Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson's disease.

Abstract

Parkinson's disease (PD) has been linked to mitochondrial dysfunction and pesticide exposure. The pesticide rotenone (ROT) inhibits complex I and reproduces features of PD in animal models, suggesting that environmental agents that inhibit complex I may contribute to PD. We have previously demonstrated that ROT toxicity is dependent upon complex I inhibition and that oxidative stress is the primary mechanism of toxicity. In this study, we examined the in vitro toxicity and mechanism of action of several putative complex I inhibitors that are commonly used as pesticides. The rank order of toxicity of pesticides to neuroblastoma cells was pyridaben > rotenone > fenpyroximate > fenazaquin > tebunfenpyrad. A similar order of potency was observed for reduction of ATP levels and competition for (3)H-dihydrorotenone (DHR) binding to complex I, with the exception of pyridaben (PYR). Neuroblastoma cells stably expressing the ROT-insensitive NADH dehydrogenase of Saccharomyces cerevisiae (NDI1) were resistant to these pesticides, demonstrating the requirement of complex I inhibition for toxicity. We further found that PYR was a more potent inhibitor of mitochondrial respiration and caused more oxidative damage than ROT. The oxidative damage could be attenuated by NDI1 or by the antioxidants alpha-tocopherol and coenzyme Q(10). PYR was also highly toxic to midbrain organotypic slices. These data demonstrate that, in addition to ROT, several commercially used pesticides directly inhibit complex I, cause oxidative damage, and suggest that further study is warranted into environmental agents that inhibit complex I for their potential role in PD.

• Authors: Todd B Sherer, Jason R Richardson, Claudia M Testa, Byoung Boo Seo, Alexander V Panov, Takao Yagi, Akemi Matsuno-Yagi, Gary W Miller, J Timothy Greenamyre
• Journal: Journal of neurochemistry (J Neurochem) Vol. 100 Issue 6 Pg. 1469-79 (Mar 2007) ISSN: 0022-3042 [Print] England
• PMID: 17241123 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antioxidants
• Ndi1 protein, S cerevisiae
• Pesticides
• Saccharomyces cerevisiae Proteins
• Rotenone
• 1',2'-dihydrorotenone
• Adenosine Triphosphate
• Tyrosine 3-Monooxygenase
• NADH Dehydrogenase
• Electron Transport Complex I
• alpha-Tocopherol

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Animals, Newborn
• Antioxidants (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Interactions
• Electron Transport Complex I (metabolism)
• Humans
• In Vitro Techniques
• Male
• Mesencephalon (ultrastructure)
• Mitochondria (drug effects)
• NADH Dehydrogenase (pharmacology)
• Neuroblastoma
• Pesticides (chemistry, toxicity)
• Protein Carbonylation (drug effects)
• Rats
• Rats, Inbred Lew
• Rotenone (analogs & derivatives, pharmacokinetics)
• Saccharomyces cerevisiae Proteins (pharmacology)
• Tyrosine 3-Monooxygenase (metabolism)
• alpha-Tocopherol (pharmacology)