Various mechanisms have been advanced for bee toxicity resulting in declining numbers.This review provides evidence for a connection between use of neonicotinoids and decrease in bee population.Most attention is given to imidacloprid.The theory involves electron transfer, production of reactive oxygen species and oxidative stress. Calculations show that electron affinity is favorable for the protonated form of the pesticide.Also, rapid decomposition occurs to NO2, which may be the actual toxic material.
Keywords:Bee Toxicity; Electron Affinity; Reactive Oxygen Species; Oxidative Stress; Neonicotinoids; Imidacloprid; Thiamethoxam; Clothianidin; Nitrogen dioxide
There has been much controversy involving a connection between use of neonicotinoids and declining bee populations. The pesticides receiving the most attention isImidacloprid (IMD) (Figure 1), thiamethoxam (Figure1), and its breakdown product clothianidin (Figure 1). The focus of our attention is on IMD. A number of foreign countries have banned this class, and a ban is under consideration by the United States. As expected, some pesticides producers have challenged the bans, whereas others have voluntarily terminated use. In recent years, there has been increasing evidence for bee toxicity from this pesticide class[1-7]
“The preponderance of bioactive substances, usually as the metabolites, incorporatesElectron Transfer (ET) functionalities. We believe these play an important role in physiological responses. The main group include quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced hydroxylamine and nitroso derivatives), and conjugated imines (or iminium species). Resultant redox cycling is illustrated in Scheme 1. In vivo redox cycling with oxygen can occur, giving rise to Oxidative Stress (OS) through generation of Reactive Oxygen Species (ROS), such as hydrogen peroxide, hydroperoxides, alkyl peroxides, and diverse radicals (hydroxyl, alkoxyl, hydroperoxyl, and superoxide) (Scheme 2)”.
In some cases, ET results in involvement with normal electrical effects (e.g., in respiration of neurochemistry). Generally, active entities possessing ET groups display reduction potentials in the physiologically responsive range, (i.e., more positive than about -0.5 V). Hence, ET in vivo can occur resulting in production of ROS which can be beneficial in cell signaling at low concentrations, but produce toxic results at high levels. Electron donors consist of phenols, N-heterocycles or disulfides in proteins which produce relatively stable radical cations. ET, ROS and OS have been increasingly implicated in the mode of action of drugs and toxins, (e.g., antiinfective agents , anticancer drugs, , carcinogens, reproductive toxins,nephrotoxins, hepatotoxins, cardiovascular toxins, nerve toxins , mitochondrial toxins,abused drugs , pulmonary toxins, ototoxins and various other categories .
There is a plethora of experimental evidence supporting the ET-ROS theoretical framework. This evidence includes generation of the common ROS, lipid peroxidation, degradation products of oxidation, depletion of AOs, effect of exogenous AOs, and DNA oxidation and cleavage products, as well as electrochemical data. This comprehensive, unifying mechanism is consistent with the frequent observation that many ET substances display a variety of activities (e.g., multiple-drug properties), as well as toxic effects.
It is important to recognize that mode of action in the biodomain is often multifaceted. In addition to the ET-ROS-OS approach, other aspects may pertain, such as, enzyme inhibition, allosteric effects, receptor binding, metabolism and physical factors.A specific example, involves protein binding by quinones in which protein and nucleophiles, such as amino or thiol, effect conjugate addition”.
We calculated the Electron Affinity (EA) of imidacloprid using density functional calculations to determine, initially, the likelihood that the molecule could serve as an ET agent. The calculations were carried out using the B3LYP method and Dunning’s augmented cc-pVDZ basis set, running under Gaussian 09 on a Linux cluster. Geometries for the negative anion, neutral molecule, and protonated cation were optimized individually to determine the EA of the neutral and protonated forms of the molecule. The EA for the neutral molecule was shown to be 0.82 eV, and the EA for the protonated cation was shown to be 6.70 eV.
The results from the calculations are listed in Table 1. The protonated form of the molecule was calculated with a multiplicity of 1, and the neutral form with a multiplicity of 2 to determine the electron affinity of the protonated molecule.
The value for the EA of the neutral molecule is greater than those of notable ET functionalities, such as quinones (0.54-0.64 eV) and aromatic nitro compounds (0.59 eV for dinitrophenol), revealing its potential to serve as a viable ET agent. EAs are predicted to be 1.63 eV and 1.30 eV for the conformers of amphotericin B .Further calculations of the protonated formreveal that its EA is much higher than those of quinones and aromatic nitro compounds. This high value is due to the decomposition of the molecule to release NO2 when it is introduced to an electron.
NO2 is a ubiquitous air toxicant which induces damage to various organs including the lung . Genes related to OS were strongly induced.The effects are associated with the oxidant properties. Inflammatory and AO responses were observed after exposure to NO2. Lipid peroxidation, as measured by ethane formation, increased appreciably . AO protective enzyme activities were complementary effects which protected cells from damage by the lipid peroxides. One of the proposed mechanisms of pulmonary injury involves peroxidation of membrane lipids [26,27]. In a study of toxic mechanism, lipid peroxyl radicals are generated in a radical-mediated peroxidation pathway . During cell damage, there is breakdown of AO alpha-tocopherol. The AO glutathione showed appreciable change on exposure to NO2. The AO is known to protect erythrocytes from generated OS.Apparently, there has not been prior recognition of possible involvement of the metabolite NO2 in bee toxicity or in pesticide action in plants arising from neonicotinamides.
- nBlacquiere T, Smagghe G, Cornelis AM, Mommaerts V (2012) Neonicotinoids in bees: a review on concentrations side-effects and risk assessment. Ecotoxicology 21: 973-992.
- Cressey D (2015) Bee studies stir up pesticide debate. Nature 520: 416.
- EFSA (2015) Conclusion on the peer review of the pesticide risk assessment for bees for the active substance clothianidin considering all uses other than seed treatments and granules. EFSA Journal 13: 4210.
- Rundlölf M, Anderson GKS, Bommarco R, Fries I, Hederström V, et al. (2015) Seed coating with a neonicotinoid insecticide negatively affects wild bees. Nature 521: 77-80.
- Stanley DA, Garratt MPD, Wickens JB, Wickens VJ, Potts SG, et al. (2015) Neonicotinoid pesticide exposure impairs crop pollination services provided by bumblebees. Nature 528.
- Straub L, Villama-Bouza L, Bruckner S, Chantawannakul P, Gauthier L, Khnogphinibunjong K, et al. (2016) Neonicotinoid insecticide can serve as inadvertent insect contraceptives. Proc Royal Soc B 283.
- Thompson HM (2003) Behavioural effects of pesticides in bees-their potential for use in risk assessment. Ecotoxicology: 12: 317-330.
- Kovacic P, Somanathan R (2009) Pulmonary Toxicity (Environmental Contamination): Radicals, Electron Transfer and Protection by Antioxidants.In: W.D.Whitacre (ed) Reviews of Environmental Contamination and Toxicology, 201: pp. 41-69 .Springer, New York. ISBN: 978-1-4419-0031-9.
- Kovacic P, Becvar LE (2000) Mode of action of anti-infective agents: focus on oxidative stress and electron transfer. Curr Pharmaceut Des 6: 143-167.
- Kovacic P, Osuna JA (2000) Mechanisms of anti-cancer agents: emphasis on oxidative stress and electron transfer. Curr Pharmaceut Des 6: 277-309.
- Kovacic P, Jacintho JD (2001a) Mechanism of carcinogenesis. Focus on oxidative stress and electron transfer. Curr Med Chem 8: 773-796.
- Kovacic P, Jacintho JD (2001b) Reproductive toxins. Pervasive theme of oxidative stress and electron transfer. Curr Med Chem 8: 863-892.
- Kovacic P, Sacman A, Wu-Weis M (2002) Nephrotoxins: Widespread role of oxidative stress and electron transfer. Curr Med Chem 9: 823-847.
- Poli G, Cheeseman KH, Dianzani MU, Slater TF (1989) Free Radicals in the Pathogenesis of Liver Injury, Pergamon, New York, pp.1-330.
- Kovacic P, Thurn LA (2005) Cardiovascular toxicity from the perspective of oxidative stress, electron transfer, and prevention by antioxidants. Curr Vasc Pharmacol 3: 107-117.
- Kovacic P, Somanathan R (2005) The broad framework of electron transfer, oxidative stress and protection by antioxidants. Curr Med Chem-CNS Agents 5: 249-25.
- Kovacic P, Pozos RS, Somanathan R, Shangari R, O’Brien PJ (2005) Mechanism of mitochondrial uncouplers, inhibitors, and toxins: Focus on electron transfer, free radicals, and structure-activity relationships. Curr Med Chem 5: 22601-2623.
- Kovacic P, Cooksy AL (2005) Unifying mechanism for toxicity and addiction of abused drugs: electron transfer and reactive oxygen species. Med Hypotheses 64: 357-367.
- Kovacic P, Somanathan R (2008) Ototoxicity and noise trauma: Electron transfer, reactive oxygen species, cell signaling, electrical effects, and protection by antioxidants: Practical medical aspects. Med. Hypotheses 70: 914-923.
- Halliwell B, Gutteridge JMC (1999) Free Radicals in Biology and Medicine; Oxford University Press, New York 1-897.
- Kovacic P, Somanathan R (2010) Mechanism of conjugated imine and iminium species, including marine alkaloids: electron transfer, reactive oxygen species, therapeutics and toxicity. Curr Bioact Compds 6: 46-59.
- Kovacic P, Cooksy A (2012) Novel, unifying mechanism for amphotericin B and other polyene drugs: electron affinity, radicals, electron transfer, antioxidation, toxicity, and antifungal action. Med Chem Comm 3: 274-280.
- Micrwsky JE, Dailey LA, Devlin RB (2016) Differential expression of pro-inflammatory and oxidative stress mediators induced by nitrogen dioxide and ozone in primary human bronchial epithelial cells. Inhal Toxicol 28: 374-382.
- Johnston CJ, Reed CK, Aviss NE, Gelein R, Finkelstein JN (2000) Antioxidant and inflammatory response after acute nitrogen dioxide and ozone exposure in C57B1/6 mice. Inhal Toxicol 12: 187-203.
- Sagai M, Ichinose T (1987) Lipid peroxidation and antioxidative protection mechanism in rat lungs upon acute and chronic exposure to nitrogen dioxide. Environ Health Perspect 73: 179-189.
- Patel JM, Block ER (1987) Biochemical and metabolic response to nitrogen dioxide-induced endothelial injury. Res Rep Health Eff Inst 3-20.
- Patel JM, Block ER (1986) Nitrogen dioxide-induced changes in cell membrane fluidity and function. Am Rev Respir Dis 134: 1196-1202.
- Rietjens IM, Poelen MC, Hempen RA, Gijbels MJ, Alink GM (1986) Toxicity of ozone and nitrogen dioxide to alveolar macrophages: comparative study revealing differences in their mechanism of toxic action. J Toxicol Environ Health 19: 555-568.
- Chaney S, Blomquist W, DeWitt P, Muller K (1981) Biochemical changes in humans upon exposure to nitrogen dioxide while at rest. Arch Environ Health 36: 53-58.
Figure 1:Structure of Imidacloprid, Thiamethoxam and Clothianidin.
|Compound||Energy (in eV)|
Table 1: Calculated EA values of neutral and protonated Imidacloprid.
Citation: Kovacic P, Somanathan R, Nguyen H, Lopez AC (2017) Unifying Mechanism involving Neonicotinoids for Bee Toxicity: Electron Affinity, Nitrogen dioxide, Oxidative Stress, Reactive Oxygen Species. Adv Biochem Biotehcnol: ABIO-140. DOI: 10.29011/2574-7258.000040