The Perplexing Paradox of Paraquat: The Case for Host-Based Susceptibility and Postulated Neurodegenerative Effects

Jones, Byron C.; Huang, Xuemei; Mailman, Richard B.; Lu, Lu; Williams, Robert W.

doi:10.1002/jbt.21552

Cited by 19 publications

(14 citation statements)

References 64 publications

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“…Paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride), a non-selective herbicide, leads to severe multiple organ damage involving circulatory and respiratory systems [1][2][3]. Both acute exposure and prolonged exposure of the prooxidant paraquat result in the depletion of dopaminergic neurons in the midbrain, en route to apoptotic cell death and development of Parkinson's disease, in a manner reminiscent of the dopaminergic neurotoxin MPP?…”

Section: Introductionmentioning

confidence: 99%

Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction

Wang

Zheng

et al. 2015

Cardiovasc Toxicol

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Paraquat (1,1'-dim ethyl-4-4'-bipyridinium dichloride), a highly toxic quaternary ammonium herbicide widely used in agriculture, exerts potent toxic prooxidant effects resulting in multi-organ failure including the lung and heart although the underlying mechanism remains elusive. Recent evidence suggests possible involvement of endothelin system in paraquat-induced acute lung injury. This study was designed to examine the role of endothelin receptor A (ETA) in paraquat-induced cardiac contractile and mitochondrial injury. Wild-type (WT) and cardiac-specific ETA receptor knockout mice were challenged to paraquat (45 mg/kg, i.p.) for 48 h prior to the assessment of echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties, as well as apoptosis and mitochondrial damage. Levels of the mitochondrial proteinsfor biogenesis and oxidative phosphorylation including UCP2, HSP90 and PGC1α were evaluated. Our results revealed that paraquat elicited cardiac enlargement, mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic and end-diastolic diameters as well as reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca(2+) handling, overt apoptosis and mitochondrial damage. ETA receptor knockout itself failed to affect myocardial function, apoptosis, mitochondrial integrity and mitochondrial protein expression. However, ETA receptor knockout ablated or significantly attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) defect, apoptosis and mitochondrial damage. Taken together, these findings revealed that endothelin system in particular the ETA receptor may be involved in paraquat-induced toxic myocardial contractile anomalies possibly related to apoptosis and mitochondrial damage.

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Section: Introductionmentioning

confidence: 99%

Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction

Wang

Zheng

et al. 2015

Cardiovasc Toxicol

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“…[38] Thus, gene–environment interactions may be crucial for resolving heterogeneity of results reported in human pesticide studies.…”

Section: Introductionmentioning

confidence: 99%

Of Pesticides and Men: a California Story of Genes and Environment in Parkinson’s Disease

Ritz

Paul

Bronstein³

2016

Curr Envir Health Rpt

115

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At the start of the post-genomics era, most Parkinson’s disease (PD) etiology cannot be explained by our knowledge of genetic or environmental factors alone. For more than a decade, we have explored gene-environment (GxE) interactions possibly responsible for the heterogeneity of genetic as well as environmental results across populations. We developed three pesticide exposure measures (ambient due to agricultural applications, home and garden use, occupational use) in a large population-based case-control study of incident PD in central California. Specifically, we assessed interactions with genes responsible for pesticide metabolism (PON1); transport across the blood brain barrier (ABCB1); pesticides interfering with or depending on dopamine transporter activity (DAT) and dopamine metabolism (ALDH2); impacting mitochondrial function via oxidative/nitrosative stress (NOS1) or proteasome inhibition (SKP1); and contributing to immune dysregulation (HLA-DR). These studies established some specificity for pesticides’ neurodegenerative actions, contributed biologic plausibility to epidemiologic findings, and identified genetically susceptible populations.

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“…The herbicide paraquat was used to generate oxidative stress, and the proteasome inhibitor MG132 was used to model proteotoxic stress. Paraquat exposure is a risk factor for Parkinson's disease and has been used by many investigators to model this condition in animals (Tanner et al, ; Blesa et al, ; Jones et al, ). Oral paraquat administration has been shown to reduce ATP generation and increase oxidative stress in the hippocampus in vivo, and to elicit neurological impairments in the Morris water maze test, a behavioral assay closely associated with hippocampal integrity (Chen et al, ).…”

Section: Introductionmentioning

confidence: 99%

Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual‐hit hypothesis of neurodegeneration

et al. 2016

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The dual hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, we developed a relatively high-throughput dual hit model of stress synergy in primary hippocampal neurons. In order to increase the rigor of our study and strengthen our interpretations, we employed three independent, unbiased viability assays at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48h. MG132 and paraquat only elicited additive effects 24h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. Our findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, we present a new model of hippocampal vulnerability in which to test therapies, because neuroprotective treatments that are effective against severe, synergistic stress are more likely to succeed in the clinic.

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The Perplexing Paradox of Paraquat: The Case for Host-Based Susceptibility and Postulated Neurodegenerative Effects

Cited by 19 publications

References 64 publications

Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction

Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction

Of Pesticides and Men: a California Story of Genes and Environment in Parkinson’s Disease

Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual‐hit hypothesis of neurodegeneration

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