Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases—A mechanistic approach
Graphical abstract
Introduction
The World Health Organization currently estimates that around a billion people worldwide are affected by a neurodegenerative disease (WHO, 2006). As aging corresponds to the greatest risk factor for neurodegeneration, the prevalence of neurological disorders is expected to increase dramatically in next few years due to the higher life expectancy worldwide (Brown et al., 2005). Another risk factor for neurodegeneration, alongside with the aging process, is long-term/low-dose pesticide exposure. The role of pesticide exposure in the genesis of neurodegenerative diseases has been especially scrutinized for Parkinson's disease (PD) (Franco et al., 2010).
PD is a progressive movement disorder characterized by progressive bradykinesia (slowness of voluntary movement), rigidity, rest tremor, and postural disturbances. Nonetheless, it is also increasingly recognized that non-motor symptoms, including autonomic and cognitive impairment, sleep disturbances, olfactory dysfunction, and depression occur in PD patients, and these features are probably due to the spread of the pathology beyond the basal ganglia (Shulman et al., 2011). The PD's motor manifestations are attributed to the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) resulting in secondary dysfunction of the basal ganglia, which are involved in the initiation and execution of movements (Shulman et al., 2011). The subcellular hallmarks of PD are the intraneuronal inclusions of various structures consisting mostly of fibrillar α-synuclein (Lewy bodies and Lewy neurites) (Halliday et al., 2011).
The etiology of PD is currently unknown but it is assumed that there is a significant non-genetic contribution. It seems that the disease results from combination and accumulation of environmental exposures, and complex gene–environment interactions sustained by the slow and progressive development during aging (Cannon and Greenamyre, 2011, Dinis-Oliveira et al., 2006). Most of the forms of PD are idiopathic, but approximately 10–30% of the cases have a familial history, and in a minority of them the disease follows a Mendelian inheritance pattern. The disease is characterized by an early-onset (typically under 40 years) and so far 15 PD loci (PARK1-15) and 11 genes for PARK loci, specially a-synuclein, leucine-rich repeat kinase 2, parkin, PTEN-induced putative kinase 1, DJ-1, and ATP13A2 have been described to cause typical forms of inherited PD or parkinsonian syndromes (Coppede, 2012). Parkinsonism is often observed as one of the symptoms in other monogenic diseases, when mutations in non-PARK loci (MAPT, SCA1, SCA2, spatacsin, POLG1) occur. In sporadic PD, genetic polymorphisms in four loci (SNCA, MAPT, GBA and LRRK2) are considered strong risk factors (Coppede, 2012). It is consensual that both etiologies share the same pathological pathways. SNpc is highly sensitive to diverse genetic, cellular and environmental factors that independently or concomitantly cause cell death over time. For instance, evidence suggests that mitochondrial dysfunction, accumulation of misfolded and aggregated proteins (ubiquitin-proteasome system and autophagy pathway impairment) and oxidative and nitrosative stress play an essential role in the pathogenesis of both idiopathic and familial forms of PD (Kanthasamy et al., 2012).
Since the discovery of the ability of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to reproduce some of the features of PD, research has been focused on finding other environmental risk factors implicated in the etiology of PD, which revealed that occupational exposures to paraquat (PQ), maneb (MB) and rotenone have been associated with higher incidence of PD.
Besides PD, several studies have also suggested that Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), dementia and deficits in cognitive function are linked to occupational pesticide exposure (Cannon and Greenamyre, 2011, Chang and Wu, 2009, Kamel and Hoppin, 2004, Kamel et al., 2012, Migliore and Coppede, 2009a, Sutedja et al., 2009). AD is a chronic disease characterized by progressive loss of memory and cognitive capacity, ultimately leading to dysfunction in daily life or work abilities. The neurodegeneration seen in AD involves two main protein aggregates, senile/amyloid plaques and neurofibrillary tangles (Palop and Mucke, 2010). Senile plaques are deposits of fibrils of the β-amyloid peptide, a fragment derived from the proteolytic processing of the amyloid precursor protein whereas neurofibrillary tangles are a compact filamentous network of helical filaments from hyperphosphorylated tau protein (Maccioni et al., 2001). Initially, the entorhinal cortex and hippocampus are particularly affected, as shown by the impaired synaptic transmission, especially reduction in the glutamatergic synaptic transmission strength and plasticity, and cholinergic dysfunction (Danysz and Parsons, 2012, Nyakas et al., 2011). The cause for development of AD as other neurodegenerative diseases is not fully understood, however roughly 0.1% of the cases arise from mutation in three genes (APP, PSEN 1 and PSEN 2) that result in a familial early-onset (<65 years) autosomal dominant forms (Migliore and Coppede, 2009b). Metals, pesticides, solvents, electromagnetic fields, brain injuries, inflammation, educational levels, lifestyles and dietary factors have been proposed as environmental AD risk factors (Cannon and Greenamyre, 2011, Dosunmu et al., 2007). Carbamates, organophosphates (OPs) and organochlorines are the pesticides more frequently associated with occupational exposure and AD (Hayden et al., 2010, Parron et al., 2011, Tyas et al., 2001, Zaganas et al., 2013).
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease evidenced by progressive loss of motor neurons at the anterior horn of the spinal cord and brain, resulting in progressive weakness, muscle atrophy, and respiratory failure within 3–5 years after diagnosis (Al-Chalabi et al., 2012). Around 5% of the cases are familial forms of ALS that arise from mutations in several genes including SOD1, TARDBP, FUS, UBQLN2, C9orf72, and TAF15 (Al-Chalabi et al., 2012, Lill et al., 2011, Maccioni et al., 2001). Studies in mutations in SOD1 have provided new insight into the pathogenesis of ALS, namely the generation of reactive oxygen (ROS) and nitrogen species (RNS), dramatic gliosis characterized by abnormalities of astrocytes, widespread astrocytosis, increased expression of inducible nitric oxide synthase (NOS) and activated microglial cells (Almer et al., 1999, Cha et al., 2000, Nagy et al., 1994). Interestingly, the neuronal cytoplasmic inclusions of ALS are constituted by aggregates of proteins encoded by the mutated genes described above (Ince et al., 2011). ALS and sporadic frontotemporal lobar degeneration share the same pathologic lesion, the ‘ubiquitin-only inclusion’ body, within lower motor neurons and cerebral neurons (hippocampal and frontotemporal neocortex neurons), and both are considered proteinopathies (Ince et al., 2011). The remaining 95% of cases do not have an obvious family history of ALS and appear to occur sporadically throughout the community (Schymick et al., 2007). Despite this fact, the etiology of the majority of sporadic ALS cases is presumably due to several interactions between genetic and environmental factors. The genes that have been identified as being causative of ALS are related to DNA repair (APEX1 and hOGG1), angiogenesis (ANG and VEGF), paraoxonases (PON1, PON2 and PON3), iron metabolism (HFE), neurofilaments (NEFH), and survival motor neuron (SMN1 and SMN2) (Maccioni et al., 2001, Migliore and Coppede, 2009b, Schymick et al., 2007). Several studies suggest that occupational exposure to pesticides is a significant risk factor of ALS (Bonvicini et al., 2010, Govoni et al., 2005, Kamel et al., 2005, Kanavouras et al., 2011, Qureshi et al., 2006). For instance, Horner and colleagues reported a two-fold increase in the risk of ALS among veterans of the 1991 Gulf War over the subsequent 10 years (Coffman et al., 2005, Horner et al., 2003, Miranda et al., 2008). Although the information about the chemicals to which soldiers were exposed is scarce and biased, the possibilities include OPs, other pesticides, nerve gases, pyridostigmine, petrochemicals and depleted uranium (Spencer et al., 1998).
Recently, two different research groups conducted a retrospective meta-analysis of studies relating ALS and pesticides as a group (Malek et al., 2012), and one of them investigated the association of ALS with specific pesticides, using data from the Agricultural Health Study, a cohort including 84739 private pesticide applicators and spouses (Kamel et al., 2012). From the eight case–control studies (Bonvicini et al., 2010, Chancellor et al., 1993, Deapen and Henderson, 1986, Granieri et al., 1988, Gunnarsson, 1994, McGuire et al., 1997, Morahan and Pamphlett, 2006, Savettieri et al., 1991) and one cohort study (Weisskopf et al., 2009), the major finding was the strong association observed between agricultural activities and ALS, although the chemical or class of agrochemical was not specified by the majority of studies (Kamel et al., 2012, Malek et al., 2012, Sutedja et al., 2009). On the other hand, in the Agricultural Health Study, ALS was not associated with pesticides as a group, but was associated with use of organochlorine insecticides, herbicides, pyrethroids, and fumigants (Kamel et al., 2012).
There is mounting evidence that long-term/low dose pesticide exposure is potentially neurotoxic and increases risk of PD and with lesser extent other neurological diseases, such as AD and ALS. PQ and MB are the most studied pesticides, though pesticides such as dieldrin, pyrethroids and OPs are also described as neurotoxics. The pesticides addressed in this review represent the five important classes of pesticides that have been more extensively studied in this matter. The neonicotinoids, acetamiprid and imidacloprid belong to a new class of insecticides and the latter is considered the most widely used within this class in the world. Nonetheless, so far neonicotinoids are considered safer than other compounds due to their higher selectivity for the nicotinic receptors of insects than mammalian receptors (Casida and Durkin, 2013). There are few studies reporting nervous system depression following acute poisoning with imidacloprid or acetamiprid, but currently there is no evidence or human data reporting health effects on humans after prolonged exposure to neonicotinoids (Imamura et al., 2010, Karatas, 2009, Phua et al., 2009, Proenca et al., 2005).
This review aims to clarify some of the mechanisms involved in the genesis of idiopathic PD and other neurological syndromes and the role of pesticides as environmental risk factors.
Section snippets
Oxidative stress and inflammation
The herbicide PQ has increasingly been reported in epidemiological studies to enhance the risk of developing PD. PQ belongs to the chemical class of bipyridyl (also called bipyridylium) quaternary ammonium herbicides characterized by two covalently linked methylpyridine rings (Calderbank, 1968). The toxicity of PQ has been extensively described concerning the effects to the main target organ, the lungs, and also the kidneys, liver and heart (Dinis-Oliveira et al., 2008). However, only in the
MB and PQ + MB
In rodent models, MB was shown to alter behavioral function, reduce locomotor activity and increase aggressiveness (Morato et al., 1989). Direct injection of MB to the rat lateral ventricles resulted in selective dopaminergic neurodegeneration, induced extensive striatal DA efflux, and preferentially inhibited mitochondrial complex III (Zhang et al., 2003). Barlow and colleagues also reported that MB and other dithiocarbamates were able to increase synaptosomal DA accumulation in vitro at
Dieldrin
Dieldrin, an organochlorine, is one of the most environmentally persistent insecticides. Despite having been banned in the 1970s in most of the developed countries, its low volatility, and high lipophilic properties lead to an extensively bioaccumulation and biomagnification in non-target species and soil. Nowadays, humans continue to be chronically exposed to dieldrin through contaminated food, polluted ground water, and environmental residues (Jorgenson, 2001).
Post mortem studies indicate
Pyrethroids
Pyrethroids are a class of synthetic insecticides derived from the naturally occurring pyrethrins isolated from the Chrysanthemum genus of plants (Ray and Fry, 2006). Pyrethroids are divided into two classes of compounds based on their toxic signs and structure:
- (a)
Type I or T (tremor) syndrome (i.e. permethrin, allethrin, cimethrin, bifenthrin, bioallethrin) – are devoid of a cyano moiety at the α-position (α-cyano), produce aggressive behavior, fine tremor progressing to whole-body tremor and
Organophosphates and carbamates
OP are a group of acetylcholinesterase (AChE) inhibitors and represent the largest group of insecticides sold worldwide. Acute OP poisonings leads to the development of three main syndromes: (i) acute cholinergic crisis; (ii) intermediate syndrome (IMS), and (iii) OP-induced delayed polyneuropathy (OPIDP) (Moretto, 1998). Both IMS and OPIDP result of an acute exposure to OP, usually after a suicide attempt or accidental ingestion. The acute cholinergic crisis results from the inhibition of AChE
Concluding remarks
In humans, pesticides can be responsible for diverse acute and long-term health effects. Even though not consistent, there is a growing body of epidemiologic evidence linking long-term/low-dose pesticide exposure to cancer, reproductive health issues, neurodegenerative diseases such as AD, PD, and neurodevelopment impairments in children. Experiments concerning the environmental etiology of PD are more frequent than for other diseases, and several different animal models have been proposed (
Conflict of interest
The authors declare that there are no conflicts of interest.
Transparency document
Acknowledgements
This work received financial support of the Cooperativa de Ensino Superior Politécnico e Universitário (CESPU), CRL and of the Faculty of Medicine of Porto University. Ricardo Dinis-Oliveira and Maria Teresa Baltazar, acknowledges FCT for their investigator (IF/01147/2013) and PhD grants (SFRH/BD/65387/2009), respectively. The Research Centre on Physical Activity Health and Leisure (CIAFEL) is supported by Pest-OE/SAU/UI0617/2011. We also acknowledge the designer Joana Macedo for the artwork
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