Abstract
Recent studies suggest that N, N-diethyl-meta-toluamide (DEET) is an acetylcholinesterase inhibitor and that this action may result in neurotoxicity and pose a risk to humans from its use as an insect repellent. We investigated the mode of action of DEET neurotoxicity in order to define the specific neuronal targets related to its acute toxicity in insects and mammals. Although toxic to mosquitoes (LD50 ca. 1.5 µg/mg), DEET was a poor acetylcholinesterase inhibitor (<10% inhibition), even at a concentration of 10 mM. IC50 values for DEET against Drosophila melanogaster, Musca domestica, and human acetylcholinesterases were 6–12 mM. Neurophysiological recordings showed that DEET had excitatory effects on the housefly larval central nervous system (EC50: 120 µM), but was over 300-fold less potent than propoxur, a standard anticholinesterase insecticide. Phentolamine, an octopamine receptor antagonist, completely blocked the central neuroexcitation by DEET and octopamine, but was essentially ineffective against hyperexcitation by propoxur and 4-aminopyridine, a potassium channel blocker. DEET was found to illuminate the firefly light organ, a tissue utilizing octopamine as the principal neurotransmitter. Additionally, DEET was shown to increase internal free calcium via the octopamine receptors of Sf21 cells, an effect blocked by phentolamine. DEET also blocked Na+ and K+ channels in patch clamped rat cortical neurons, with IC50 values in the micromolar range. These findings suggest DEET is likely targeting octopaminergic synapses to induce neuroexcitation and toxicity in insects, while acetylcholinesterase in both insects and mammals has low (mM) sensitivity to DEET. The ion channel blocking action of DEET in neurons may contribute to the numbness experienced after inadvertent application to the lips or mouth of humans.
Highlights
The insect repellent N, N-diethyl-meta-toluamide (DEET) is used more often than any other mosquito repellent, with over 200 million users, worldwide [1]
Homogenates were used to prepare Aedes aegypti AChE (AeAChE) from mosquitoes provided by the CMAVE, USDAARS, Gainesville, FL, USA; Musca domestica AChE (MdAChE) from flies cultured in the Department of Entomology and Nematology, Medical Entomology Laboratory, University of Florida, Gainesville, FL, USA); and Drosophila melanogaster AChE (DmAChE) from flies (Oregon-R strain) cultured in the Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA
No significant differences were observed between mosquito species, but some statistical difference was observed between the G3 and AKRON strains, indicating little species variability and cross-resistance to DEET in the AKRON strain of An. gambiae that carries multiple resistance mechanisms [14,15]
Summary
The insect repellent N, N-diethyl-meta-toluamide (DEET) is used more often than any other mosquito repellent, with over 200 million users, worldwide [1]. Because there is deliberate and widespread human exposure to DEET from its use as an insect repellent, questions have arisen regarding its toxicological profile and risk to humans. A recent study [2] suggested the toxic action of DEET may be due to an anticholinesterase effect, with implications for human safety. Large oral doses (blood concentration of 1 mmol/liter) of DEET lead to nausea, vomiting, bradycardia, and seizures [3,4], as well as cardiotoxicity [5] in exposed humans. Contact exposure to DEET has the potential for dermal effects, as it can lead to numbness and redness of the affected area [6]. The numbing sensation appears similar to that observed with local anesthetics, such as lidocaine, suggesting DEET might be acting on neuronal ion channels to yield an anesthetic-like effect
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