure. Schematic overview of cellular mechanisms of pesticide-induced Parkinsonism
Ub = ubiquitin, DA = dopamine, PQ = paraquat, DOPAL = 3, 4-dihydroxyphenylacetaldehyde, DOPAC = 3, 4-dihydroxyphenylacetic acid, ALDH = aldehyde dehydrogenase, MAO = monoamine oxidase, NAD+ = oxidized form of nicotinamide adenine dinucleotide, NADH = reduced form of nicotinamide adenine dinucleotide, MPTP = 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPP+ = 1-methyl-4-phenylpyridinium
Mitochondrial dysfunction has been long implicated as one of the underlying mechanisms of PD.14 MPTP is the first recognized agent that induced Parkinsonism in an animal model. Additionally, it was associated with rapid-onset Parkinsonism in young drug abusers who responded to dopaminergic therapy. After it crosses the blood brain barrier, MPTP is converted to 1-methyl-4-phenylpyridinium (MPP+) which has selective toxicity to dopaminergic neurons by inhibiting Complex 1 of the electron transport chain.15 MPP+ has been used as a herbicide under the trade name Cyperquat.
Similarly, Rotenone, a broad-spectrum pesticide, also inhibits complex I of mitochondrial electron transport chain, which leads to neuronal death in in vitro dopaminergic cell cultures.16 Later, animal studies showed that chronically and intravenously rotenone-treated rats had selective damage to the striatum and globus pallidus, which caused Parkinsonian features.17,18 Recently, Pan-Montojo and colleagues demonstrated that intragastric administration of rotenone also caused Parkinsonian phenotypes in a mouse model.19 In addition, several other pesticides (e.g., manganese ethylene-bis-dithiocarbamate [maneb], permethrin) also inhibit the mitochondrial complex I, leading to Parkinsonism.20,21 Data from several case-control studies showed that exposure to rotenone and maneb is a significant risk factor for PD in humans.12,20,22 According to a Taiwanese study, people with the mitochondrial haplogroup B5 had lower PD risk, and cytoplasmic hybrid cells harboring this haplogroup also had a higher resistance to rotenone exposure than other haplogroups.23
Leucine-rich-repeat-kinase-2 (LRRK2) mutations have been identified in both familial and sporadic PD.24,25 These mutations are considered the most common cause of autosomal dominant form of PD.26 Both in vitro and in vivo experiments have demonstrated a role for LRRK2 in the regulation of mitochondrial dynamics and function.27 In addition, a subsequent mouse-model study demonstrated that mutant LRRK2 mice had higher susceptibility to rotenone-induced dopaminergic neuron death in a dose-dependent manner and had greater locomotor deficits than wild-type mice.28
Oxidative stress may have a role in pesticide-related PD. For example, paraquat, a well-known herbicide, is an oxidative stressor which contributes to neuronal loss.29 Both in vitro and in vivo studies have demonstrated that paraquat-induced oxidative stress leads to cellular apoptosis via c-JUN N-terminal kinase (JNK) pathway, especially in dopaminergic neurons.30-40 Several case-controlled studies also show an association between paraquat exposures and PD.20,41-43
Glutathione transferases are enzymes in the glutathione-mediated anti-oxidant and detoxifying defense system.44,45 Dysfunction of these enzymes may lead to various neurodegenerative diseases.45 A case-controlled study demonstrated that risk of PD is increased in subjects with homozygous deletion of glutathione S-transferase T1 (GSTT1).46 Recently, Goldman and colleagues reported an association between homozygous deletion of glutathione S-transferase T1 (GSTT1) gene and greater PD risk from paraquat exposure.47 In addition to paraquat, there are many other oxidative-stressor pesticides, such as permethrin, carbon disulfide, chloranil, etc. However, there are no reports of an association between these pesticides and PD in any epidemiological studies.20
UBIQUITIN-PROTEASOME SYSTEM DYSFUNCTION
The ubiquitin-proteasome system (UPS) has an important role in degradation of potentially cytotoxic proteins. Dysfunction in the UPS causes unwanted protein (especially alpha-synuclein) accumulations that ultimately cause cellular dysfunction and neuronal death.48 In vitro experiments have suggested that dimethyl- and diethyldithiocarbamates, including ziram, cause damage to the dopaminergic neurons by inhibiting E1 ligase and the 26S proteasome in the UPS. Moreover, chronic exposure to sodium dimethyldithiocarbamates caused motor deficits and damage to the nigrostriatal pathway in mice.49 Recently several epidemiological studies reported a significant association between ziram and PD.12,50 Additionally, benomyl, cyanazine, dieldrin, endosulfan, metam, propargite and triflumizole were also reported as UPS-inhibiting pesticides and were associated with increased PD risk. Furthermore, the risks of exposure to these pesticides are modified by genetic variation in the s-phase kinase-associated protein 1 (SKP1) gene.50
INHIBITION OF ALDEHYDE DEHYDROGENASE ACTIVITY
The dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL), is neurotoxic and related to pathogenesis of PD.51-54 In the central nervous system, aldehyde dehydrogenase (ALDH) has a critical role in DOPAL detoxification. Fitzmaurice and colleagues have demonstrated that benomyl exposure induces selective dopaminergic neuronal damage in vitro (primary mesencephalic cultures) and in vivo (a zebrafish system) by ALDH inhibition causing DOPAL toxicity. Additionally, they also reported the epidemiological association of higher benomyl exposure and higher PD risk.55 A subsequent study reported that other ALDH-inhibiting pesticides (i.e., maneb, ziram, triflumizole, captan, and folpet) are also associated with 2- to 6-fold increase in PD risk and that ALDH2 genetic variations exacerbated the risk of PD in subjects exposed to ALDH-inhibiting pesticides.56
Furthermore, a recent epidemiological study has clearly demonstrated that pesticide exposures affecting different mechanisms have synergistic effects in increasing risk of PD.12 Therefore, a farmer using multiple pesticides tends to have higher risk of PD.
There are no differences in clinical features between PD patients who had history of exposures to pesticides discussed above and those without this history.20 Most PD patients have good response to dopaminergic therapy. There is no disease-modifying therapy for any pesticide-induced PD at present. However, several recent laboratory studies on disease modification have had promising results.
The main preventive strategy involves physical protection from pesticide exposure. Using protective gloves (chemically resistance) significantly reduces PD risk from paraquat and permethrin exposures.57 Neither paraquat nor permethrin exposure was associated with PD among protective glove users, whereas both were linked with PD among non-users. However, protective glove use did not modify the PD risk from rotenone exposure.57
Dietary fat intake modifies PD risk with paraquat or rotenone exposure in different ways. Higher N-3 polyunsaturated fatty acids (PUFAs) intake was associated with lower PD risk in paraquat-exposed workers, while higher saturated fats intake increased PD risk in rotenone-exposed workers.58 The molecular basis for this finding may involve the role of PUFA which attenuates inflammatory responses and the role of saturated fats which cause oxidative stress.59,60
Several laboratory studies have reported the effect of neuroprotective agents in pesticide-induced Parkinsonism. The neuroprotective effect of Coenzyme Q10 has been demonstrated in both rotenone- and paraquat-induced Parkinsonian rat models.61-63 In addition, Ginkgo biloba extract is neuroprotector in paraquat-induced apoptosis in vitro,64 while acetyl–L-carnitine, sodium butyrate, vildagliptin, Hipercium perforatum, etc. had neuroprotective effects in rotenone-induced Parkinsonism in animals.65-71 However, the roles of these agents in humans needs more studies.
Furthermore, many European countries ban rotenone and paraquat because of health concerns.72 However, these pesticides have been approved by US Environmental Protection. Therefore, agriculturists and other people at risk should be educated about the preventive measures, such as protective gloves, and proper dietary intake, to prevent the sequelae of pesticide use.
The pathogenesis of PD involves both genetic and environmental interaction. In this review, we focused on the relationship between pesticide exposures and PD and summarized four major cellular mechanisms of pesticide-induced Parkinsonism. Genetic variation has a role in the susceptibility of each individual to different pesticides. Exposures to different pesticides affecting different mechanisms have synergistic effect in increasing the risk of PD. Furthermore, protective glove use, amount of fat intake, and neuroprotective agents modify the association between pesticides and PD in epidemiological studies.
- Pringsheim T, Jette N, Frolkis A, Steeves TD. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Movement disorders:official journal of the Movement Disorder Society. 2014;29(13):1583-1590.
- Hirsch L, Jette N, Frolkis A, Steeves T, Pringsheim T. The Incidence of Parkinson’s Disease: A Systematic Review and Meta-Analysis. Neuroepidemiology. 2016;46(4):292-300.
- Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of aging. 2003;24(2):197-211.
- Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neuroscience letters. 2006;396(1):67-72.
- Klingelhoefer L, Reichmann H. Pathogenesis of Parkinson disease–the gut-brain axis and environmental factors. Nature reviews Neurology. 2015;11(11):625-636.
- Goldman SM. Environmental toxins and Parkinson’s disease. Annual review of pharmacology and toxicology. 2014;54:141-164.
- Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Frontiers in cellular neuroscience. 2015;9:124.
- Breckenridge CB, Berry C, Chang ET, Sielken RL, Jr., Mandel JS. Association between Parkinson’s Disease and Cigarette Smoking, Rural Living, Well-Water Consumption, Farming and Pesticide Use: Systematic Review and Meta-Analysis. PloS one. 2016;11(4):e0151841.
- Nandipti S, Litvan I. Environmental Exposures and Parkinson’s Disease. Int J ENviron Res Public Health. 2016;13:881.
- Mostafalou S, Abdollahi M. Pesticides: an update of human exposure and toxicity. Archives of toxicology. 2016.
- Barbeau A, Roy M, Bernier G, Campanella G, Paris S. Ecogenetics of Parkinson’s disease: prevalence and environmental aspects in rural areas. The Canadian journal of neurological sciences Le journal canadien des sciences neurologiques. 1987;14(1):36-41.
- Wang A, Costello S, Cockburn M, Zhang X, Bronstein J, Ritz B. Parkinson’s disease risk from ambient exposure to pesticides. Eur J Epidemiol. 2011;26(7):547-555.
- Hirsch EC, Jenner P, Przedborski S. Pathogenesis of Parkinson’s disease. Movement disorders: official journal of the Movement Disorder Society. 2013;28(1):24-30.
- Henchcliffe C, Beal MF. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nature clinical practice Neurology. 2008;4(11):600-609.
- Langston JW, Langston EB, Irwin I. MPTP-induced parkinsonism in human and non-human primates–clinical and experimental aspects. Acta neurologica Scandinavica Supplementum. 1984;100:49-54.
- Hartley A, Stone JM, Heron C, Cooper JM, Schapira AH. Complex I inhibitors induce dose-dependent apoptosis in PC12 cells: relevance to Parkinson’s disease. Journal of neurochemistry. 1994;63(5):1987-1990.
- Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nature neuroscience. 2000;3(12):1301-1306.
- Ferrante RJ, Schulz JB, Kowall NW, Beal MF. Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra. Brain research. 1997;753(1):157-162.
- Pan-Montojo F, Anichtchik O, Dening Y, et al. Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. PloS one. 2010;5(1):e8762.
- Tanner CM, Kamel F, Ross GW, et al. Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect. 2011;119(6):866-872.
- Zhang J, Fitsanakis VA, Gu G, et al. Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction. Journal of neurochemistry. 2003;84(2):336-346.
- Dhillon AS, Tarbutton GL, Levin JL, et al. Pesticide/environmental exposures and Parkinson’s disease in East Texas. J Agromedicine. 2008;13(1):37-48.
- Liou CW, Chuang JH, Chen JB, et al. Mitochondrial DNA variants as genetic risk factors for Parkinson disease. European journal of neurology. 2016;23(8):1289-1300.
- Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44(4):595-600.
- Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44(4):601-607.
- Lesage S, Brice A. Parkinson’s disease: from monogenic forms to genetic susceptibility factors. Human molecular genetics. 2009;18(R1):R48-59.
- Wang X, Yan MH, Fujioka H, et al. LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Human molecular genetics. 2012;21(9):1931-1944.
- Liu HF, Ho PW, Leung GC, et al. Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson’s disease. Scientific reports. 2017;7:40887.
- Dinis-Oliveira RJ, Remiao F, Carmo H, et al. Paraquat exposure as an etiological factor of Parkinson’s disease. Neurotoxicology. 2006;27(6):1110-1122.
- Chang X, Lu W, Dou T, et al. Paraquat inhibits cell viability via enhanced oxidative stress and apoptosis in human neural progenitor cells. Chemico-biological interactions. 2013;206(2):248-255.
- Frederiksen CM, Clausen J. The effects of oxidative stress in in vitro cultured astroglial cells. Alternatives to laboratory animals:ATLA. 1999;27(3):351-357.
- McCarthy S, Somayajulu M, Sikorska M, Borowy-Borowski H, Pandey S. Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-soluble Coenzyme Q10. Toxicology and applied pharmacology. 2004;201(1):21-31.
- Peng J, Mao XO, Stevenson FF, Hsu M, Andersen JK. The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway. The Journal of biological chemistry. 2004;279(31):32626-32632.
- Yang WL, Sun AY. Paraquat-induced cell death in PC12 cells. Neurochem Res. 1998;23(11):1387-1394.
- Chen P, Chen Z, Li A, et al. Catalytic metalloporphyrin protects against paraquat neurotoxicity in vivo. Biomedical and environmental sciences:BES. 2008;21(3):233-238.
- Cicchetti F, Lapointe N, Roberge-Tremblay A, et al. Systemic exposure to paraquat and maneb models early Parkinson’s disease in young adult rats. Neurobiology of disease. 2005;20(2):360-371.
- Shimizu K, Matsubara K, Ohtaki K, Shiono H. Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture. Neuroscience research. 2003;46(4):523-532.
- McCormack AL, Thiruchelvam M, Manning-Bog AB, et al. Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiology of disease. 2002;10(2):119-127.
- Purisai MG, McCormack AL, Cumine S, Li J, Isla MZ, Di Monte DA. Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. Neurobiology of disease. 2007;25(2):392-400.
- Shimizu K, Matsubara K, Ohtaki K, Fujimaru S, Saito O, Shiono H. Paraquat induces long-lasting dopamine overflow through the excitotoxic pathway in the striatum of freely moving rats. Brain research. 2003;976(2):243-252.
- Costello S, Cockburn M, Bronstein J, Zhang X, Ritz B. Parkinson’s disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. American journal of epidemiology. 2009;169(8):919-926.
- Lee PC, Bordelon Y, Bronstein J, Ritz B. Traumatic brain injury, paraquat exposure, and their relationship to Parkinson disease. Neurology. 2012;79(20):2061-2066.
- Liou HH, Tsai MC, Chen CJ, et al. Environmental risk factors and Parkinson’s disease: a case-control study in Taiwan. Neurology. 1997;48(6):1583-1588.
- Garcia-Garcia A, Zavala-Flores L, Rodriguez-Rocha H, Franco R. Thiol-redox signaling, dopaminergic cell death, and Parkinson’s disease. Antioxidants & redox signaling. 2012;17(12):1764-1784.
- Mazzetti AP, Fiorile MC, Primavera A, Lo Bello M. Glutathione transferases and neurodegenerative diseases. Neurochemistry international. 2015;82:10-18.
- Singh M, Khan AJ, Shah PP, Shukla R, Khanna VK, Parmar D. Polymorphism in environment responsive genes and association with Parkinson disease. Molecular and cellular biochemistry. 2008;312(1-2):131-138.
- Goldman SM, Kamel F, Ross GW, et al. Genetic modification of the association of paraquat and Parkinson’s disease. Movement disorders: official journal of the Movement Disorder Society. 2012;27(13):1652-1658.
- Betarbet R, Sherer TB, Greenamyre JT. Ubiquitin-proteasome system and Parkinson’s diseases. Experimental neurology. 2005;191 Suppl 1:S17-27.
- Chou AP, Maidment N, Klintenberg R, et al. Ziram causes dopaminergic cell damage by inhibiting E1 ligase of the proteasome. The Journal of biological chemistry. 2008;283(50):34696-34703.
- Rhodes SL, Fitzmaurice AG, Cockburn M, Bronstein JM, Sinsheimer JS, Ritz B. Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinsons disease. Environ Res. 2013;126:1-8.
- Burke WJ, Li SW, Chung HD, et al. Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases. Neurotoxicology. 2004;25(1-2):101-115.
- Burke WJ, Li SW, Williams EA, Nonneman R, Zahm DS. 3,4-Dihydroxyphenylacetaldehyde is the toxic dopamine metabolite in vivo: implications for Parkinson’s disease pathogenesis. Brain research. 2003;989(2):205-213.
- Marchitti SA, Deitrich RA, Vasiliou V. Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase. Pharmacological reviews. 2007;59(2):125-150.
- Panneton WM, Kumar VB, Gan Q, Burke WJ, Galvin JE. The neurotoxicity of DOPAL: behavioral and stereological evidence for its role in Parkinson disease pathogenesis. PloS one. 2010;5(12):e15251.
- Fitzmaurice AG, Rhodes SL, Lulla A, et al. Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(2):636-641.
- Fitzmaurice AG, Rhodes SL, Cockburn M, Ritz B, Bronstein JM. Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease. Neurology. 2014;82(5):419-426.
- Furlong M, Tanner CM, Goldman SM, et al. Protective glove use and hygiene habits modify the associations of specific pesticides with Parkinson’s disease. Environ Int. 2015;75:144-150.
- Kamel F, Goldman SM, Umbach DM, et al. Dietary fat intake, pesticide use, and Parkinson’s disease. Parkinsonism Relat Disord. 2014;20(1):82-87.
- Witkowska AM, Zujko ME. Dietary Fats and the Risk of Oxidative Stress in a Group of Apparently Healthy Women – a Short Report. Pol J Food Nutr Sci. 2013;63:117-121.
- Trepanier MO, Hopperton KE, Orr SK, Bazinet RP. N-3 polyunsaturated fatty acids in animal models with neuroinflammation: An update. European journal of pharmacology. 2016;785:187-206.
- Somayajulu-Nitu M, Sandhu JK, Cohen J, et al. Paraquat induces oxidative stress, neuronal loss in substantia nigra region and parkinsonism in adult rats: neuroprotection and amelioration of symptoms by water-soluble formulation of coenzyme Q10. BMC neuroscience. 2009;10:88.
- Muthukumaran K, Leahy S, Harrison K, et al. Orally delivered water soluble Coenzyme Q10 (Ubisol-Q10) blocks on-going neurodegeneration in rats exposed to paraquat: potential for therapeutic application in Parkinson’s disease. BMC neuroscience. 2014;15:21.
- Abdin AA, Hamouda HE. Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism. Neuropharmacology. 2008;55(8):1340-1346.
- Kang X, Chen J, Xu Z, Li H, Wang B. Protective effects of Ginkgo biloba extract on paraquat-induced apoptosis of PC12 cells. Toxicology in vitro : an international journal published in association with BIBRA. 2007;21(6):1003-1009.
- Zaitone SA, Abo-Elmatty DM, Shaalan AA. Acetyl-L-carnitine and alpha-lipoic acid affect rotenone-induced damage in nigral dopaminergic neurons of rat brain, implication for Parkinson’s disease therapy. Pharmacology, biochemistry, and behavior. 2012;100(3):347-360.
- St Laurent R, O’Brien LM, Ahmad ST. Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson’s disease. Neuroscience. 2013;246:382-390.
- Ning X, Yuan M, Guo Y, et al. Neuroprotective effects of (E)-3,4-diacetoxystyryl sulfone and sulfoxide derivatives in vitro models of Parkinson’s disease. Journal of enzyme inhibition and medicinal chemistry. 2016;31(3):464-469.
- Guo B, Xu D, Duan H, et al. Therapeutic effects of multifunctional tetramethylpyrazine nitrone on models of Parkinson’s disease in vitro and in vivo. Biological & pharmaceutical bulletin. 2014;37(2):274-285.
- Gomez del Rio MA, Sanchez-Reus MI, Iglesias I, et al. Neuroprotective Properties of Standardized Extracts of Hypericum perforatum on Rotenone Model of Parkinson’s Disease. CNS & neurological disorders drug targets. 2013;12(5):665-679.
- Gokul K, Muralidhara. Oral supplements of aqueous extract of tomato seeds alleviate motor abnormality, oxidative impairments and neurotoxicity induced by rotenone in mice: relevance to Parkinson’s disease. Neurochem Res. 2014;39(7):1382-1394.
- Abdelsalam RM, Safar MM. Neuroprotective effects of vildagliptin in rat rotenone Parkinson’s disease model: role of RAGE-NFkappaB and Nrf2-antioxidant signaling pathways. Journal of neurochemistry. 2015;133(5):700-707.
- “EUR-Lex”. Judgement of the Court of First Instance: European Directive 91/414/EEC case T-229/04. In: EUR-Lex, ed2007.
Article citation: Thakolwiboon S, Julayanont P, Ruthirago D. Pesticides and Parkinson’s disease: a potential hazard in agricultural communities. The Southwest Respiratory and Critical Care Chronicles 2017;5(20):60-67.
From: Department of Neurology, Texas Tech University Health Sciences Center, Lubbock TX
Reviewer: Todd Anderson PhD, Henrik Wilms MD, PhD
Conflicts of interest: none
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