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The Pesticide Metabolites Paraoxon and Malaoxon Induce Cellular Death by Different Mechanisms in Cultured Human
Daniel J Angelini1, Robert A Moyer2, Stephanie Cole3
1National Research Council, Research Associates Program, Washington DC, USA Excet Inc, Springfield, VA, USA daniel.j.angelini2.ctr@mail.mil.
Abstract:
Organophosphorus (OP) pesticides are known to induce pulmonary toxicity in both humans and experimental animals. To elucidate the mechanism of OP-induced cytotoxicity, we examined the effects of parathion and malathion and their respective metabolites, paraoxon and malaoxon, on primary cultured human large and small airway cells. Exposure to paraoxon and malaoxon produced a dose-dependent increase in cytotoxicity following a 24-hour exposure, while treatment with parathion or malathion produced no effects at clinically relevant concentrations. Exposure to paraoxon-induced caspase activation, but malaoxon failed to induce this response. Since caspases have a major role in the regulation of apoptosis and cell death, we evaluated OP-induced cell death in the presence of a caspase inhibitor. Pharmacological caspase inhibition protected against paraoxon-induced cell death but not malaoxon-induced cell death. These data suggest that caspase activation is a key signaling element in paraoxon-induced cell death, but not malaoxon-induced cellular death in the pulmonary epithelium.
Insights
Organophosphorus pesticides cause lung damage. Their metabolites, paraoxon and malaoxon, induce dose-dependent cytotoxicity in airway cells, with paraoxon triggering cell death via caspase activation.
Area of Science:
- Toxicology
- Pulmonary Medicine
- Cell Biology
Background:
- Organophosphorus (OP) pesticides are recognized for their potential to cause pulmonary toxicity in humans and animals.
- Understanding the precise mechanisms underlying OP-induced cytotoxicity is crucial for assessing risks and developing interventions.
Purpose of the Study:
- To investigate the cytotoxic effects of parathion and malathion, along with their active metabolites paraoxon and malaoxon, on human airway cells.
- To elucidate the role of caspase activation in OP-induced pulmonary cell death.
Main Methods:
- Primary human large and small airway cells were exposed to parathion, malathion, paraoxon, and malaoxon.
- Cytotoxicity was assessed after 24-hour exposure.
- Caspase activation and cell death were evaluated in the presence and absence of a caspase inhibitor.
Main Results:
- Paraoxon and malaoxon induced a dose-dependent increase in cytotoxicity, whereas parent compounds parathion and malathion showed no significant effects at relevant concentrations.
- Paraoxon exposure led to caspase activation, a response not observed with malaoxon.
- Caspase inhibition protected cells from paraoxon-induced death but not from malaoxon-induced death.
Conclusions:
- Caspase activation is a critical mediator of paraoxon-induced cell death in pulmonary epithelial cells.
- Malaoxon-induced cytotoxicity in these cells does not appear to involve caspase-dependent pathways.
- These findings differentiate the mechanisms of toxicity for different OP metabolites in the pulmonary system.
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