Investigations on organophosphorus insecticideinduced neurotoxicity with Caenorhabditis elegans as a model system

The main objectives of the thesis were to (a) develop a model system employing
Caenorhabditis elegans for investigating the toxicity of selected organophosphorus
insecticides (OPI) using multiple end-points (b) investigate the biochemical mechanisms
involved in OPI toxicity in C. elegans (c) compare the pattern and extent of cholinesterase
inhibition induced by OPI in C. elegans and rat brain homogenates in vitro. Our
experimental approach involved behavioral, physiological and biochemical studies
employing C. elegans as a model system. Initially we screened three OPI dichlorvos
(DDVP), dimethoate (DM) and monocrotophos (MC) for their toxicity in N2 and (PC 72)
strain of C. elegans. Results revealed that DDVP was most toxic and all the three OPI
elicited Hsp response in the transgenic strain. A good correlation was evident between
feeding inhibition, AChE inhibition and Hsp induction in dichlorvos treated worms.
Dichlorvos at sublethal concentrations induced cessation in feeding and paralysis in
C. elegans (N2) and these worms also hyper contracted their nose muscles and showed
marked decrease in egg laying. The treated worms exhibited significant reduction in the
AChE activity and increase in ACh content. Worms exposed to both dichlorvos + atropine
showed inhibition in feeding as in worms treated with dichlorvos alone. Worms exposed to
dichlorvos + atropine showed a concentration related decrease in the extent of paralysis
while worms treated with dichlorvos + atropine followed by treatment with 2-PAM showed
100% recovery from AChE and feeding inhibition. Exposure to dichlorvos significantly
decreased the brood size, decreased life span, increased reactive oxygen species and
altered antioxidant status in the worms. The results of the qualitative analysis of the fatty
acid methyl esters derived from lipids of the worms exposed to dichlorvos showed
variations in the fatty acids. Exposure to dichlorvos resulted in significant accumulation of
lipofuscin throughout body of the worm. Comparative kinetic studies with AChE of rat brain
homogenate and C. elegans homogenate revealed inhibition of AChE to be of irreversible
in nature in both the systems. AChE of C. elegans was more sensitive to inhibition by
dichlorvos. A similar pattern of inhibition was also observed with carboxylesterase of
C. elegans. In conclusion, data obtained from the present series of investigations support
the premise that the nematode, C. elegans is a good model organism for studying the
neurotoxicity of OPI, since this organism offers several simple and easily measurable
physiological and biochemical endpoints for studying the mechanistic toxicity of the OPI.