Pesticide-Induced Diseases: Parkinson’s Disease
The second most common neurodegenerative disease, Parkinson’s disease (PD) occurs when nerve cells in the substantia nigra region of the brain are damaged or destroyed and can no longer produce dopamine, a nerve-signaling molecule that helps control muscle movement. People with PD have a variety of symptoms including loss of muscle control, trembling and lack of coordination. They may also experience anxiety, constipation, dementia, depression, urinary difficulties, and sleep disturbances. Over time, symptoms intensify. At least one million Americans have PD and about 50,000 new cases are diagnosed each year. With less than one percent of cases caused by genetics, researchers have been looking for the potential risk factors for developing Parkinson’s disease (PD). The epidemiological and toxicological evidence is repeatedly identifying exposure to pesticides, as well as specific gene-pesticide interactions, as significant adverse risk factors that contribute to PD. See Beyond Pesticides' Parkinson's Disease article from the Spring 2008 issue of Pesticides and You.
- Pesticides: an update of human exposure and toxicity.
Pesticides are a family of compounds which have brought many benefits to mankind in the agricultural, industrial, and health areas, but their toxicities in both humans and animals have always been a concern. Regardless of acute poisonings which are common for some classes of pesticides like organophosphoruses, the association of chronic and sub-lethal exposure to pesticides with a prevalence of some persistent diseases is going to be a phenomenon to which global attention has been attracted. In this review, incidence of various malignant, neurodegenerative, respiratory, reproductive, developmental, and metabolic diseases in relation to different routes of human exposure to pesticides such as occupational, environmental, residential, parental, maternal, and paternal has been systematically criticized in different categories of pesticide toxicities like carcinogenicity, neurotoxicity, pulmonotoxicity, reproductive toxicity, developmental toxicity, and metabolic toxicity. A huge body of evidence exists on the possible role of pesticide exposures in the elevated incidence of human diseases such as cancers, Alzheimer, Parkinson, amyotrophic lateral sclerosis, asthma, bronchitis, infertility, birth defects, attention deficit hyperactivity disorder, autism, diabetes, and obesity. Most of the disorders are induced by insecticides and herbicides most notably organophosphorus, organochlorines, phenoxyacetic acids, and triazine compounds.
[Mostafalou S and Abdollahi M.2017. Arch Toxicol. 91(2):549-599]
- Association of Parkinson's Disease and Its Subtypes with Agricultural Pesticide Exposures in Men: A Case-Control Study in France.
Pesticides have been associated with Parkinson's disease (PD), but there are few data on important exposure characteristics such as dose-effect relations. It is unknown whether associations depend on clinical PD subtypes. This study examined quantitative aspects of occupational pesticide exposure associated with PD and investigated whether associations were similar across PD subtypes. As part of a French population-based case-control study including men enrolled in the health insurance plan for farmers and agricultural workers, cases with clinically confirmed PD were identified through antiparkinsonian drug claims. Authors examined the relation between pesticides and PD subtypes (tremor dominant/non-tremor dominant).There appeared to be a stronger association with intensity than duration of pesticide exposure based on separate models and a synergistic interaction between duration and intensity. High intensity exposure to insecticides was positively associated with PD among those with low intensity exposure to fungicides and vice versa, suggesting independent effects. Pesticide exposure in farms specialized in vineyards was associated with PD (OR = 2.56; 95% CI: 1.31, 4.98). The association with intensity of pesticide use was stronger, although not significantly, for tremor dominant than for non-tremor dominant PD.This study helps to better characterize different aspects of pesticide exposure associated with PD, and shows a significant association of pesticides with tremor dominant PD in men, the most typical PD presentation.
[Moisan F1, Spinosi J, Delabre L, et al. 2015. Environ Health Perspec. DOI:10.1289/ehp.1307970]
- Blood α-synuclein in agricultural pesticide handlers in central Washington State.
Epidemiologic studies suggest that occupational exposure to pesticides might increase Parkinson disease risk. Some pesticides, such as the organophosphorus insecticide chlorpyrifos, appear to increase the expression of α-synuclein, a protein critically involved in Parkinson disease. Therefore, study assessed total blood cell α-synuclein in 90 specimens from 63 agricultural pesticide handlers, mainly Hispanic men from central Washington State, who participated in the state's cholinesterase monitoring program in 2007-2010. Additionally, authors assessed whether α-synuclein levels were associated with butyrylcholinesterase-chlorpyrifos adducts or cholinesterase inhibition measured in peripheral blood, or with self-reported pesticide exposure or paraoxonase (PON1) genotype. There was no evidence by any of those indicators that exposure to chlorpyrifos was associated with greater blood α-synuclein. Authors observed somewhat greater α-synuclein with the PON1-108T (lower paraoxonase enzyme) allele, and with ≥ 10 h of exposure to cholinesterase inhibiting insecticides in the preceding 30 days, but neither of these associations followed a clear dose-response pattern. Results suggest that selected genetic and environmental factors may affect α-synuclein blood levels. However, longitudinal studies with larger numbers of pesticide handlers will be required to confirm and elucidate the possible associations observed in this exploratory cross-sectional study.
[Searles Nielsen S, Checkoway H, Zhang J, et al. 2015. Environ Res.136:75-81.]
- Changes in neuronal dopamine homeostasis following 1-methyl-4-phenylpyridinium (MPP+) exposure.
To investigate the effects of acute MPP(+) exposure on neuronal DA homeostasis, study measured stimulation-dependent DA release and non-exocytotic DA efflux from mouse striatal slices and extracellular, intracellular, and cytosolic DA (DAcyt) levels in cultured mouse ventral midbrain neurons. In acute striatal slices, MPP(+) exposure gradually decreased stimulation-dependent DA release, followed by massive DA efflux that was dependent on MPP(+) concentration, temperature, and DA uptake transporter activity. Similarly, in mouse midbrain neuronal cultures, MPP(+) depleted vesicular DA storage accompanied by an elevation of cytosolic and extracellular DA levels. In neuronal cell bodies, increased DAcyt was not due to transmitter leakage from synaptic vesicles but rather to competitive MPP(+)-dependent inhibition of monoamine oxidase activity. Results demonstrate the utility of comprehensive analysis of DA metabolism using various electrochemical methods and reveal the complexity of the effects of MPP(+) on neuronal DA homeostasis and neurotoxicity.
[Choi SJ, Panhelainen A, Schmitz Y, et al. 2015. J Biol Chem.290(11):6799-809.]
- Environment-contact administration of rotenone: A new rodent model of Parkinson's disease.
Authors describe a novel environment-contact administration of rotenone model, in which male C57BL/6 mice (15 per group per time-point) were placed in one bedding-free, rotenone-applied cage for 2h every day over a period of 2-6 weeks, mimicking the common ways a person may be exposed to pesticides. results showed significant impairments in motor function (open field test, pole test, and rotarod test) from 4 weeks that were responsive to apomorphine. Accordingly, rotenone caused significant dopamine depletion from the striatum (HPLC analysis), nigrostriatal degeneration (quantitative tyrosine hydroxylase immunohistochemistry and western blot), and accumulation of α-synuclein in the substantia nigra and striatum (α-synuclein immunohistochemistry) in a time-dependent manner. In addition, rotenone-exposed mice also developed deficits in gastrointestinal and olfactory function (fecal pellet output and buried food pellet test) prior to the motor dysfunction. In summary, this novel rotenone model was able to reproduce many key aspects of PD progression. Results provide new insight into how environmental factors could trigger PD and provides a useful tool for studying PD pathogenesis and testing neuroprotective strategies.
[Liu Y, Sun JD, Song LK, et al. 2015. Behav Brain Res.294:149-161]
- Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases.
Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles (NFTs) characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies (LB), a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzyme (IDE)s such as neprilysin or insulin IDE. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action.
[Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. 2015. Front Cell Neurosci. 9:124]
- Groundwater pesticide levels and the association with Parkinson disease.
It is unclear whether exposure to environmentally relevant levels of pesticides in groundwater is associated with an increased risk of Parkinson disease (PD). The purpose of this study was to examine the relationship between PD and pesticide levels in groundwater. This cross-sectional study included 332 971 Medicare beneficiaries, including 4207 prevalent cases of PD from the 2007 Colorado Medicare Beneficiary Database. Residential pesticide levels were estimated from a spatial model based on 286 well water samples with atrazine, simazine, alachlor, and metolachlor measurements. A logistic regression model with known PD risk factors was used to assess the association between residential groundwater pesticide levels and prevalent PD. Results found that for every 1.0 µg/L of pesticide in groundwater, the risk of PD increases by 3% while adjusting for age, race/ethnicity, and gender suggesting that higher age-standardized PD prevalence ratios are associated with increasing levels of pesticides in groundwater.
[James KA, Hall DA. 2015. Int J Toxicol.34(3):266-73.]
- Occupational exposures and Parkinson's disease mortality in a prospective Dutch cohort.
Study investigated the association between six occupational exposures (ie, pesticides, solvents, metals, diesel motor emissions (DME), extremely low frequency magnetic fields (ELF-MF) and electric shocks) and Parkinson's disease (PD) mortality in a large population-based prospective cohort study. The Netherlands Cohort Study on diet and cancer enrolled 58,279 men and 62,573 women aged 55-69 years in 1986. Following a case-cohort design, a subcohort of 5,000 participants was randomly sampled from the complete cohort. Information on occupational history and potential confounders was collected at baseline. Job-exposure matrices were applied to assign occupational exposures. Associations with PD mortality were evaluated using Cox regression. Among men, elevated HRs were observed for exposure to pesticides and ever high exposed to ELF-MF. No association with exposure duration or trend in cumulative exposure was observed for any of the occupational exposures. Associations with PD mortality were observed for occupational exposure to pesticides and ELF-MF. However, the weight given to these findings is limited by the absence of a monotonic trend with either duration or cumulative exposure.
[Brouwer M, Koeman T, van den Brandt PA, et al. 2015. Occup Environ Med. 72(6):448-55.]
- Oxidative stress and Parkinson's disease.
Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The molecular mechanisms underlying the loss of these neurons still remain elusive. Oxidative stress is thought to play an important role in dopaminergic neurotoxicity. Complex I deficiencies of the respiratory chain account for the majority of unfavorable neuronal degeneration in PD. Environmental factors, such as neurotoxins, pesticides, insecticides, dopamine (DA) itself, and genetic mutations in PD-associated proteins contribute to mitochondrial dysfunction which precedes reactive oxygen species formation. In this mini review, authors give an update of the classical pathways involving these mechanisms of neurodegeneration, the biochemical and molecular events that mediate or regulate DA neuronal vulnerability, and the role of PD-related gene products in modulating cellular responses to oxidative stress in the course of the neurodegenerative process.
[Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. 2015. Front Neuroanat. 8(9):91]
- Rotenone decreases intracellular aldehyde dehydrogenase activity: implications for the pathogenesis of Parkinson's disease.
Repeated systemic administration of the mitochondrial complex I inhibitor rotenone produces a rodent model of Parkinson's disease (PD). Mechanisms of relatively selective rotenone-induced damage to nigrostriatal dopaminergic neurons remain incompletely understood. Authors tested whether rotenone interferes with vesicular uptake and intracellular ALDH activity. Rotenone dose dependently increased DOPAL, F-DOPAL, and 3,4-dihydroxyphenylethanol (DOPET) levels while decreasing dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels and the ratio of dopamine to the sum of its deaminated metabolites. In test tubes, rotenone did not affect conversion of DOPAL to DOPAC by ALDH when NAD(+) was supplied, whereas the direct-acting ALDH inhibitor benomyl markedly increased DOPAL and decreased DOPAC concentrations in the reaction mixtures. Study proposes that rotenone builds up intracellular DOPAL by decreasing ALDH activity and attenuating vesicular sequestration of cytoplasmic catecholamines. The results provide a novel mechanism for selective rotenone-induced toxicity in dopaminergic neurons.
[Goldstein DS, Sullivan P, et al. 2015. J Neurochem.133(1):14-25.]
- Rotenone exerts similar stimulatory effects on H2O2 production by isolated brain mitochondria from young-adult and old rats.
The aim of the present study was to evaluate whether brain mitochondria from old rats (24 months old) would be more susceptible to rotenone-induced inhibition of oxygen consumption and increased generation of H2O2 than mitochondria from young-adult rats (3-4 months old). Isolated brain mitochondria were incubated in the presence of different rotenone concentrations (5, 10, and 100nM), and oxygen consumption and H2O2 production were measured during respiratory states 3 (ADP-stimulated respiration) and 4 (resting respiration). Respiratory state 3 and citrate synthase activity were significantly lower in mitochondria from old rats. Mitochondria from young-adult and old rats showed similar sensitivity to rotenone-induced inhibition of oxygen consumption. Similarly, H2O2 production rates by both types of mitochondria were dose-dependently stimulated to the same extent by increasing concentrations of rotenone. We conclude that rotenone exerts similar effects on oxygen consumption and H2O2 production by isolated brain mitochondria from young-adult and old rats. Therefore, aging does not increase the mitochondrial H2O2 generation in response to complex I inhibition.
[Michelini LG, Figueira TR, et al. 2015. Neurosci Lett. 589:25-30.]
- The rotenone-induced rat model of Parkinson's disease: behavioral and electrophysiological findings.
The study aims at providing new and more specific evidence for the validity of the rotenone rat model of Parkinson's disease (PD) by examining whether neuronal activity in the subthalamic nucleus (STN) is altered. Male Sprague Dawley rats were treated with rotenone injections (2.5mg/kg bodyweight intraperitoneally) for 60 days. Behavioral analysis showed an impairment in the rotarod and hanging wire test in the rotenone group, accompanied by a decline in tyrosine hydroxylase immunoreactive neurons in the nigro-striatal region. Thereafter, single unit (SU) activities and local field potentials were recorded in the STN in urethane anesthetized rats. The SU analysis revealed a higher neuronal discharge rate, more bursts per minute and a higher oscillatory activity in the STN of rotenone treated rats. Spectral analysis showed an increase of relative beta power in the STN as well as in the motor cortex. Study also found found electrophysiological key features of PD pathology and pathophysiology in the STN of rotenone treated rats. The rotenone-induced rat model of PD deserves further attention since it covers more aspects than dopamine depletion and implies the reproducibility of PD specific features.
[von Wrangel C1, Schwabe K, et al. 2015. Behav Brain Res. 279:52-61.]
- A variety of pesticides trigger in vitro α-synuclein accumulation, a key event in Parkinson's disease.
Whereas epidemiological studies largely failed to identify pesticides specifically involved in Parkinson's disease (PD), it is of critical importance to set up in vitro toxicity studies of pesticides. Study measured changes of αS levels following pesticide exposures of human cell lines in vitro, using either ELISA detection of endogenous αS or flow cytometry after overexpression using recombinant adenoviruses. We showed that three pesticides (paraquat, rotenone and maneb), which have frequently been associated with PD, produced a dose-dependent increase in cellular αS levels, but also of αS released into the culture medium. Examining an additional series of 20 pesticides from different families and chemical structures, study found that beside some insecticides, including an organophosphate and three pyrethroids, a majority of the 12 studied fungicides were also producing an αS accumulation, three of them (thiophanate-methyl, fenhexamid and cyprodinil) having similar or more pronounced effects than paraquat. A variety of pesticides can disrupt αS homeostasis in vitro; our data illustrate an experimental strategy that could help in the identification of chemicals that could be specifically involved in PD etiology.
[Chorfa A, Lazizzera C, Bétemps D, et al. 2014. Arch Toxicol. doi:10.1007/s00204-014-1388-2]
- Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease.
The objective of this study was to determine whether environmental and genetic alterations of neuronal aldehyde dehydrogenase (ALDH) enzymes were associated with increased Parkinson disease (PD) risk in an epidemiologic study.A novel ex vivo assay was developed to identify pesticides that can inhibit neuronal ALDH activity. These were investigated for PD associations in a population-based case-control study, the Parkinson's Environment & Genes (PEG) Study. All of the metal-coordinating dithiocarbamates tested (e.g., maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin) inhibited ALDH activity, potentially via metabolic byproducts (e.g., carbon disulfide, thiophosgene). Fifteen screened pesticides did not inhibit ALDH. Exposures to ALDH-inhibiting pesticides were associated with 2- to 6-fold increases in PD risk; genetic variation in ALDH2 exacerbated PD risk in subjects exposed to ALDH-inhibiting pesticides. ALDH inhibition appears to be an important mechanism through which environmental toxicants contribute to PD pathogenesis, especially in genetically vulnerable individuals.
[Fitzmaurice AG, Rhodes SL, et al. 2014. Neurology.82(5):419-26.]
- Cypermethrin alters the status of oxidative stress in the peripheral blood: relevance to Parkinsonism.
While oxidative stress is implicated in Parkinson's disease (PD), prolonged exposure to moderate dose of cypermethrin induces Parkinsonism. The study aimed to investigate the status of oxidative stress indicators and antioxidant defence system of the polymorphonuclear leukocytes (PMNs), platelets and plasma to delineate the effect of Parkinsonian dose of cypermethrin in the peripheral blood of rats and its subsequent relevance to Parkinsonism. The striatal dopamine was measured to assess the degree of neurodegeneration/neuroprotection. Cypermethrin increased nitrite and LPO in the plasma, platelets and PMNs while it reduced the striatal dopamine content. Catalase and glutathione-S-transferase (GST) activity were increased in the PMNs and platelets; however, it was reduced in the plasma. Conversely, SOD and GR activities were reduced in the PMNs and platelets but increased in the plasma. Minocycline or syndopa reduced the cypermethrin-mediated changes towards normalcy. The results demonstrate that cypermethrin alters the status of oxidative stress indicators and impairs antioxidant defence system of the peripheral blood, which could be effectively salvaged by minocycline or syndopa. The results could be of value for predicting the nigrostriatal toxicity relevant to Parkinsonism.
[Tripathi P, Singh A, Agrawal S, et al. 2014. J Physiol Biochem. 70(4):915-24.]
- Developmental exposure to the organochlorine insecticide endosulfan damages the nigrostriatal dopamine system in male offspring.
Recent epidemiological evidence has found exposure to the organochlorine insecticide endosulfan to be a risk factor for Parkinson's disease (PD). However, the specific dopaminergic targets or vulnerable developmental time points related to endosulfan exposure have not been investigated.Study sought to investigate dopaminergic neurotoxicity following developmental exposure to endosulfan as well as following an additional challenge with MPTP. In vitro findings demonstrate a reduction in SK-N-SH cells and ventral mesencephalic primary cultures after endosulfan treatment. Using an in vivo developmental model, exposure to endosulfan during gestation and lactation caused a reduction in DAT and TH in the striatum of male offspring. These alterations were exacerbated following subsequent treatment with MPTP. In contrast, exposure of adult mice to endosulfan did not elicit dopaminergic damage and did not appear to increase the vulnerability of the dopamine neurons to MPTP. These findings suggest that development during gestation and lactation represents a critical window of susceptibility to endosulfan exposure and development of the nigrostriatal dopamine system. Furthermore, these exposures appear to sensitize the dopamine neurons to additional insults that may occur later in life.
[Wilson WW, Shapiro LP, et al. 2014. Neurotoxicology. 44:279-87]
- Dietary fat intake, pesticide use, and Parkinson's disease.
Dietary fat intake may modify Parkinson's disease (PD) risk directly or by altering the response to environmental neurotoxicants including pesticides.Researchers conducted a case-control study of PD nested in the Agricultural Health Study (AHS), a cohort of pesticide applicators and spouses. They evaluated diet and pesticide use before diagnosis in 89 PD cases, confirmed by movement disorder specialists, or a corresponding date in 336 frequency-matched controls.
In the AHS, associations of PD with the pesticides paraquat and rotenone were modified by fat intake. The OR for paraquat was 4.2 in individuals with PUFA intake below the median but 1.2 in those with higher intake. The OR for rotenone was 5.8 in those with saturated fat intake above the median but 1.5 in those with lower intake.PUFA intake was consistently associated with lower PD risk, and dietary fats modified the association of PD risk with pesticide exposure. If confirmed, these findings suggest that a diet high in PUFAs and low in saturated fats might reduce risk of PD.
[Kamel F, Goldman SM, Umbach DM, et al. 2014. Parkinsonism Relat Disord. 20(1):82-7.]
- Environmental toxins and Parkinson's disease.
Parkinson's disease (PD) is a chronic, progressive, disabling neurodegenerative disorder that begins in mid to late life and is characterized by motor impairment, autonomic dysfunction, and, in many, psychological and cognitive changes. Recent advances have helped delineate pathogenetic mechanisms, yet the cause of PD in most individuals is unknown. Although at least 15 genes and genetic loci have been associated with PD, identified genetic causes are responsible for only a few percent of cases. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, solvents, metals, and other pollutants, and many of these compounds recapitulate PD pathology in animal models. This review summarizes the environmental toxicology of PD, highlighting the consistency of observations across cellular, animal, and human studies of PD pathogenesis
[Goldman SM. 2014. Annu Rev Pharmacol Toxicol.54:141-64]
- In vitro dopaminergic neurotoxicity of pesticides: a link with neurodegeneration?
From epidemiological studies, it is known that there is a link between exposure to certain chemical classes of these so-called pesticides and the prevalence of neurodegenerative disorders such as Parkinson's disease in humans. However, which particular compound(s) account for this link or what underlying mechanisms are involved is still largely unresolved. The degenerative process in Parkinson's disease is largely limited to the dopaminergic neurons in the basal ganglia. Cellular mechanisms that are implicated in parkinsonian neurodegeneration include mitochondrial dysfunction, oxidative stress, disturbance of intracellular calcium homeostasis and endoplasmic reticulum (ER) stress. A major characteristic that distinguishes the dopaminergic neurons in the basal ganglia from other dopaminergic neurons is a particular reliance on intracellular calcium for spontaneous activity. Considering the energy consuming nature of maintenance of the intracellular calcium homeostasis and its involvement in life and death of a neuron, this may explain the specific vulnerability of this neuronal population. Despite a large variation in primary mechanism of action it has been demonstrated that pesticides from different classes disturb intracellular calcium homeostasis, thus interfering with intracellular calcium signalling. This relates to altered dopaminergic signalling, disturbed protein homeostasis and increased oxidative stress. Therefore, effects of (mixtures of) pesticides on the intracellular calcium homeostasis may play a role in the development of Parkinson's disease in humans. Although human exposure to pesticides via e.g. food often occurs in complex mixtures, (human) risk assessment is largely based on the assessment of single compounds. The discovery of common modes of action across different classes of pesticides therefore underpins the urgency of development of new models and approaches in risk assessment.
[Heusinkveld HJ, van den Berg M, Westerink RH. 2014. Veterinary Quarterly. 34(3):120-31.]
- Microstructural changes in the substantia nigra of asymptomatic agricultural workers.
Epidemiological studies suggest that pesticide exposure is linked to higher Parkinson's disease (PD) risk, but there are no studies demonstrating substantia nigra (SN) changes with chronic pesticide exposure in human subjects. Thus, high resolution T2-weighted magnetic resonance imaging (MRI) and diffusion tensor (DTI) images were obtained from 12 agricultural workers with chronic pesticide exposure, 12 controls, and 12 PD subjects. Neither controls nor pesticide-exposed subjects, had any parkinsonian symptoms. Exposure history to pesticides was assessed by a structured questionnaire. DTI measures in the SN, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were obtained for all subjects and compared among groups. Compared to controls, PD patients showed the expected significant changes in all DTI measurements in the SN. The pesticide-exposed subjects, compared to controls, had significantly lower FA values, but no significant differences in RD, MD, or AD measures. The study is the first to demonstrate microstructural changes in the SN of human subjects with chronic pesticide exposure. The changes detected by MRI may mark "one of the hits" leading to PD, and underlie the increased risk of PD in pesticide users found in epidemiological studies. Further human studies assisted by these imaging markers may be useful in understanding the etiology of PD.
[Du G, Lewis MM, Sterling NW, et al. 2014. Neurotoxicol Teratol. 41:60-4.]
- Occupational exposure to pesticides and endotoxin and Parkinson disease in the Netherlands.
Authors studied the associations of Parkinson disease (PD) with occupational exposure to pesticides, specifically to the functional subclasses insecticides, herbicides and fungicides, and to airborne endotoxin. We used data from a hospital-based case-control study, including 444 patients with PD and 876 age and sex matched controls. Exposures to pesticides from application and re-entry work were estimated with the ALOHA+job-exposure matrix and with an exposure algorithm based on self-reported information on pesticide use.The results showed almost no significant associations. However, ORs were elevated in the higher exposure categories for pesticides in general, insecticides, herbicides and fungicides, and below unity for endotoxin exposure. The analyses on specific active ingredients showed a significant association of PD risk with the fungicide benomyl.This study did not provide evidence for a relation between pesticide exposure and PD. However, the consistently elevated ORs in the higher exposure categories suggest that a positive association may exist. The possible association with the active ingredient benomyl requires follow-up in other studies. This study did not provide support for a possible association between endotoxin exposure and PD.
[van der Mark M, Vermeulen R, Nijssen PC. 2014. Occup Environ Med. 71(11):757-64.]
- Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases-A mechanistic approach.
The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood.For the main neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss.This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes by highlighting the most relevant epidemiological and experimental data.
[Baltazar MT, Dinis-Oliveira RJ, de Lourdes Bastos M, et al. 2014. Toxicol Lett.S0378-4274(14)00059-9.]
- Rotenone and paraquat perturb dopamine metabolism: A computational analysis of pesticide toxicity.
Pesticides, such as rotenone and paraquat, are suspected in the pathogenesis of Parkinson's disease (PD), whose hallmark is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Thus, compounds expected to play a role in the pathogenesis of PD will likely impact the function of dopaminergic neurons. To explore the relationship between pesticide exposure and dopaminergic toxicity, the authors developed a custom-tailored mathematical model of dopamine metabolism and utilized it to infer potential mechanisms underlying the toxicity of rotenone and paraquat, asking how these pesticides perturb specific processes. They performed two types of analyses, which are conceptually different and complement each other. The first analysis, a purely algebraic reverse engineering approach, analytically and deterministically computes the altered profile of enzyme activities that characterize the effects of a pesticide. The second method consists of large-scale Monte Carlo simulations that statistically reveal possible mechanisms of pesticides. The results from the reverse engineering approach show that rotenone and paraquat exposures lead to distinctly different flux perturbations. Rotenone seems to affect all fluxes associated with dopamine compartmentalization, whereas paraquat exposure perturbs fluxes associated with dopamine and its breakdown metabolites. The statistical results of the Monte-Carlo analysis suggest several specific mechanisms. The findings are interesting, because no a priori assumptions are made regarding specific pesticide actions, and all parameters characterizing the processes in the dopamine model are treated in an unbiased manner. The results show how approaches from computational systems biology can help identify mechanisms underlying the toxicity of pesticide exposure.
[Qi Z, Miller GW, Voit EO. 2014. Toxicology.315:92-101]
- The disease intersection of susceptibility and exposure: chemical exposures and neurodegenerative disease risk.
Alzheimer's disease, Parkinson's disease, and motor neuron disease, the most common of the late-life neurodegenerative disorders, are in most cases thought to have complex etiologies. Common features among these disorders include insidious onset, pathological findings of protein aggregates and selected neuronal degeneration, and resulting characteristic clinical syndromes. The number of elders in the US, including aging veterans, is increasing. Investigation of causes and preventive interventions for neurodegenerative disorders is increasingly relevant. Recent epidemiological and laboratory studies suggest that exposures years or decades before diagnosis can trigger the processes that ultimately result in a neurodegenerative disease. If this is correct, preventive measures may be needed in midlife or earlier. This article focuses on putative risk factors relevant to military service.
[Tanner CM, Goldman SM, Ross GW, Grate SJ. 2014. Alzheimers Dement.10(3 Suppl):S213-25]
- Younger age at onset of sporadic Parkinson's disease among subjects occupationally exposed to metals and pesticides.
An earlier age at onset of Parkinson's disease (PD) has been reported to be associated with occupational exposures to manganese and hydrocarbon solvents suggesting that exposure to neurotoxic chemicals may hasten the progression of idiopathic PD. In this study the role of occupational exposure to metals and pesticides in the progression of idiopathic PD was assessed by looking at age at disease onset. The effects of heritable genetic risk factors, which may also influence age at onset, was minimized by including only sporadic cases of PD with no family history of the disease (n=58). Independent samples Student t-test revealed that subjects with occupational exposure to metals and/or pesticides were significantly younger than unexposed controls. These subjects were then divided into three groups to ascertain if duration of exposure further influenced age at onset of PD. One-way ANOVA revealed that subjects in the high exposure group were significantly younger (mean age: 50.33 years) than unexposed subjects (mean age: 60.45 years). Subjects were also stratified by exposure type (metals vs. pesticides). These results suggest that chronic exposure to metals and pesticides is associated with a younger age at onset of PD among patients with no family history of the disease and that duration of exposure is a factor in the magnitude of this effect.
[Ratner MH1, Farb DH, et al. 2014. Interdiscip Toxicol. 7(3):123-33.]
- Chronic exposure to rotenone, a dopaminergic toxin, results in peripheral neuropathy associated with dopaminergic damage.
Rotenone, a widely used pesticide, causes a syndrome in rats that replicates, both pathologically and behaviorally, the symptoms of Parkinson's disease (PD). In the present study, authors sought to determine if a chronic exposure to rotenone, resulting in dopaminergic loss, could also lead to peripheral neuronal damage related to motor dysfunction. Adult male Sprague-Dawley rats were treated with rotenone. The motor nerve conduction velocity (MCV) was assessed using action potentials detected from the tail muscle through surface receiver electrodes installed around the distal portion of the tail. Rats exposed to rotenone often developed hind limb paresis with a significant decrease in MCV as detected in tail nerves. Time-dependent rotenone-induced striatal depletion of DA (60% after 7 days and 80% after 27 days) was observed. Furthermore, Neurofilament-neurofilament B, Flouro-Jade C and myelin basic protein analyses suggested a time-dependent rotenone-induced neurodegeneration in sciatic nerves. These data, for the first time, indicate an association between dopaminergic damage and peripheral motor nerve degeneration in an animal model of dopaminergic toxicity. Peripheral motor nerve dysfunction in rats following a chronic exposure to rotenone may serve not only as a relevant experimental model of motor neuropathy but also as a peripheral marker of dopaminergic neuronal damage to the central nervous system.
[Binienda ZK, Sarkar S, et al. 2013. Neurosci Lett. 541:233-7]
- Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: Relevance to sporadic Parkinson's disease.
Despite several years of research, the aetiology of Parkinson's disease (PD) is quite far from being solved. Considering the nonrestricted commercial availability and common use of several pesticides, such as paraquat and maneb, in agriculture of less developed countries, the aim of this study was to investigate the involvement of nociceptin/orphanin-NOP and prodynorphin-KOP systems in a chronic paraquat and maneb animal model of Parkinson's disease. Results showed that after paraquat/maneb treatment, a significant reduction in tyrosine hydroxylase (TH) levels, the rate-limiting enzyme for dopamine synthesis, was observed. Also, the association of paraquat and maneb induced an increase in nociceptin/orphanin and a decrease of prodynorphin gene expression levels in the substantia nigra with a down-regulation of NOP and KOP receptors after both treatments in the substantia nigra and caudate putamen. These data further confirm that paraquat and maneb toxicity can modulate gene expression of the nociceptin/orphanin-NOP receptor and prodynorphin-KOP receptor systems in the substantia nigra and caudate putamen, offering further support to the hypothesis that chronic exposure to these agrochemicals might be implicated in the mechanisms underlying sporadic Parkinson's disease.
[Bastías-Candia S, Di Benedetto M, D'Addario C, Candeletti S, Romualdi P. 2013. Environ Toxicol. doi: 10.1002/tox.21943]
- Exposure to pesticides or solvents and risk of Parkinson disease.
Study investigated the risk of Parkinson disease (PD) associated with exposure to pesticides and solvents using meta-analyses of data from cohort and case-control studies. A total of 104 studies/3,087 citations fulfilled inclusion criteria for meta-analysis. In prospective studies, study quality was not a source of heterogeneity. PD was associated with farming and the association with pesticides was highly significant in the studies in which PD diagnosis was self-reported. In case-control studies, study quality appeared to be a source of heterogeneity in risk estimates for some exposures. Higher study quality was frequently associated with a reduction in heterogeneity. In high-quality case-control studies, PD risk was increased by exposure to any-type pesticides, herbicides, and solvents. Exposure to paraquat or maneb/mancozeb was associated with about a 2-fold increase in risk. In high-quality case-control studies including an appreciable number of cases (>200), heterogeneity remained significantly high (>40%) only for insecticides, organochlorines, organophosphates, and farming; also, the risk associated with rural living was found to be significant. The literature supports the hypothesis that exposure to pesticides or solvents is a risk factor for PD. Further prospective and high-quality case-control studies are required to substantiate a cause-effect relationship. Future studies should also focus on specific chemical agents.
[Pezzoli G, Cereda E. 2013. Neurology. 80(22):2035-41]
- Household organophosphorus pesticide use and Parkinson's disease.
Parkinson's disease (PD) has been linked to pesticide exposures but little is known about the contributions of chronic exposures to household pesticides. The study investigates whether long-term use of household pesticides, especially those containing organophosphates (OPs), increases the odds of PD. In a population-based case-control study, authors assessed frequency of household pesticide use for 357 cases and 807 controls, relying on the California Department of Pesticide Regulation product label database to identify ingredients in reported household pesticide products and the Pesticide Action Network pesticide database of chemical ingredients. Frequent use of any household pesticide increased the odds of PD by 47%; frequent use of products containing OPs increased the odds of PD more strongly by 71% and frequent organothiophosphate use almost doubled the odds of PD. Sensitivity analyses showed that estimated effects were independent of other pesticide exposures (ambient and occupational) and the largest odds ratios were estimated for frequent OP users who were carriers of the 192QQ paraoxonase genetic variant related to slower detoxification of OPs. Study provides evidence that household use of OP pesticides is associated with an increased risk of developing PD.
[Narayan S, Liew Z, Paul K, et al. 2013. Int J Epidemiol. 42(5):1476-85.]
- Neurotoxicity of pesticides: its relationship with neurodegenerative diseases
Several epidemiological studies suggest that pesticides could lead to neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Among pesticides, insecticides appear more neurotoxic than others but the neurotoxic mechanisms leading to adverse health effects remain unclear. The currently used pesticides such as rotenone and paraquat could disrupt mitochondrial bioenergetic function, reactive oxygen metabolism, redox function and promote α-synuclein aggregation. In addition, recent studies demonstrate that genetic susceptibility to Parkinson's disease could monitor pesticide susceptibility, as demonstrated for polymorphisms in pesticide metabolizing enzymes that are involved in organophosphorus sensitivity.
[Thany SH, Reynier P, Lenaers G. 2013. Med Sci (Paris). 29(3):273-8]
- Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease.
Genetic and environmental factors affect the pathogenesis of Parkinson's disease (PD). Genetic variants of the enzyme glutathione S-transferases (GST) may be related to the disease. This study aimed to evaluate the influence of genetic variants of GST (GSTT1/GSTM1) and their association with the exposure to environmental toxins in PD patients. 254 patients with PD and 169 controls were studied. The GSTM1/GSTT1 variants were analyzed by polymerase chain reaction. The present and absence for GSTT1 and GSTM1 were similar in patients and controls. The null for GSTT1 and GSTM1 (0/0) and exposure to pesticides prevailed in patients (18%) compared to controls. This study suggests the association between PD and previous exposure to pesticides, whose effect may be enhanced in combination with null for GSTT1/GSTM1.
[Pinhel MA, Sado CL, Longo Gdos S, Gregório ML, et al. 2013. Arq Neuropsiquiatr. 71(8):527-32]
- Occupational pesticide exposure and screening tests for neurodegenerative disease among an elderly population in Costa Rica.
Pesticides have been associated with Parkinson's disease (PD) in many studies, and with Alzheimer's disease (AD) in a few. Authors conducted screening tests for neurologic disease and occupational pesticide use in a population-based sample of 400 elderly subjects at two government-run clinics in Costa Rica. Initial screens were given: mini-mental states exam (MMSE) and a modified version of a 10-item united Parkinson's disease rating motor subscale (UPDRS). Past occupational pesticide exposure was reported by 18% of subjects. Exposed subjects performed worse on the MMSE than the non-exposed. The exposed had significantly elevated risks of abnormal scores on two UPDRS items, tremor-at-rest, and finger-tapping. Thirty-three (23%) of those examined by the neurologist were diagnosed with possible/probable PD, 3-4 times the expected based on international data. Among subjects who took the UPDRS, the exposed had an increased risk of PD. No excess risk was found for a diagnosis of AD or mild cognitive impairment. Authors conclude that elderly subjects with past occupational pesticide exposure performed significantly worse on screening tests for dementia and PD, and had an increased risk of an eventual PD diagnosis. Screening may be particularly appropriate among elderly subjects with past pesticide exposure.
[Steenland K, Wesseling C, Román N, Quirós I, Juncos JL. 2013. Environ Res.120:96-101]
- Parkinson's disease and pesticide exposure--a new assessment.
Some commonly used pesticides possess neurotoxicity, and exposure to such compounds may trigger mechanisms similar to those in the development of idiopathic Parkinson's disease (PD). Authors conducted a systematic review of epidemiological studies, aiming at a critical evaluation of the association between the development of PD and pesticide exposure. Reported effect sizes (ES) in the relevant studies were pooled into the meta-analysis to derive summary ES. The summary ES suggested a significantly positive association between PD and overall pesticide use (non-occupational and/or occupational pesticide use), as well as between PD and occupational pesticide exposure. Both occupational herbicide and occupational insecticide exposure showed a significant association with PD. The results of the meta-analysis reported in this study suggest the existence of a statistically positive association between PD and pesticide exposure. The majority of the studies that were pooled in the meta-analysis were case-control design with very few cohort studies and most with poor exposure characterization thus, any further case-control studies using similar methodologies are unlikely to have a significant impact or understanding on the currently-reported association between pesticide exposure and the development of idiopathic PD. Therefore, authors believe that if further epidemiological studies are going to be conducted in the area, they should be prospective cohort studies that will include accurate exposure assessment.
[Allen MT, Levy LS. 2013. Crit Rev Toxicol. 43(6):515-34]
- Parkinson's disease: evidence for environmental risk factors.
Parkinson's disease (PD) has no known cause. Although recent research has focused particularly on genetic causes of PD, environmental causes also play a role in developing the disease. This article reviews environmental factors that may increase the risk of PD, as well as the evidence behind those factors. Enough evidence exists to suggest that age has a causal relationship to PD. Significant evidence exists that gender, tobacco use, and caffeine consumption are also associated with the development of PD. Other environmental factors (pesticide exposure, occupation, blood urate levels, NSAID use, brain injury, and exercise) have limited or conflicting evidence of a relationship to PD. Future research must not neglect the impact of these environmental factors on the development of PD, especially with respect to potential gene-environment interactions.
[Kieburtz K, Wunderle KB. 2013. Mov Disord. 28(1):8-13]
- Pesticide-induced gene mutations and Parkinson disease risk: a meta-analysis.
Increasing scientific evidence suggests that pesticide-induced gene mutations may contribute to increasing susceptibility to Parkinson disease (PD), but many existing studies have yielded inconclusive results. This meta-analysis aims at assessing the exact roles of pesticide-induced gene mutations in the development of PD. An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1st, 2013. Ten case-control studies were included with a total of 1248 PD patients and 1831 healthy controls. Our meta-analysis revealed that PD patients with pesticide exposure had higher gene mutation rates than those of healthy controls. Subgroup analysis by gene type indicated that the mutation rates in the GSTP1, SLC6A3, and MDR1 genes of PD patients with pesticide exposure were higher than those of healthy controls. The current meta-analysis indicates that pesticide-induced gene mutations may contribute to increasing susceptibility to PD, especially in the GSTP1, SLC6A3, and MDR1 genes.
[Liu X, Ma T, Qu B, et al. 2013. Genet Test Mol Biomarkers. 17(11):826-32]
- Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinson׳s disease.
Cytoplasmic inclusions known as Lewy bodies, a hallmark of Parkinson's disease (PD) pathology, may protect against cytotoxic proteins. Since the ubiquitin-proteasome system (UPS) degrades cytotoxic proteins, dysfunction in the UPS may contribute to PD etiology. The goal in this study was to screen pesticides for proteasome inhibition and investigate (i) whether ambient exposures to pesticides that inhibit the UPS increase PD risk and (ii) whether genetic variation in candidate genes of the UPS pathway modify those increased risks. Study assessed 26S UPS activity in SK-N-MC(u) cells by fluorescence. We recruited idiopathic PD cases and population-based controls from three counties in California with considerable commercial agriculture. Study determined ambient pesticide exposure by our validated GIS-based model utilizing residential and workplace address histories. Study limited effect measure modification assessment to Caucasians. Eleven of 28 pesticides screened inhibited 26S UPS activity at 10 µM. Benomyl, cyanazine, dieldrin, endosulfan, metam, propargite, triflumizole, and ziram were associated with increased PD risk. Authors estimated an odds ratio of 2.14 for subjects with ambient exposure to any UPS-inhibiting pesticide at both residential and workplace addresses; this association was modified by genetic variation in the s-phase kinase-associated protein 1 gene. Results provide evidence that UPS-inhibiting pesticides play a role in the etiology of PD and suggest that genetic variation in candidate genes involved in the UPS pathway might exacerbate the toxic effects of pesticide exposures.
[Rhodes SL, Fitzmaurice AG, Cockburn M, et al. 2013. Environ Res. 126:1-8]
- The interplay between environmental and genetic factors in Parkinson's disease susceptibility: the evidence for pesticides.
Several genetic and environmental factors have been implicated in the pathogenesis of PD. Single risk factors are likely to exert relatively minor effects, whereas their interaction may prove to be sufficient to cause PD. In the present review authors summarize current knowledge from human genetic association studies regarding the interaction between gene polymorphisms and pesticide exposure in the risk of PD. A number of genetic association studies have investigated joint effects between genes and pesticides on PD risk. They have provided some evidence that genetic susceptibility either in metabolism, elimination and transport of pesticides or in the extent of mitochondrial dysfunction, oxidative stress and neuronal loss may predispose individuals to PD if they have been exposed to pesticides. These findings confirm the importance of considering pesticide-gene interactions in future studies in order to gain a better understanding of the pathogenic mechanisms of PD.
[Dardiotis E, Xiromerisiou G, et al. 2013. Toxicology. 307:17-23]
- The role of pesticide exposure in the genesis of Parkinson's disease: epidemiological studies and experimental data.
The aim of this study is to address the uncertainties provided by epidemiological studies on the role of pesticide exposures in the development of Parkinson's disease (PD), with the help of experimental toxicological data. Animal models that reproduce all clinical and pathological features of human PD are not available. In addition, the fundamental questions relate to the extrapolation from experimental to actual human exposure, taking also into account the role of genetic factors. Available measurements or estimates of human exposure levels that are significantly lower than those used in animal experimentation provide little support for a causal correlation between pesticide exposure and development of PD in humans. A possible role of acute poisonings or episodes of excessive exposure, and/or of combined exposures especially at early age and/or in the presence of certain genetic variants can be hypothesised. Follow up of survivors of acute poisonings by pesticides would provide information useful in this respect. According to the available data, from a public health point of view, prevention of "high" exposures, even asymptomatic ones, especially in utero and during early age is a priority.
[Moretto A, Colosio C. et al. 2013. Toxicology. 307:24-34]
- Genetic modification of the association of paraquat and Parkinson's disease
Authors investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione S-transferase M1 (GSTM1) or T1 (GSTT1). Eighty-seven PD subjects and 343 matched controls were recruited from the Agricultural Health Study, a study of licensed pesticide applicators and spouses in Iowa and North Carolina. Two hundred and twenty-three (52%) subjects had GSTM1*0, 95 (22%) had GSTT1*0, and 73 (17%; all men) used paraquat. GSTT1 genotype significantly modified the association between paraquat and PD. In men with functional GSTT1, the odds ratio (OR) for association of PD with paraquat use was 1.5; in men with GSTT1*0, the OR was 11.1. Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. GSTT1*0 is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat.
[Goldman, S, Kamel, F, Webster Ross, G, et al. 2012. Movement Disorders. 27(13):1652-1658]
- Is Pesticide Use Related to Parkinson Disease? Some Clues to Heterogeneity in Study Results
This study is updates the literature published on PD and exposure to pesticides by performing a systematic review and meta-analysis.Summary estimates for subclasses of pesticides indicated a positive association with herbicides and insecticides, but not with fungicides. This review affirms the evidence that exposure to herbicides and insecticides increase the risk of PD. Future studies should focus on more objective and improved methods of pesticide exposure assessment.
[van der Mark, M, Brouwer, M et al. 2012. Environ Health Perspect. 120(3):340-347]
- Occupational exposure to pesticides and Parkinson's disease: A systematic review and meta-analysis of cohort studies
The aim of this study was to systematically review available cohort studies and estimate quantitatively the association between occupational exposure to pesticides and Parkinson's disease (PD). Relative risk (RR) estimates were extracted from 12 studies published between 1985 and 2011. Meta-analyses were performed on the whole set of data and separate analyses were conducted after stratification for gender, exposure characterisation, PD cases identification, geographic location, reported risk estimator and cohort study design.A statistically significant increased risk of PD was observed when all studies were combined. A significant increased risk was also seen for banana, sugarcane and pineapple plantation workers. Study concludes that there is some support for the hypothesis that occupational exposure to pesticides increases the risk of PD.
[Van Maele-Fabry, G, Hoet, P, Vilain, F and Lison, D. 2012. Envrionment International. 46:30-43]
- Traumatic brain injury, paraquat exposure, and their relationship to Parkinson disease
Traumatic brain injury (TBI) increased risk of Parkinson disease (PD) in many but not all epidemiologic studies, giving rise to speculations about modifying factors. The objective of this study was to investigate PD risk due to both TBI and paraquat exposure in humans.From 2001 to 2011, study enrolled 357 incident idiopathic PD cases and 754 population controls in central California. Study participants were asked to report all head injuries with loss of consciousness for >5 minutes. Paraquat exposure was assessed via a validated geographic information system (GIS) based on records of pesticide applications to agricultural crops in California since 1974. Study observed a 2-fold increase in risk of PD for subjects who reported a TBI and a weaker association for paraquat exposures. However, the risk of developing PD was 3-fold higher in study participants with a TBI and exposure to paraquat than those exposed to neither risk factor. While TBI and paraquat exposure each increase the risk of PD moderately, exposure to both factors almost tripled PD risk. These environmental factors seem to act together to increase PD risk in a more than additive manner.
[Lee PC, Bordelon Y, Bronstein J, Ritz B. 2012. Neurology. 79(20):2061-6]
- Parkinson’s disease risk from ambient exposure to pesticides
A study has found that people whose workplaces were close to fields sprayed with chemicals — not just those who live nearby — are at higher risk of developing Parkinson’s disease (PD). From 2001 to 2007, researchers enrolled 362 incident PD cases and 341 controls living in the Central Valley of California and estimated ambient exposures to the pesticides ziram, maneb, and paraquat at work places and residences from 1974 to 1999. Risk estimates for ambient workplace exposure were greater than for exposures at residences and were especially high for younger onset PD patients and when exposed in both locations. Study is the first to implicate ziram in PD etiology. Combined ambient exposure to ziram and paraquat as well as combined ambient exposure to maneb and paraquat at both workplaces and residences increased PD risk substantially. Those exposed to ziram, maneb, and paraquat together experienced the greatest increase in PD risk. Results suggest that pesticides affecting different mechanisms that contribute to dopaminergic neuron death may act together to increase the risk of PD considerably. Daily News
[Wang A, et al. 2011. Eur J Epidemiol. DOI: 10.1007/s10654-011-9574-5]
- Rotenone, Paraquat and Parkinson's Disease
Study investigated whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. Reserachers assessed lifetime use of pesticides selected by mechanism in a casecontrol study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists.n 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial Complex I including rotenone and with use of a group of pesticides that cause oxidative stress including paraquat.PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally: those which impair mitochondrial function and those which increase oxidative stress, supporting a role for these mechanisms in PD pathophysiology.
[Tanner, CM. et al. 2011. Environ Health Perspect.doi:10.1289/ehp.1002839]
- Interaction Between ABCB1 and Professional Exposure to Organochlorine Insecticides in Parkinson Disease
Study examined the association between Parkinson disease (PD) and 2 polymorphisms in ABCB1 among subjects enrolled in the French health system for agricultural workers, as well as the interaction between ABCB1 and organochlorine insecticides. Among 101 male cases and 234 matched controls, the odds ratio for organochlorines was 3.5 times higher among homozygous carriers of variant G2677(A,T) alleles than noncarriers. Among cases only, study found an association between carrying 2 variant G2677(A,T) alleles and organochlorines as well as with the number of cumulative lifetime number of hours of exposure. Findings suggest that the ABCB1 gene and exposure to organochlorine insecticides interact to increase PD risk: in subjects professionally exposed to organochlorines, polymorphisms associated with a decreased ability of ABCB1 to clear xenobiotics from the brain increased the risk of PD. These findings support the hypothesis of gene x pesticides interactions in PD.
[Dutheil. F. et al. 2010. Arch Neurol;67(6):739-745]
- Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease
Study found that participants with two copies of a common gene variant showed an increased risk of Parkinson's disease (PD) when exposed to pesticides used in agriculture. In the study group, 14 percent of the pesticide-exposed subjects and 10 percent of the control subjects had the genotype with two copies of the methionine PON1 variant - the MM PON1-55 genotype. Individuals with the variant genotype have an increased risk of Parkinson's disease with exposure to specific insecticides. Participants with the MM PON1-55 genotype and exposed to diazinon or chlorpyrifos showed a twofold increased risk of Parkinson's disease (PD) compared to exposed subjects with wildtype genotype or only one variant copy or non-pesticide exposed subjects. The authors found no increased risk of PD with parathion exposure regardless of genotype.
[Manthripragada AD, et al. 2010. Epidemiology 21(1):87-94]
- Dopamine Transporter Genetic Variants and Pesticides in Parkinson’s Disease
324 incident PD patients and 334 population controls from this rural California case–control study were genotyped; rs2652510, rs2550956 (for the DAT 5' clades), and 3' variable number of tandem repeats (VNTR). Using geographic information system methods, authors determined residential exposure to agricultural maneb and paraquat applications. Occupational pesticide use data was also collected. PD risk was increased separately in DAT A clade diplotype carriers and 3' VNTR 9/9 carriers, and data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold, and in carriers of two or more alleles more than 4-fold. Similar results for occupational pesticide measures were obtained.
[Ritz BR, et al. 2009. Environ Health Perspect 117(6)]
- Occupation and Risk of Parkinsonism:
This multicenter case-control study compared lifelong occupational and job task histories to determine associations with parkinsonism and certain clinical subtypes (postural instability and gait difficulty and age at diagnosis). Risk of parkinsonism increased with pesticide use (odds ratio, 1.90; 95% confidence interval, 1.12-3.21), use of any of 8 pesticides mechanistically associated with experimental parkinsonism (2.20; 1.02-4.75), and use of 2,4-dichlorophenoxyacetic acid (2.59; 1.03-6.48).
[Tanner, C.M. 2009. Arch Neurol ;66(9):1106-1113]
- Parkinson's Disease and Residential Exposure to Maneb and Paraquat From Agricultural Applications in the Central Valley of California
In 1998–2007, the authors enrolled 368 incident PD cases and 341 population controls from the Central Valley of California in a case-control study. They generated estimates for maneb and paraquat exposures incurred between 1974 and 1999. Exposure to both pesticides within 500 m of the home increased PD risk by 75% (95% confidence interval (CI): 1.13, 2.73). Persons aged =60 years at the time of diagnosis were at much higher risk when exposed to either maneb or paraquat alone (odds ratio = 2.27, 95% CI: 0.91, 5.70) or to both pesticides in combination (odds ratio = 4.17, 95% CI: 1.15, 15.16) in 1974–1989. This study provides evidence that exposure to a combination of maneb and paraquat increases PD risk, particularly in younger subjects and/or when exposure occurs at younger ages.
[Costello, S. et al. 2009. American Journal of Epidemiology, doi:10.1093/aje/kwp006]
- Professional exposure to pesticides and Parkinson disease
Study found a positive association between PD and overall professional pesticide use (odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.1-3.1), with a dose-effect relation for the number of years of use (p = 0.01). In men, insecticides were associated with PD (OR = 2.2, 95% CI = 1.1-4.3), in particular organochlorine insecticides (OR = 2.4, 95% CI = 1.2-5.0). These associations were stronger in men with older onset PD than in those with younger onset PD, and were characterized by a dose-effect relation in the former group. Results support an association between PD and professional pesticide exposure, and show that some pesticides (ie, organochlorine insecticides) may be more particularly involved.
[Elbaz, A.et al. 2009. Ann Neurol;66:494-504]
- Well-Water Consumption and Parkinson’s Disease in Rural California
Study investigated whether consuming water from private wells located in areas with documented historical pesticide use was associated with an increased risk of PD.Cases were more likely to have consumed private well water and to have consumed it on average 4.3 years longer than controls. High levels of possible well-water contamination with methomyl, chlorpyrifos, and propargite resulted in approximately 70–90% increases in relative risk of PD. Exposure to a higher number of water-soluble pesticides and organophosphate pesticides also increased the relative risk of PD.
[Gatto NM, et al. 2009. Environ Health Perspect 117:1912-1918]
- Pesticide exposure and risk of Parkinson's disease: A family-based case-control study
Using 319 cases and 296 relative and other controls, associations of direct pesticide application, well-water consumption, and farming residences/occupations with PD were examined using generalized estimating equations while controlling for age-at-examination, sex, cigarette smoking, and caffeine consumption. Overall, individuals with PD were significantly more likely to report direct pesticide application than their unaffected relatives (odds ratio = 1.61; 95% confidence interval, 1.13–2.29). Frequency, duration, and cumulative exposure were also significantly associated with PD in a dose-response pattern (p = 0.013). Associations of direct pesticide application did not vary by sex but were modified by family history of PD, as significant associations were restricted to individuals with no family history. When classifying pesticides by functional type, both insecticides and herbicides were found to significantly increase risk of PD. Two specific insecticide classes, organochlorines and organophosphorus compounds, were significantly associated with PD. Consuming well-water and living/working on a farm were not associated with PD. Data corroborate positive associations of broadly defined pesticide exposure with PD in families, particularly for sporadic PD.
[Hancock, D.B., et al. 2008. BMC Neurology 8(6):1471-2377]
- Ziram Causes Dopaminergic Cell Damage by Inhibiting E1 Ligase of the Proteasome
Study measured the relative toxicity of ziram (a UPS inhibitor) and analogs to dopaminergic neurons and examined the mechanism of cell death. Results demonstrate that ziram causes selective dopaminergic cell damage in vitro by inhibiting an important degradative pathway implicated in the etiology of PD. Chronic exposure to widely used dithiocarbamate fungicides may contribute to the development of PD.
[Chou, A. et al. 2008. Journal of Biological Chemistry; 283 pp.34696-34703]
- Developmental exposure to pesticides zineb and/or endosulfan renders the nigrostriatal dopamine system more susceptible to these environmental chemicals later in life.
The purpose of this study was to test the hypothesis that exposure to pesticides such as endosulfan and/or zineb during critical periods of postnatal development could result in neuronal dysfunction and enhance the impact of these pesticides during exposure as adults. Mice exposed to these pesticides as juveniles and re-exposed at 8 months of age had significantly altered striatum and brain cortex neurotransmitter levels. Thus, mice re-exposed during adulthood to zineb, endosulfan and their mixtures showed a significantly depleted striatal dopamine levels, to 22, 16 and 35% of control, respectively. Acetylcholinesterase activity in the cerebral cortex was significantly increased in all pesticide treated groups (rho< or =0.05) upon repeated exposure, and pesticide mixture treatment also significantly increased levels of normal and aggregated alpha-synuclein. Collectively, these findings support our hypothesis that exposure to pesticides such as endosulfan and zineb during critical periods of postnatal development contributes to neurotransmitter changes upon re-challenge in adulthood.
[Jia, Z., et al. 2007. Neurotoxicology 28(4):727-735]
- Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids.
Pyrethroids are a class of insecticides involved in different neurological disorders. They cross the blood-brain barrier and exert their effect on dopaminergic system, contributing to the burden of oxidative stress in Parkinson's disease through several pathways. The aim of this study was to evaluate the effect of neonatal exposition to permethrin and cypermethrin (1/10 of DL(50)) in rats from the eighth to the fifteenth day of life. Open-field studies showed increased spontaneous locomotor activity in the groups treated with permethrin and the one treated with cypermethrin, while a higher number of center entries and time spent in the center was observed for the cypermethrin-treated group. Lower dopamine and higher homovanillic acid levels were measured in the striatum from both treated groups. A reduction of blood glutathione peroxidase content was measured, while no change in blood superoxide dismutase was observed. Carbonyl group formation increased in striatum, but not in erythrocytes. Lipid peroxidation occurred in erythrocytes, but not in striatum. No changes in fluidity at different depths of plasma membrane were measured in striatum or erythrocytes. The activation of monocyte NADPH oxidase by phorbol esters (PMA) shows that superoxide anion production was reduced in the pyrethroid-treated groups compared to the control group. Study suggests that neonatal exposition to permethrin or cypermethrin induces long-lasting effects after developmental exposure giving changes in open-field behaviors, striatal monoamine level, and increased oxidative stress. Although the action of pyrethroids on various target cells is different, a preferential interaction with the extracellular side of plasma membrane proteins can be observed.
[Nasuti C, Gabbianelli R, Falcioni ML, et al.2007. Toxicology. 229(3):194-205.]
- Environmental risk factors for Parkinson’s disease and parkinsonism: the Geoparkinson study
A case–control study of 959 prevalent cases of parkinsonism (767 with Parkinson’s disease) and 1989 controls in Scotland, Italy, Sweden, Romania and Malta was carried out. Adjusted logistic regression analyses showed significantly increased odds ratios for Parkinson’s disease/parkinsonism with an exposure–response relationship for pesticides. Hypnotic, anxiolytic or antidepressant drug use for more than 1 year and a family history of Parkinson’s disease showed significantly increased odds ratios. The association of pesticide exposure with Parkinson’s disease suggests a causative role. Repeated traumatic loss of consciousness is associated with increased risk.
[Dich, F.D. et al. 2007. Occup Environ Med;64:666-672]
- GSTpi expression mediates dopaminergic neuron sensitivity in experimental parkinsonism
Study uses a MPTP model of parkinsonism to examine the role of a dual function protein, GSTpi, in dopaminergic neuron death. GSTpi is the only GST family member expressed in substantia nigra neurons. GSTpi reduction by pharmacological blockade, RNA inhibition, and gene targeting increases sensitivity to the pesticide MPTP, suggesting that differential expression of GSTpi contributes to the sensitivity to xenobiotics in the substantia nigra and may influence the pathogenesis of reactive oxygen species-induced neurological disorders including PD.
[Smeyne, M., et al. 2007. Proceedings of the National Academy of Sciences 104(6)1977-1982]
- Interaction between genes and environment in neurodegenerative diseases.
Study found that the inverse association between smoking and the risk of PD depended on a polymorphism of the iNOS (inducible NO synthase) gene. We also found that the cytochrome P450 2D6 gene could have a modifying effect on the risk of PD among persons exposed to pesticides. Both interactions have biological plausibility supported by laboratory studies and could contribute to better understand the aetiology of PD.
[Elbaz, A. et al. 2007. Comptes Rendus Biologies 330(4):318-328]
- Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration
Authors found that a single paraquat exposure was followed by an increase in the number of cells with immunohistochemical, morphological and biochemical characteristics of activated microglia, including induction of NADPH-oxidase. If this microglial response was inhibited by the anti-inflammatory drug minocycline, subsequent exposures to the herbicide failed to cause oxidative stress and neurodegeneration. On the other hand, if microglial activation was induced by pre-treatment with lipopolysaccharide, a single paraquat exposure became capable of triggering a loss of dopaminergic neurons. Finally, mutant mice lacking functional NADPH-oxidase were spared from neurodegeneration caused by repeated paraquat exposures. Data indicate that microglial activation and consequent induction of NADPH-oxidase may act as risk factors for Parkinson’s disease by increasing the vulnerability of dopaminergic cells to toxic injury.
[Purisai, M.G., et al. 2007. Neurobiology of Disease 25(2):392-400]
- Pesticide exposure and self-reported Parkinson's disease in the agricultural health study.
The authors used data obtained from licensed private pesticide applicators and spouses participating in the Agricultural Health Study to evaluate the relation of self-reported PD to pesticide exposure. Cohort members, who were enrolled in 1993-1997, provided detailed information on lifetime pesticide use. Incident PD was associated with cumulative days of pesticide use at enrollment (for highest quartile vs. lowest, odds ratio (OR) = 2.3, 95% confidence interval: 1.2, 4.5; p-trend = 0.009), with personally applying pesticides more than half the time (OR = 1.9, 95% confidence interval: 0.7, 4.7), and with some specific pesticides (ORs > or = 1.4). Prevalent PD was not associated with overall pesticide use. This study suggests that exposure to certain pesticides may increase PD risk.
[Kamel, F., et al. 2007. American Journal of Epidemiology 165(4):364-74]
- Pesticide exposure on southwestern Taiwanese with MnSOD and NQO1 polymorphisms is associated with increased risk of Parkinson's disease.
From southwestern region of Taiwan, 153 patients with idiopathic PD and 155 healthy control subjects matched for age, sex and origin were studied. Exposure to pesticides associated with PD was significant among patients with an increased odds ratio (OR) of 1.69 (95%CI, 1.07-2.65), and this association remained significant after adjustment for age, sex, and cigarette smoking (aOR=1.68, 95%CI, 1.03-2.76, P=0.023). Considering genetic factors, there were no significant differences in frequencies of both genotypes of manganese-containing superoxide dismutase (MnSOD) and quinone oxidoreductase 1 (NQO1) polymorphisms between PD patients and the control subjects (P>0.05). However, this difference in genotype distribution was significant among subjects who had been exposed to pesticide, for MnSOD C allele and for NQO1 T allele, respectively. Moreover, among subjects exposed to pesticide, the combined MnSOD/NQO1 variant genotype was significantly associated with a 4.09-fold increased risk of PD (95%CI, 1.34-10.64, P=0.0052).
[Fong, C., et al. 2007. Clinica Chimica Acta 378(1-2):136-141]
- Chemical exposures and Parkinson's disease: a population-based case-control study.
Study identified all subjects who developed PD in Olmsted County, Minnesota, from 1976 through 1995, and matched them by age (+/- 1 year) and sex to general population controls. Authors assessed exposures to chemical products by means of telephone interview with cases, controls, or their proxies (149 cases; 129 controls). Exposure to pesticides related or unrelated to farming was associated with PD in men (odds ratio, 2.4; 95% confidence interval, 1.1-5.4; P = 0.04). The association remained significant after adjustment for education or smoking. This population-based study suggests a link between pesticides use and PD that is restricted to men. Pesticides may interact with other genetic or nongenetic factors that are different in men and women.
[Frigerio, R., et al. 2006. Movement Disorders 21(10): 1688-1692]
- Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson’s disease
Study reports that perinatal exposure of mice during gestation and lactation to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic neurochemistry in their offspring and exacerbates MPTP toxicity. Results suggest that developmental exposure to dieldrin leads to persistent alterations of the developing dopaminergic system and that these alterations induce a "silent" state of dopamine dysfunction, thereby rendering dopamine neurons more vulnerable later in life. In all cases there were greater effects observed in the male offspring than the female, similar to that observed in human cases of PD.
[Richardson, J.R., et al. 2006. The FASEB Journal 20(10):1695-1697]
- Parkinson Disease: PD Gene and Oxidative Stress
Drosophila flies lacking the DJ-1 gene showed selective sensitivity to widely used agricultural toxicants that kill neurons mainly through oxidative stress. DJ-1 mutant flies exposed to the herbicide paraquat died much sooner than normal flies. The mutants also showed marked sensitivity to the insecticide rotenone and to hydrogen peroxide-both agents that promote oxidative stress. These results suggest that DJ-1 normally protects against oxidative stress and that its inactivation may leave neurons susceptible to oxidative damage. The study also found that exposure to paraquat led to biochemical modification of the DJ-1ß protein, a change which may influence the ability of DJ-1 to protect neurons from oxidative damage. Studies of DJ-1 in Drosophila will provide greater understanding of fundamental activities of the gene, helping to elucidate how its function may be critical in PD.
[Phillips, M.L. 2006. Environmental Health Perspectives 114(2)]
- Pesticide exposure and risk for Parkinson's disease
Exposure to pesticides was reported by 7,864 participants (5.7%), including 1,956 farmers, ranchers, or fishermen. Individuals exposed to pesticides had a 70% higher incidence of PD than those not exposed (adjusted relative risk, 1.7; 95% confidence interval, 1.2-2.3; p = 0.002). The relative risk for pesticide exposure was similar in farmers and nonfarmers. No relation was found between risk for PD and exposure to asbestos, chemical/acids/solvents, coal or stone dust, or eight other occupational exposures. These data support the hypothesis that exposure to pesticides may increase risk for PD.
[Ascherio, Al, et al. 2006. Annals of Neurology 60(2): 197-203.]
- Pesticides and Parkinson’s Disease—Is There a Link?
A comprehensive review of the published epidemiologic and toxicologic literature and critical evaluation of whether a relationship exists between pesticide exposure and PD. From the epidemiologic literature, there does appear to be a relatively consistent relationship between pesticide exposure and PD. This relationship appears strongest for exposure to herbicides and insecticides, and after long durations of exposure. Toxicologic data suggest that paraquat and rotenone may have neurotoxic actions that potentially play a role in the development of PD, with limited data for other pesticides. At present, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists but is insufficient for concluding that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined pesticide and other exogenous toxicant exposure.
[Brown, T.P., et al. 2006. Environmental Health Perspectives 114(2):156-164]
- Principles for evaluating health risks in children associated with exposure to chemicals
The United Nation’s World Health Organization report on children’s heightened vulnerability to chemical exposures at different periods of their growth and development states, “neurotoxic insults during development that result in no observable phenotype at birth or during childhood could manifest later in life as earlier onset of neurodegenerative diseases such as [PD].”
[Louis, G.B., et al. 2006. Environmental health criteria: 237. World Health Organization. Geneva, Switzerland]
- Pyrethroid pesticide-induced alterations in dopamine transporter function.
Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Study reports that repeated exposure of mice to two commonly used pyrethroid pesticides, deltamethrin and permethrin, increases DAT-mediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, study determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 microM) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 microM) or 24 h (1, 5, and 10 microM) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD.
[Elwan MA, Richardson JR, Guillot TS, et al. 2006. Toxicol Appl Pharmacol.211(3):188-97]
- Developmental pesticide exposures and the Parkinson's disease phenotype.
Study found that postnatal exposures of mice to pesticides, paraquat + maneb, led not only to a permanent and selective loss of dopaminergic neurons in the substantia nigra pars compacta but also enhanced the impact of these pesticides administered during adulthood relative to developmental only or adult only treatment. Exposure to maneb alone during gestation resulted in a dramatic response to paraquat in adulthood, including notable reductions in levels of dopamine and metabolites and a loss of nigral dopamine (DA) neurons, despite the fact that paraquat does not share structural similarity to or mechanisms of action with maneb. Collectively, these studies provide developmental environmental models of the PD phenotype.
[Cory-Slechta D.A., et al. 2005. Birth Defects Res A Clin Mol Teratol 73:136–139]
- Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease
Study involoving Drosophila flies to develop an animal model that would allow integrative study of genetic and environmental influences. Study demonstrates that fly DJ-1 activity is selectively involved in protection from environmental oxidative insult in vivo and that the inherited PD gene, DJ-1beta protein, is biochemically responsive to oxidative stress. Study of these flies will provide insight into the critical interplay of genetics and environment in PD.
[Meulener, M., et. al. 2005. Current Biology 15(17): 1572-1577]
- Modulation of antioxidant defense systems by the environmental pesticide maneb in dopaminergic cells.
Authors believe environmental contaminants such as pesticides make dopamine cells more vulnerable to damage from normal aging, infection, or subsequent exposure to pollutants. Study primarily utilized the PC12 cell line, which displays a catecholaminergic phenotype. Low concentrations of maneb (50-1000 ng/ml) had little effect on cell viability, as measured by LDH release. hese same concentrations, however, led to increases in glutathione (GSH) and its oxidized form, GSSG. Results suggest that following an insult to the GSH antioxidant system, maneb can act as an additional insult to the system and prevent the normal recovery of those defenses. Dopaminergic neurons, as a population, are inherently vulnerable to oxidative stress, and the disruption of antioxidant systems by the fungicide maneb may contribute to the neurodegeneration of these cells, especially with concurrent exposures to other environmentally relevant oxidative stressors.
[Barlow, B.K., et al. 2005. Neurotoxicology 26(1):63-75]
- Perinatal heptachlor exposure increases expression of presynaptic dopaminergic markers in mouse striatum.
In this study, authors examined the effects of developmental exposure to heptachlor on the dopamine transporter (DAT), and other key components of the dopaminergic system, including the vesicular monoamine transporter 2 (VMAT2), tyrosine hydroxylase (TH), and aromatic amino acid decarboxylase (AADC). On postnatal day 28, DAT, VMAT2, and TH levels were increased by 100, 70, and 30%, respectively, with no change in AADC levels or total dopamine levels. The ratio of DAT:VMAT2 was increased 29%. Since an increase in the DAT:VMAT2 ratio appears to predict susceptibility of brain regions to Parkinson's disease (PD) and results in increased toxicity of MPTP, these results suggest that alterations of the dopaminergic system by developmental heptachlor exposure may increase the susceptibility of dopamine neurons to toxic insult.
[Caudle, W.M., et al. 2005. NeuroToxicology 26(4):721-728]
- Pesticides and risk of Parkinson disease: a population-based case-control study.
Study investigated associations between pesticide exposures and idiopathic PD and found significantly increased ORs from lifelong well water consumption (OR, 1.81; 95% CI, 1.02-3.21). Study also found elevated ORs from herbicides (OR, 1.41; 95% CI, 0.51-3.88) and paraquat (OR, 1.67; 95% CI, 0.22-12.76).
[J.A., et al. 2005. Archives of Neurology 62(1):91-95]
- A case-control study of Parkinson's disease in a horticultural region of British Columbia
Study compared personal histories of 127 cases and 245 controls to identify possible environmental risk factors for idiopathic parkinsonism (IP). Data found a significant association between IP and having had an occupation in which exposure through handling or directly contacting pesticides was probable, but no specific chemicals were associated with IP. Study concluded that although occupations involving the use of agricultural chemicals may predispose to the development of IP, it seems likely that the pathogenesis is multifactorial rather than related to a specific agent.
[Hertzman, C., et al. 2004. Movement Disorders 9(1):69-75]
- A fetal risk factor for Parkinson's disease.
This study hypothesized that prenatal exposure to pesticides would disrupt the development of the nigrostriatal dopamine (DA) system and enhance its vulnerability to dopaminergic neurotoxicant exposures later in life. One week after the last exposure to maneb or paraquat, only male mice exposed to prenatal maneb and adulthood paraquat showed significant reductions in locomotor activity (95%) and changes in striatal neurochemistry. Stereological assessment of the substantia nigra pars compacta (SNpc) and ventral tegmental area correspondingly confirmed selective dopaminergic-neuron loss in SNpc. The lack of changes in other exposure groups suggests a specificity to the sequence of exposures as well as gender specificity. These results suggest that prenatal exposure to maneb produces selective, permanent alterations of the nigrostriatal dopaminergic system and enhances adult susceptibility to paraquat exposure.
[Barlow, B.K., et al. 2004. Dev Neurosci 26(1):11-23]
- No evidence for heritability of Parkinson disease in Swedish twins
The aim of the study was to evaluate heritability of PD in same-sexed and opposite-sexed twin pairs in the Swedish Twin Registry (STR). For possible PD, there were only two concordant pairs, both female dizygotic. Similarly, concordances were low in all zygosity groups when the definition of affected was expanded to include twins with suspected parkinsonism or movement disorder in addition to possible PD. Sex differences in the relative importance of genetic and environmental effects were indicated with a marginally larger familial component in women. Results suggest that environmental factors are most important in the etiology of PD. Compared with other complex diseases, the importance of genetic effects in PD is notably low. The preponderance of discordant twin pairs provides an ideal material for studying environmental risk factors and potential genotype-by-environment interaction.
[Wirdefeldt, K., et al. 2004. Neurology 63(2):305-311]
- Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype.
Study tested exposed C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb-induced reductions in locomotor activity and motor coordination were age dependent, with 18-month-old mice most affected and exhibiting failure to recover 24 h post-treatment. Three months post-treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5-month-old and further reduced in 18-month-old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18-month-old paraquat + maneb and paraquat groups 3 months post-treatment. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity.
[Thiruchelvam, M., et al. 2003. Eur J Neurosci 18(3):589-600]
- Association between Parkinson’s disease and exposure to pesticides in southwestern France.
A case-control study was performed in southwestern France in order to assess the relationship between pesticide exposure and Parkinson's disease (PD) in the elderly. During the period from 1997 to 1999, 84 cases were recruited together with 252 population-based controls. A positive association was found with occupational pesticide exposure (odds ratio = 2.2, 95% confidence interval 1.1-4.3) in conditional logistic multiple regression analysis taking into account age, sex, educational level and smoking; however, no clear dose relationship was found.
[Baldi, I., et al. 2003. Neuroepidemiology 22(5):305-310]
- Neurodegenerative Diseases and Exposure to Pesticides in the Elderly.
Study of 1,507 French elderly (1992–1998) shows lower cognitive performance was observed in subjects who had been occupationally exposed to pesticides. In men, the relative risks of developing Parkinson’s disease and Alzheimer’s disease for occupational exposure assessed by a job exposure matrix were 5.63 (95% confidence interval: 1.47, 21.58) and 2.39 (95% confidence interval: 1.02, 5.63), respectively.
[Baldi, I, et al. Am J Epidemiol 2003; 157:409-414.]
- Developmental exposure to the pesticides paraquat and maneb and the Parkinson's disease phenotype.
This study hypothesized that paraquat (PQ) and maneb (MB) exposure during critical periods of development could permanently change the nigrostriatal dopamine (DA) system and enhance its vulnerability to subsequent neurotoxicant challenges. Mice exposed developmentally to PQ + MB and rechallenged as adults were the most affected, showing a 70% reduction in motor activity 2 weeks following the last rechallenge dose. Striatal DA levels were reduced by 37% following developmental exposure to PQ + MB only, butfollowing adult re-challenge levels were reduced by 62%. A similar pattern of nigral dopaminergic cell loss was observed, with the PQ + MB treated group exhibiting the greatest reduction, with this loss being amplified by adult re-challenge. Following adult re-challenge, significant decreases in DA and nigral cell counts were observed, suggesting that exposure to either neurotoxicant alone produced a state of silent toxicity that was unmasked following adult re-exposure. Taken together, these findings indicate that exposure to pesticides during the PN period can produce permanent and progressive lesions of the nigrostriatal DA system, and enhanced adult susceptibility to these pesticides, suggesting that developmental exposure to neurotoxicants may be involved in the induction of neurodegenerative disorders and/or alter the normal aging process.
[Thiruchelvam, M., et al. 2002. Neurotoxicology 23(4-5):621-633]
- Familial and environmental risk factors in Parkinson's disease: a case-control study in north-east Italy
Study of136 patients with neurologist confirmed PD and 272 age- and sex-matched controls, affected by neurological diseases not related to PD. The risk of developing idiopathic PD associated with the following familial and environmental factors: positive family history of PD, positive family history of essential tremor (ET), age of mother at subject's birth, rural birth, rural living, well water use, farming as an occupation, exposure to pesticides, head tremor, exposure to general anaesthesia and to ionizing radiations, food restriction, concentration camp imprisonment and smoking has been assessed by using univariate and multivariate statistical techniques.
[Zorzon, M., et al. 2002. Acta Neurol Scand 105(2):77-82]
- Plantation work and risk of Parkinson disease in a population-based longitudinal study.
Objective of this study was to determine whether working on a plantation in Hawaii and exposure to pesticides are associated with an increased risk of PD decades later. During follow-up, 116 men developed PD. Age-adjusted incidence increased significantly among men who worked more than 10 years on a plantation. The relative risk of PD was 1.0 (95% confidence interval, 0.6-1.6), 1.7 (95% confidence interval, 0.8-3.7), and 1.9 (95% confidence interval, 1.0-3.5) for men who worked on a plantation 1 to 10 years, 11 to 20 years, and more than 20 years compared with men who never did plantation work (P =.006, test for trend). These longitudinal observations regarding plantation work in Hawaii support case-control studies suggesting that exposure to pesticides increases the risk of PD.
[Petrovitch, H., et al. 2002. Archives of Neurology 59(11):1787-1792]
- Environmental Risk Factors and Parkinson's Disease: A Metaanalysis
A series of metaanalyses of peer-reviewed studies were performed, using 16 studies for living in rural area, 18 studies for well water drinking, 11 studies for farming, and 14 studies for pesticides.The majority of the studies reported consistent elevation in the risk of PD with exposure to environmental factors such as rural living and farming. Findings suggest that living in a rural area, drinking well water, farming, and exposure to pesticides may be a risk factor for developing PD.
[Priyadarshi, A., et al. 2001.Environ Res 86(2):122-127]
- Parkinsonism and occupational exposure to pesticides
Parkinsonism may be associated with long term occupational exposure to pesticides, although no associations with specific pesticides could be detected. This finding is consistent with most of the publications on this topic.
[Engel, L.S., et al. 2001.Occupational and Environmental Medicine 58(9):582-589]
- A meta-analysis of Parkinson's disease and exposure to pesticides.
A series of meta-analysis of peer-reviewed studies were performed, using 19 studies published between 1989 and 1999. The majority of the studies reported consistent elevation in the risk of PD with exposure to pesticides. The combined OR studies was 1.94 [95% confidence interval (95% CI) 1.49-2.53] for all the studies, and 2.15 (95% CI 1.14-4.05) for studies performed in United States. Although the risk of PD increased with increased duration of exposure to pesticides, no significant dose-response relation was established, and no specific type of pesticide was identified. Findings suggest that exposure to pesticides may be a significant risk factor for developing PD.
[Priyadarshi, A., et al. 2000. Neurotoxicology 21(4):435-440.]
- Agricultural work and the risk of Parkinson's disease in Denmark, 1981-1993
This study examined the possible association between agricultural and horticultural work and the subsequent morbidity of Parkinson's disease. A high risk of Parkinson's disease was found for the men and women in agriculture and horticulture (134 cases, SHR 132, 95% CI 111-156). Statistically significantly high risks were found for farmers (79 cases, SHR 130, 95% CI 103-163) and for all men in agriculture and horticulture (109 cases, SHR 134, 95% CI 109-162).
[Tuchsen, F., et al. 2000. Scand J Work Environ Health 26(4):359-362]
- Exposure to home pesticides linked to Parkinson disease.
This study raises concerns for residential pesticide exposure. Stanford University researchers find a 70 percent increased risk of developing PD for individuals that use pesticides in their home. Exposure to garden insecticides carries a 50 percent increased risk of developing the disease. Among herbicide users, the risk of developing PD increases as the number of days in contact with herbicides grows. Respondents who reported handling or applying herbicides for up to 30 days are 40 percent more likely to develop the disease, whereas respondents that reported 160 days exposure, have a 70 percent increase.
[Stephenson, J. 2000. JAMA 283:3055-3056]
- Parkinson's disease mortality and pesticide exposure in California 1984-1994.
A California mortality study of individuals whose death certificates mention PD as an underlying cause of death and cross-referenced with agricultural and pesticide use data finds that the counties using restricted use pesticides (RUP) for agricultural purposes have about a 40 percent increase in PD mortality when compared to those counties reporting no RUP.
[Ritz B, and Yu F. 2000. International Journal of Epidemiology 29(2):323-329]
- Nutritional and occupational factors influencing the risk of Parkinson's disease: a case-control study in southeastern Sweden.
Study investigates the possible impact of nutritional and environmental risk factors for idiopathic Parkinson's disease (IP), a case-control study was performed in the county of Ostergötland in southeastern Sweden. The study involved 113 cases of IP and 263 control subjects. A reduced risk was found for coffee, wine, and liquor at various consumption levels but also for fried or broiled meat, smoked ham or meat, eggs, French loaf or white bread, and tomatoes. All these food and drink items contain niacin. As in many studies, the frequency of preceding and present smoking was reduced in IP patients. Various occupational groups and exposures were analyzed and increased risks of IP in men were found for agricultural work along with pesticide exposure; this was also the case for male carpenters and female cleaners.
[Fall, P., et al. 1999. Movement Disorders 14(1):28-37]
- Gene-toxin interaction as a putative risk factor for Parkinson's disease with dementia.
Study explores the hypothesis that genetic traits coupled with nongenetic factors may raise the risk of development of Parkinson's disease with dementia (PD + D). The study cohort of 43 PD + D and 51 PD-D subjects was analyzed examining environmental, sociodemographic and clinical variables along with 3 candidate gene markers. Subjects who had pesticide exposure and at least 1 copy of the CYP 2D6 29B+ allele had 83% predicted probability of PD + D (stepwise logistic regression model: p = 0.0491). This case-control study provides preliminary evidence that a gene-toxin interaction may play an etiological role in PD + D.
[Hubble, J.P., et al. 1998. Neuroepidemiology 17(2):96-104]
- Genetic and environmental risk factors for Parkinson’s disease in a Chinese population
An epidemiological study of the environmental and genetic factors as well as the possible interplay between them was conducted among 215 patients with Parkinson’s disease and 313 controls in a Chinese population in Hong Kong. In multivariate analysis, current smoking reached borderline significance at the 5% level and the variables, years exposed to pesticides and family history were significant at the 10% level.
[Chan, D.K. 1998. Journal of Neurology, Neurosurgery and Psychiatry 65:781-784]
- Parkinson's disease, pesticides, and glutathione transferase polymorphisms.
Study investigated the role of GST polymorphisms in the pathogenesis of idiopathic Parkinson's disease. Authors genotyped by PCR polymorphisms in four glutathione transferases (GST) classes (GSTM1, GSTT1, GSTP1, and GSTZ1) in 95 Parkinson's disease patients and 95 controls. The distribution of the GSTP1 genotypes differed significantly between patients and controls who had been exposed to pesticides No association was found with any of the other GST polymorphisms. Pesticide exposure and a positive family history were risk factors for Parkinson's disease. GSTP1-1, which is expressed in the blood-brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides.
[Menegon, A., et al. 1998. The Lancet 352(9137):1344-1346]
- The Epidemiology of Parkinson’s Disease in an Australian Population
A prevalence study of Parkinson’s disease (PD) was conducted in the rural town of Nambour, Australia. A positive family history of PD was the strongest risk factor for the development of the disease (odds ratio = 3.4; p < 0.001). In addition, rural residency was a significant risk factor for PD (odds ratio = 1.8, p < 0.001).
[McCann, S.J., et al. 1998. Neuroepidemiology 17(6):310-317]
- The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living.
Study assessed exposure to pesticides, farming, well water use, and rural living as risk factors for Parkinson's disease (PD) in a population-based case-control study consisting of men and women > or = 50 years of age. Farming as an occupation was significantly associated with PD (OR, 2.79; 95% CI, 1.03, 7.55). The association of occupational exposure to herbicides or insecticides with PD remained after adjustment for farming. The association of farming with PD was maintained after adjustment for occupational herbicide exposure and was of borderline significance after adjustment for occupational insecticide exposure. These results suggest that PD is associated with occupational exposure to herbicides and insecticides and to farming and that the risk of farming cannot be accounted for by pesticide exposure alone.
[Gorell, J.M., et al. 1998. Neurology 50:1346-1350]
- Neurodegenerative diseases: occupational occurrence and potential risk factors, 1982 through 1991.
To identify potential occupational risk factors, this study examined the occupational occurrence of various neurodegenerative diseases:presenile dementia, Alzheimer's disease, Parkinson's disease, and motor neuron disease. Excess mortality was observed for all four categories in the following occupational categories: teachers; medical personnel; machinists and machine operators; scientists; writers/designers/entertainers; and support and clerical workers. Clusters of three neurodegenerative diseases were also found in occupations involving pesticides, solvents, and electromagnetic fields and in legal, library, social, and religious work.
[Schulte, P.A., et al. 1996. American Journal of Public Health 86(9):1281-1288]
- Possible environmental, occupational, and other etiologic factors for Parkinson's disease: A case-control study in Germany
A case-control study investigated the possible etiologic relevance to Parkinson's disease (PD) of rural factors such as farming activity, pesticide exposures, well-water drinking, and animal contacts; toxicologic exposures such as wood preservatives, heavy metals, and solvents; general anesthesia; head trauma; and differences in the intrauterine environment. There were significantly elevated odds ratios (OR) for pesticide use, in particular, for organochlorines and alkylated phosphates, but no association was present between PD and other rural factors. A significantly elevated OR was present for exposure to wood preservatives.
[Seidler, A. et al. 1996.Nuerology; 46:1275]
- The Role of the Environment in Parkinson's Disease
Thirty leading scientists in the field of Parkinson's disease research attended a conference, "The Role of the Environment in Parkinson's Disease," 17-19 September 1995, sponsored and hosted by the National Institute of Environmental Health Sciences. The role of the environment was highlighted, but considerable attention was given to pathological neurochemistry and genetic issues in the etiopathogenesis of Parkinson's disease.
[Gorrell, J.M. et al. 1996. Meeting Report. National Institute of Environmental Health Sciences. Environmental Health Perspectives;104(6)]
- Environmental antecedents of young-onset Parkinson's disease
An exploratory study of young-onset Parkinson's disease (YOPD) to examine occupational and environmental factors associated with disease risk.PD was positively associated with insecticide exposure (OR = 5.75, p < 0.001), past residency in a fumigated house (OR = 5.25, p = 0.046), herbicide exposure (OR = 3.22, p = 0.033), rural residency at time of diagnosis (OR = 2.72, p = 0.027), and nuts and seed eating 10 years before diagnosis (OR = 1.49, p = 0.021). These findings are consistent with hypotheses linking PD to exposure to pesticide agents.
[Butterfield, P.G., et al. 1993. Neurology 43(6):1150-1158.]
- Risk factors for Parkinson's disease
Study examined social and medical histories of predominantly rural populations to determine relative risk factors for PD. Significant predictors of PD emerged (in order of strength): pesticide use, family history of neurologic disease, and history of depression. The predicted probability of PD was 92.3% (odds ratio = 12.0) with all three predictors positive. Pesticide use (distinguishable from rural living) can be considered a risk factor for the development of PD, with family history of neurologic disease and history of depression serving as weaker predictors of PD.
[Hubble, J.P., et al. 1993. Neurology 43:1693-97]
- Parkinson's disease and exposure to agricultural work and pesticide chemicals.
A population-based case-control study of 130 Calgary residents with neurologist-confirmed idiopathic Parkinson's disease (PD) and 260 randomly selected age- and sex-matched community controls to determine whether agricultural work or the occupational use of pesticide chemicals is associated with an increased risk for PD. In the multivariate analysis, which controlled for potential confounding or interaction between the exposure variables, previous occupational herbicide use was consistently the only significant predictor of PD risk.
[Semchuk, K.M., et al. 1992. Neurology 42:1328-1335]
- Parkinson's disease in Ferrara, Italy, 1967 through 1987
Authors studied the frequency of Parkinson's disease in the Local Health Service of Ferrara, northeastern Italy. The study revealed a significantly higher incidence rate among agricultural workers (20.6/100,000). These results would seem to give further support to the hypothesis of a possible causal role of environmental factors that are mainly linked to agriculture, most likely due to the continual exposure to toxic agents in this area.
[Granieri, E., et al. 1991. Archives of Neurology 48(8):854-857]
- Environmental risk factors in Parkinson's disease
Study investigated possible risk factors for Parkinson's disease (PD) and conducted a case-control study of 150 PD patients and 150 age- and sex-matched controls. Rural living and drinking well water were significantly increased in the PD patients. This was observed regardless of age at disease onset. Drinking well water was dependent on rural living. There were no significant differences between cases and controls for farming or any measure of exposure to herbicides or pesticides. These data provide further evidence that an environmental toxin could be involved in the etiology of PD.
[Koller, W. et al. 1990. Neurology. 40(8):1218-1221]
- Ecogenetics of Parkinson's disease: prevalence and environmental aspects in rural areas.
Study demonstrates that the prevalence of Parkinson's disease is of uneven distribution within rural areas of Quebec, Canada. Study further investigates the characteristics of the regions of high prevalence. These regions which are predominantly agricultural and areas of intensive market gardening were also the areas with the highest use of pesticides.
[Barbeau, A., et al. 1987. Can J Neurol Sci 14(1) 36-41]