Neurotoxic Effects of Neonicotinoids on Mammals: What Is There beyond the Activation of Nicotinic Acetylcholine Receptors?—A Systematic Review

Abstract

Neonicotinoids are a class of insecticides that exert their effect through a specific action on neuronal nicotinic acetylcholine receptors (nAChRs). The success of these insecticides is due to this mechanism of action, since they act as potent agonists of insect nAChRs, presenting low affinity for vertebrate nAChRs, which reduces potential toxic risk and increases safety for non-target species. However, although neonicotinoids are considered safe, their presence in the environment could increase the risk of exposure and toxicity. On the other hand, although neonicotinoids have low affinity for mammalian nAChRs, the large quantity, variety, and ubiquity of these receptors, combined with its diversity of functions, raises the question of what effects these insecticides can produce in non-target species. In the present systematic review, we investigate the available evidence on the biochemical and behavioral effects of neonicotinoids on the mammalian nervous system. In general, exposure to neonicotinoids at an early age alters the correct neuronal development, with decreases in neurogenesis and alterations in migration, and induces neuroinflammation. In adulthood, neonicotinoids induce neurobehavioral toxicity, these effects being associated with their modulating action on nAChRs, with consequent neurochemical alterations. These alterations include decreased expression of nAChRs, modifications in acetylcholinesterase activity, and significant changes in the function of the nigrostriatal dopaminergic system. All these effects can lead to the activation of a series of intracellular signaling pathways that generate oxidative stress, neuroinflammation and, finally, neuronal death. Neonicotinoid-induced changes in nAChR function could be responsible for most of the effects observed in the different studies.

Statement on the active substance acetamiprid

“…Common symptoms of acute intoxication include nausea, vomiting, abdominal pain, dizziness, hypertension, tachycardia, eye irritation, dermatitis and oral mucosal lesions. Neurological symptoms consist of fatigue, headache, agitation, fasciculations, seizures, disorientation, drowsiness, decreased muscle tone and coma (Selvam and Srinivasan, 2019 ; Costas‐Ferreira and Faro, 2021 ). Furthermore, symptoms specific of stimulation of nicotinic acetylcholine receptors in the autonomic nervous system (e.g.…”

The neuroprotective effect of ascorbic acid against imidacloprid-induced neurotoxicity and the role of HO-1 in mice

“…Repeated exposure to IMI, in particular, has been suggested to cause a varying ratio of neuronal toxicity, including learning and memory impairment, neurodegenerative disorder development, axonal flow impairments, and diminished (BBB) blood-brain barrier integrity ( 4 , 5 ). The suppression of acetylcholinesterase activity in the hippocampus contributes to IMI toxicity ( 6 ). The activation of the oxidative stress pathways is one of the molecular routes by which IMI impacts behavior and cognition ( 7 ), indicating antioxidants as possible treatments for IMI-induced oxidative stress and its deleterious effects.…”

Next-generation effects of fetal and lactational exposure to the neonicotinoid pesticide clothianidin on the immune system and gut microbiota

“…However, NNs were found to affect nAChR-mediated neuroexcitatory action in mammals [ 27 ]. Reproductive toxicity [ 22 , 28 , 48 , 58 ], cognitive/emotional alterations, and developmental neurotoxicity of NNs [ 17 , 18 , 19 , 21 , 32 , 45 , 46 , 59 ] were later reported, in addition to a systematic review [ 9 ] of NNs. nAChR is expressed widely in the nervous system and skeletal muscle as well as in immune cells [ 26 ] and regulates antigen presentation, cytokine production, and anti-inflammatory responses [ 38 , 60 ].…”