Abstract
Organophosphorus pesticides (OPs) are a chemically diverse class of insecticides that inhibit acetylcholinesterase (AChE). Many OPs require bioactivation to their active oxon form via cytochrome P450 to effectively inhibit AChE. OP toxicity can be mitigated by detoxification reactions performed by carboxylesterase and paraoxonase. The relative extent of bioactivation to detoxification varies among individuals and between species, leading to differential susceptibility to OP toxicity. Because of these species differences, it is imperative to characterize OP metabolism in model systems used to assess OP toxicity. We have shown that the asexual freshwater planarian Dugesia japonica is a suitable model to assess OP neurotoxicity and developmental neurotoxicity via rapid, automated testing of adult and developing organisms in parallel using morphological and behavioral endpoints. D. japonica has two cholinesterase enzymes with intermediate properties between AChE and butyrylcholinesterase that are sensitive to OP inhibition. Here, we demonstrate that D. japonica contains the major OP metabolic machinery to be a relevant model for OP neurotoxicity studies. Adult and regenerating D. japonica can bioactivate chlorpyrifos and diazinon into their respective oxons. Significant AChE inhibition was only observed after in vivo metabolic activation but not when the parent OPs were directly added to planarian homogenate using the same concentrations and timing. Using biochemical assays, we found that D. japonica has both carboxylesterase (24 nmol/(min*mg protein)) and paraoxonase (60 pmol/(min*mg protein)) activity. We show that planarian carboxylesterase activity is distinct from cholinesterase activity using benzil and tacrine. These results further support the use of D. japonica for OP toxicity studies.
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Acknowledgements
We thank Veronica Bochenek for help with experiments, Dr. Alexander Baugh for use of his plate reader, and Kevin Bayingana and Yeh Seo Jung for help with planarian care. Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number R15ES031354 (to E.M.S.C). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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EMC is the founder of Inveritek, LLC, which offers planarian HTS commercially. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Ireland, D., Rabeler, C., Gong, T. et al. Bioactivation and detoxification of organophosphorus pesticides in freshwater planarians shares similarities with humans. Arch Toxicol 96, 3233–3243 (2022). https://doi.org/10.1007/s00204-022-03387-y
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DOI: https://doi.org/10.1007/s00204-022-03387-y