Review
Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models?

https://doi.org/10.1016/j.tips.2009.06.005Get rights and content

Parkinson's disease (PD) is a common neurodegenerative disorder largely of idiopathic nature with the exceptions of rare familial forms, and is characterized by both motor and non-motor disturbances. Pathologically, most motor features are the result of a dramatic loss of ventral tier mesencephalic dopaminergic neurons and thus dopamine content at their target sites. Although the exact etiology of the disease remains to be elucidated, it is thought to be multifactorial, with a critical role for environmental factors, such as pesticides, that may act on genetically predisposed individuals. Arising from consideration of the potential environmental triggers of PD, in vivo animal models of the disease utilizing these compounds are increasingly reported in the literature. Here, we review recent advances in the predominant models employing the insecticide Rotenone, the herbicide Paraquat and the fungicide Maneb, discuss their scientific merit and evaluate their relevance in the study of PD pathogenesis.

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder typified in part by motor disturbances, including tremor, rigidity, and bradykinesia [1], originating from loss of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). PD pathology is not restricted to the DA system, however, progressively involving noradrenergic and serotonergic neurons within the locus ceruleus and raphe nucleus, for example. Degeneration in these and other structures induces non-motor symptomatology including autonomic, mood, arousal and cognitive disturbances [2]. Additionally, predominant peripheral abnormalities (olfactory deficit or constipation) in PD are present early in the course, even before any pathological signs are visible in the central nervous system (CNS). The symptomatic features of familial and genetic forms of PD as compared to sporadic PD are distinguishable only by the occurrence of onset at young age (typically <40 years) in the former. On the cellular level, the pathological hallmark of PD is the presence of Lewy bodies - nuclear inclusions composed predominantly of the protein α-synuclein - found in both idiopathic and genetic forms of PD.

The etiology of PD has yet to be convincingly established. Prevalence increases exponentially from ages 65 to 90. While a fraction of PD occurrence is related to mutations in genes such as α-synuclein and parkin, over 90% of PD is likely linked to environmental causes, in part due to pesticide exposure [3]. Specifically, the herbicide Paraquat (PQ) [4] and the fungicide Maneb (MB: manganese ethylene-bis-dithiocarbamate) [5] have been associated with the incidence of PD. However, a causal role for pesticides in the etiology of PD has yet to be definitively established.

Section snippets

Current benchmark criteria for an adequate animal model of PD

Animal models can provide a critical link in establishing a causal role for environmental toxins such as pesticides in the etiology of PD by allowing studies that are impossible to perform in patients. Their usefulness critically resides in the translatability of biochemical findings to the human condition. Ultimately, however, animal models are limited by their failure to mimic perfectly the disease state, related to several potential shortcomings. (i) Inadequate characterization of the

Rotenone, PQ and MB: The compounds and their mechanisms of action

Rotenone, a chemical that belongs to the family of isoflavones naturally found in the roots and stems of several plants, is used as a broad-spectrum pesticide. Surprisingly, Rotenone can be used in organic food farming, based on its label as a natural product. Highly lipophilic, it easily crosses the BBB, and for cellular entry [1], does not depend on the dopamine transporter (DAT) – a transmembrane protein, residing in DA neurons, whose purpose is to clear DA from the synaptic cleft and which

Rotenone models of PD

Although the effects of Rotenone on the brain were first tested over 20 years ago, the model received the most attention when reproduced with a chronic mode of intravenous (i.v.) delivery [15]. Rotenone infusion via osmotic mini-pumps produced motor deficits reminiscent of several clinical features of PD – including hypokinesia, rigidity, hunched posture, unsteady movements and even resting tremor, the severity of which was associated with the extent of lesions. These motor impairments

What have we learned from the Rotenone model of PD?

As discussed, issues of variability, mortality, non-specificity both within and outside the CNS, and reproducibility across laboratories remain major challenges for the chronic Rotenone model of PD. In addition, there remain critical issues regarding the translatability of the model: does the Rotenone model truly recapitulate human PD? The first issue is route of exposure. Although it is possible that in human disease Rotenone, or other toxins, gains access to the CNS via the BBB, and that i.v.

PQ/MB: Synergistic effects of compounds and developmental vulnerability

An important aspect of human pesticide exposure is that it is usually to a number of agents, rather than a single one, and it occurs over time. In addition, there is the possibility that in utero exposure to toxins, such as lipopolysaccharide as part of bacterial vaginosis during pregnancy, predisposes to specific nigral DA cell loss [30]. Based on these premises, several studies have been initiated to explore this concept in animals. Concurrent exposure to PQ and MB in adult mice led to

What have we learned from the PQ/MB-induced animal model of PD?

The PQ/MB model has certainly been useful for its demonstration of potential synergistic effects of various environmental compounds in producing PD features in animals. The various experimental approaches utilized to develop this model have further provided support for a multi-hit hypothesis, which is interesting in that it replicates likely scenarios of intoxication in humans, although the routes of delivery remain, as for the Rotenone model, improbable occurrences and, contrary to the primary

Concluding remarks

Are pesticide models useful in the investigation of the etiopathogenesis of human PD? First, the specificity of the pathological lesions induced raises doubts about the adequacy of these models, perhaps especially so for Rotenone. Lack of specificity may indicate disparate biochemical mechanisms underlying the degenerative process, or may reflect a failure to replicate the correct exposure route or time-course. Specificity may derive from the route of spread of the pathological process within

Disclosure

None of the authors has conflict of interests to disclose.

Acknowledgments

The authors wish to acknowledge the support of the Fondation Canadienne pour l’Innovation and the Canadian Institute of Health Research to Francesca Cicchetti. Janelle Drouin-Ouellet was initially supported by a master's scholarship from Fonds de Recherche en Santé du Québec and subsequently by a Canada Frederick Banting and Charles Best doctoral scholarship. Robert Gross was supported in part by National Institutes of Health grants from the Emory Collaborative Center for Parkinson's Disease

References (66)

  • X. Li

    Neuroprotective effects of Polygonum multiflorum on nigrostriatal dopaminergic degeneration induced by paraquat and maneb in mice

    Pharmacol Biochem Behav

    (2005)
  • M. Thiruchelvam

    Developmental exposure to the pesticides paraquat and maneb and the Parkinson's disease phenotype

    Neurotoxicology

    (2002)
  • A.L. McCormack

    Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat

    Neurobiol Dis

    (2002)
  • F. Cicchetti

    Systemic exposure to paraquat and maneb models early Parkinson's disease in young adult rats

    Neurobiol Dis

    (2005)
  • N. De Gori

    Behavioural and electrocortical changes induced by paraquat after injection in specific areas of the brain of the rat

    Neuropharmacology

    (1988)
  • M. Alam

    The neurobehavioral changes induced by bilateral rotenone lesion in medial forebrain bundle of rats are reversed by L-DOPA

    Behav Brain Res

    (2004)
  • K.S. Saravanan

    Acute intranigral infusion of rotenone in rats causes progressive biochemical lesions in the striatum similar to Parkinson's disease

    Brain Res

    (2005)
  • K.M. Sindhu

    Behavioral differences in a rotenone-induced hemiparkinsonian rat model developed following intranigral or median forebrain bundle infusion

    Brain Res

    (2005)
  • K.M. Sindhu

    Rats with unilateral median forebrain bundle, but not striatal or nigral, lesions by the neurotoxins MPP+ or rotenone display differential sensitivity to amphetamine and apomorphine

    Pharmacol Biochem Behav

    (2006)
  • K.S. Saravanan

    L-deprenyl protects against rotenone-induced, oxidative stress-mediated dopaminergic neurodegeneration in rats

    Neurochem Int

    (2006)
  • F. Garcia-Garcia

    Sleep disturbances in the rotenone animal model of Parkinson disease

    Brain Res

    (2005)
  • E. Milusheva

    Increased sensitivity of striatal dopamine release to H2O2 upon chronic rotenone treatment

    Free Radic Biol Med

    (2005)
  • T.B. Sherer

    Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha–synuclein aggregation

    Exp Neurol

    (2003)
  • Z. Ling

    Rotenone potentiates dopamine neuron loss in animals exposed to lipopolysaccharide prenatally

    Exp Neurol

    (2004)
  • J. Huang

    A delivery strategy for rotenone microspheres in an animal model of Parkinson's disease

    Biomaterials

    (2006)
  • R. Betarbet

    Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin- proteasome system

    Neurobiol Dis

    (2006)
  • A.L. Phinney

    Enhanced sensitivity of dopaminergic neurons to rotenone- induced toxicity with aging

    Parkinsonism Relat Disord

    (2006)
  • A.B. Manning-Bog

    The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein

    J Biol Chem

    (2002)
  • J. Peng

    The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway

    J Biol Chem

    (2004)
  • K.R. Shepherd

    The potentiating effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on paraquat-induced neurochemical and behavioral changes in mice

    Pharmacol Biochem Behav

    (2006)
  • K. Shimizu

    Paraquat induces long-lasting dopamine overflow through the excitotoxic pathway in the striatum of freely moving rats

    Brain Res

    (2003)
  • K. Kuter

    Toxic influence of subchronic paraquat administration on dopaminergic neurons in rats

    Brain Res

    (2007)
  • S.Y. Lim

    Overview of the extranigral aspects of Parkinson disease

    Arch Neurol

    (2009)
  • Cited by (0)

    View full text