Paraquat-Induced Ultrastructural Changes and DNA Damage in the Nervous System Is Mediated via Oxidative-Stress-Induced Cytotoxicity in Drosophila melanogaster

Abstract

Paraquat (PQ), a quaternary nitrogen herbicide, is commonly used as a pesticide despite of its high toxicity. Our study evaluated the effect of subchronic PQ exposure on the neuropathology, genotoxicity, and antioxidant activity on the nervous tissue of Drosophila melanogaster. We also explored the behavioral effect of PQ on D. melanogaster. Furthermore, we attempted to validate the mechanism by evaluating PQ-induced cytotoxicity on the D-Mel2 cell lines. The fruit fly D. melanogaster serves as a feasible model to understand the mechanism of neurodegenerative diseases. Our study shows a dose-dependent PQ-induced neuropathology in the brain tissue of D. melanogaster as evidenced by hematoxylin and eosin staining, silver nitrate staining, and transmission electron microscopy. Electron microscopic study of D. melanogaster brain tissue exhibited vacuolar degeneration and significant neuronal damage across the nervous tissue structure in comparison with control. Our findings also indicate a dose-dependent locomotor impairment and decreased superoxide dismutase (SOD) specific activity in PQ-treated D. melanogaster. These PQ-induced neuroanatomical changes and decreased SOD specific activity showed a significant association with oxidative DNA damage as observed by alkaline comet assay. Additionally, we show, for the first time, a dose-dependent PQ-induced cytotoxicity in the D-Mel2 cells suggesting loss of neuronal cell viability via cytotoxic damage. Our data suggest that PQ exposure results in neurodegeneration in D. melanogaster and that fruit fly is a suitable in vivo model for correlating the neuroanatomical changes with neurotoxic damages to nervous system.

RNASET2 is required for ROS propagation during oxidative stress-mediated cell death

“…To extend our findings, we turned to the model organism Drosophila melanogaster, which is sensitive to inducers of oxidative stress. 34 Drosophila expresses one RNASET2 homolog, RNase X25, which is induced by ROS and promotes cell death when overexpressed. 28,35 Constitutive, whole body knockdown of RNase X25 did not result in viable progeny, underscoring the importance of RNase X25 in general housekeeping functions.…”

Protective effects of melatonin-loaded lipid-core nanocapsules on paraquat-induced cytotoxicity and genotoxicity in a pulmonary cell line

“…Furthermore, PQ-induced ROS production causes DNA damage: single-and double-strand DNA breaks, base modifications, deoxyribose fragmentation, DNA -protein cross-links, and abasic sites [10,11]. Recently, a significant increase in comet tail-length in PQ-treated Drosophlia melanogaster and decreased superoxide dismutase activity have been reported, suggesting a correlation of oxidative stress and DNA damage in vivo [12]. The comet (single-cell gel electrophoresis) assay is widely used in genotoxicity testing to evaluate DNA-damage.…”

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

“…Overall neurodegeneration in the substantia nigra (Manning-Bog et al, 2003;McCormack et al, 2005;Purisai et al, 2007), striatum (Rappold et al, 2011), locus coeruleus (Fernagut et al, 2007) and in brains of fruit flies (Mehdi & Qamar, 2013) has also been reported. Lastly, locomotor deficits have been observed in paraquat-exposed rodents (Choi et al, 2010b;Fredriksson et al, 1993;Liou et al, 1996) and fruit flies (Mehdi & Qamar, 2013).…”

“…The most-studied key downstream events of paraquat-induced neurotoxicity are apoptotic cell death observed from cell lines (Garcia-Garcia et al, 2013;Gonzalez-Polo et al, 2009;Gonzalez-Polo et al, 2007;Klintworth et al, 2007;McCarthy et al, 2004;Mehdi & Qamar, 2013;Peng et al, 2005;Ramachandiran et al, 2007;Rappold et al, 2011;Richardson et al, 2005;Wu et al, 2005;Yang & Tiffany-Castiglioni, 2005) and dopaminergic neurodegeneration observed from primary neurons (Choi et al, 2010b;Klintworth et al, 2007;Peng et al, 2005;Wu et al, 2005). The activation of MAP kinases JNK in neurons and ERK1/2 in microglia has been demonstrated to be an upstream event of paraquat-induced apoptosis (Choi et al, 2010b;Klintworth et al, 2007;Peng et al, 2005;Ramachandiran et al, 2007).…”

“…The frequently-reported intermediate key events observed in vivo include oxidative stress including lipid peroxidation (McCormack et al, 2005;Mehdi & Qamar, 2013;Purisai et al, 2007;Tawara et al, 1996), accumulation of alpha-synuclein (Fernagut et al, 2007;Manning-Bog et al, 2002;ManningBog et al;, reduction in striatal dopamine levels (Fredriksson et al, 1993;Rappold et al, 2011;Tawara et al, 1996), altered dopamine metabolism (Fredriksson et al, 1993;Liou et al, 1996;McCormack et al, 2002;Ossowska et al, 2005) and activated microglia/astrocytes (Liou et al, 1996;McCormack et al, 2002;Purisai et al, 2007). One study reported no reduction in striatal dopamine levels after i.p.…”