Abstract
Neonicotinoid insecticides are nicotine-derived molecules which exert acute neurotoxic effects over the insect central nervous system by activating nicotinic acetylcholine receptors (nAChRs). However, these receptors are also present in the mammalian central and peripheral nervous system, where the effects of neonicotinoids are faintly known. In mammals, cholinergic synapses are crucial for the control of vascular tone, blood pressure and skeletal muscle contraction. We therefore hypothesized that neonicotinoids could affect cholinergic networks in mammals and sought to highlight functional consequences of acute intoxication in rats with sub-lethal concentrations of the highly used acetamiprid (ACE) and clothianidin (CLO). In this view, we characterized their electrophysiological effects on rat 34 nAChRs, knowing that it is predominantly expressed in ganglia of the vegetative nervous system and the adrenal medulla, which initiates catecholamine secretion. Both molecules exhibited a weak agonist effect on 34 receptors. Accordingly, their influence on epinephrine secretion from rat adrenal glands was also weak at 100 μM, but it was stronger at 500 μM. Challenging ACE or CLO together with nicotine (NIC) ended up with paradoxical effects on secretion. In addition, we measured the rat arterial blood pressure (ABP) in vivo by arterial catheterization. As expected, NIC induced a significant increase in ABP. ACE and CLO did not affect the ABP in the same conditions. However, simultaneous exposure of rats to both NIC and ACE/CLO promoted an increase of ABP and induced a biphasic response. Modeling the interaction of ACE or CLO on 34 nAChR is consistent with a binding site located in the agonist pocket of the receptor. We present a transversal experimental approach of mammal intoxication with neonicotinoids at different scales, including in vitro, ex vivo, in vivo and in silico. It paves the way of the acute and chronic toxicity for this class of insecticides on mammalian organisms.
Highlights
Since their introduction on the agrochemical market three decades ago, neonicotinoid insecticides are applied on a wide range of crops in 120 countries thanks to: (i) their efficacy against many pest insects; and (ii) their predicted lower mammalian toxicity [1,2,3,4]
We evaluated the acute effects of both insecticides on rat nicotinic acetylcholine receptors (nAChRs) currents, epinephrine secretion from adrenal medulla and rat systemic blood pressure
Xenopus oocytes were injected with α3 and β4 subunit RNAs (1:1) to express the functional corresponding receptors. They were challenged with increasing concentrations of each ligand (Figure 2A)
Summary
Since their introduction on the agrochemical market three decades ago, neonicotinoid insecticides are applied on a wide range of crops in 120 countries thanks to: (i) their efficacy against many pest insects; and (ii) their predicted lower mammalian toxicity [1,2,3,4]. Their application in seed-coating due to their systemic properties shifted production and sales towards large scale and led to them being an obvious choice for field crops such as maize, cotton and soybean throughout the world [2,5]. Acute intoxications with neonicotinoids are correlated with alteration of cardiovascular parameters such as arterial blood pressure (ABP) and heart rate [31,32]
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