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NRF2 Signaling as a Protective Measure Against Organophosphate Insult (Abstract ID: 268061)
Abstract   Peer reviewed

NRF2 Signaling as a Protective Measure Against Organophosphate Insult (Abstract ID: 268061)

Sarah Preston, Michael Garcia-Mares, Anna Bartman, David Martin and Jonathan Doorn
The Journal of pharmacology and experimental therapeutics, Vol.393(5 Supplement), 104850
05/2026
DOI: 10.1016/j.jpet.2026.104850

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Abstract

Human exposure to organophosphate (OP) pesticides such as chlorpyrifos (CPF) occurs in agricultural, occupational and military settings worldwide. OP pesticides, such as CPF, can lead to cholinergic crisis via acetylcholinesterase (AChE) inhibition and accumulation of the neurotransmitter acetylcholine. Downstream effects of OP intoxication include seizures and production of reactive oxygen species (ROS), likely due to glutamate (Glu) excitotoxicity. In addition to cholinergic crisis as a toxic endpoint, there is evidence that CPF exposure correlates with additional adverse outcomes, including depression and neurodegenerative diseases. Molecular mechanisms for such conditions are elusive and may involve targets other than AChE. Metabolism of CPF is critical to cholinergic toxicity as it can yield either bioactivation to the toxic chlorpyrifos-oxon (CPO) or detoxication via glutathione (GSH)/glutathione-S-transferase (GST; dechlorination) or hydrolysis of CPO via the esterases, paraoxonase 1 (PON1) and carboxylesterase 1 and 2 (CES), with CES serving as a “sink” to protect AChE. Interestingly, several of the enzymes critical to the metabolism of CPF are under the control of the transcription factor NRF2, including: GSH/GST, PON1 and CES. Activation of NRF2 is known to induce expression of numerous antioxidant enzymes to mitigate aberrant ROS production. The goal of our work is to explore the role of NRF2 modulation in mitigating risk of toxicity and adverse effects to CPF/OP agents and the therapeutic potential to target this pathway to mitigate CPF/OP toxicity. Our central hypothesis is that NRF2 activation alters CPF disposition and potential for toxicity via induction of enzymes that modulate OP metabolism and cellular damage, thus providing protection against OP insult. In our preliminary work, we have found that pretreatment of PC12 cells with potent activators of NRF2 provides protection against acute CPF and CPO treatment at sub-micromolar concentrations. In addition, we have shown that NRF2 activators induce the expression of both CES and PON1 in HepG2 cells (liver) as well as increasing general intracellular esterase activity. Finally, we found that NRF2 activation appears to protect HepG2 cells and reduce overall ROS production upon insult with CPF. These data indicate the potential for NRF2 as a target to mitigate short- and long-term OP/CPF toxicity.

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