Nicotine-Like Effects of the Neonicotinoid Insecticides Acetamiprid and Imidacloprid on Cerebellar Neurons from Neonatal Rats

Abstract

BackgroundAcetamiprid (ACE) and imidacloprid (IMI) belong to a new, widely used class of pesticide, the neonicotinoids. With similar chemical structures to nicotine, neonicotinoids also share agonist activity at nicotinic acetylcholine receptors (nAChRs). Although their toxicities against insects are well established, their precise effects on mammalian nAChRs remain to be elucidated. Because of the importance of nAChRs for mammalian brain function, especially brain development, detailed investigation of the neonicotinoids is needed to protect the health of human children. We aimed to determine the effects of neonicotinoids on the nAChRs of developing mammalian neurons and compare their effects with nicotine, a neurotoxin of brain development.Methodology/Principal FindingsPrimary cultures of cerebellar neurons from neonatal rats allow for examinations of the developmental neurotoxicity of chemicals because the various stages of neurodevelopment—including proliferation, migration, differentiation, and morphological and functional maturation—can be observed in vitro. Using these cultures, an excitatory Ca2+-influx assay was employed as an indicator of neural physiological activity. Significant excitatory Ca2+ influxes were evoked by ACE, IMI, and nicotine at concentrations greater than 1 µM in small neurons in cerebellar cultures that expressed the mRNA of the α3, α4, and α7 nAChR subunits. The firing patterns, proportion of excited neurons, and peak excitatory Ca2+ influxes induced by ACE and IMI showed differences from those induced by nicotine. However, ACE and IMI had greater effects on mammalian neurons than those previously reported in binding assay studies. Furthermore, the effects of the neonicotinoids were significantly inhibited by the nAChR antagonists mecamylamine, α-bungarotoxin, and dihydro-β-erythroidine.Conclusions/SignificanceThis study is the first to show that ACE, IMI, and nicotine exert similar excitatory effects on mammalian nAChRs at concentrations greater than 1 µM. Therefore, the neonicotinoids may adversely affect human health, especially the developing brain.

Imidacloprid, a neonicotinoid insecticide, induces insulin resistance

“…One potential mechanism of imidacloprid may be impairing insulin receptor substrate-1 (IRS-1) activation via calcium-dependent mechanisms. This is based on the fact that [i] imidacloprid is reported to increase oxidative stress, [ii] it increases intracellular calcium similar to other agonists of nicotinic acetylcholine receptors, and [iii] both of these effects are known to be associated with insulin resistance by impairing IRS-1 activation (Draznin, 1993;Zemel et al, 1995;Li et al, 2000;Kimura-Kuroda et al, 2012;Cui et al, 2013). It is further supported in a report by Tomizawa and Casida (2002) that desnitro-imidacloprid, an imidacloprid metabolite, activates nicotinic receptors via an intracellular calcium dependent mechanism (Tomizawa and Casida, 2002).…”

Selection of phage-displayed peptides for the detection of imidacloprid in water and soil

“…In animals, exposure to a high dose of imidacloprid may be associated with degenerative changes in thymus, bone marrow, and pancreas [1]. A study conducted in rats suggests that imidacloprid may adversely affect brain development [3]. Recent research suggests that widespread agricultural use of imidacloprid and other pesticides may be contributing to honey bee colony collapse disorder, the decline of honey bee colonies in Europe and North America observed recently [4,5].…”

Sex-, tissue-, and exposure duration-dependent effects of imidacloprid modulated by piperonyl butoxide and menadione in rats. Part I: oxidative and neurotoxic potentials

“…In a study by Abu-Donia et al (13), IMI increased AChE activity in newborn Sprague-Dawley rats via maternal exposure, and the authors suggested that this induction occurred due to apoptotic events via cellular Ca 2+ -uptake. In another study (48), neonicotinoid insecticides acetamiprid and IMI induced cellular Ca 2+ uptake via α 7 nAChRs in Sprague-Dawley rat cerebellar cell line, and Ca 2+ uptake was inhibited by α-bungarotoxin, a specific α 7 nAChR antagonist. Yeboah et al (49) suggest that α 7 nAChRs, which are constitutively expressed in the kidney of SpragueDawley rats, are highly permeable to Ca 2+ ions.…”

“…Duzguner and Erdogan (16) believe that higher plasma Ca 2+ concentrations could be responsible for the induction of ROS-generating enzymes xanthine oxidase and myeloperoxidase in the liver and brain of female Wistar rats treated with IMI intravenously. Kimura-Kuroda et al (48) have suggested that mammalian ACh receptors are affected by IMI exposure because of conformational changes of the receptor induced by ACh. We therefore believe that higher tChE activity that lowers ACh-assisted IMIbinding may be an adaptive response to oxidative stress induced by elevated Ca 2+ uptake.…”