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Chronic exposure to imidacloprid induces inflammation and oxidative stress in the liver & central nervous system of rats
... They have been designed to bind with higher affinities to insect than to mammalian nAChRs (Casida, 2018;Tomizawa and Casida, 2005). However, several studies indicate an impact of these insecticides on mammals (Abou-Donia et al., 2008;Berheim et al., 2019;Burke et al., 2018;Duzguner and Erdogan, 2012). In a study with neonatal rat neurons, the neonicotinoids acetamiprid and imidacloprid triggered responses in the low µM range by activating nAChRs (Kimura-Kuroda et al., 2012). ...
... This activity has been assumed to be relatively specific for the insect nervous system (Brown et al., 2006;Tan et al., 2007), as neonicotinoids have been developed to exhibit a higher affinity for insect nAChRs compared to vertebrate paralogs (Casida, 2018;Tomizawa and Casida, 2005). However, some studies suggest adverse effects of neonicotinoids on mammals (Abou-Donia et al., 2008;Berheim et al., 2019;Burke et al., 2018;Duzguner and Erdogan, 2012). A broad toxicological debate has been triggered by the observation that acetamiprid and IMI activated the nAChRs on neonatal rat neurons in the low µM range (Kimura-Kuroda et al., 2012). ...
... some studies indicate an impact of neonicotinoids on mammals(Abou-Donia et al., 2008;Berheim et al., 2019;Burke et al., 2018;Duzguner and Erdogan, 2012;Gibbons et al., 2015;Thompson et al., 2020). Some doubts on the extent of the species selectivity have been raised by experiments on neonatal rat neurons, where acetamiprid and imidacloprid triggered signaling effects at concentrations as low as 1-10 μM(Kimura-Kuroda et al., 2012). ...
... This demonstrates disruption of the balance between proinflammatory and antiinflammatory immune responses leading to immune system dysregulation. The increased IL-1β and IL-6 levels may result from the oxidative stress and activation of various transcription factors [15,58]. The proinflammatory cytokines may amplify the inflammatory response, which contributes to uncontrolled tissue damage with a massive generation of free radicals [59], and hence there is a need for anti-inflammatory cytokines to alleviate this effect as a protective response. ...
... Previous studies demonstrated that IL-10 overexpression has a pivotal role in protection against inflammation-induced injuries [59][60][61]. In agreement with our results, previous studies on other NNs revealed modulation of inflammatory cytokine production by NNs [15,58]. ...
... In agreement with our findings, Aydin [47] reported marked elevation in the NOx level in PMNs and plasma of TCP-treated rats. Similarly, imidacloprid increased NO production and expression of iNOS in the liver and brain of rats [58] and NO levels in the liver of mice [63]. ...
Thiacloprid (TCP) is a widely used neonicotinoid insecticide with a probable toxic hazard to animals and human beings. This intensified the demand for natural compounds to alleviate the expected toxic insults. This study aimed at determining whether astaxanthin (ASX) could mitigate the hepatotoxic effect of TCP and diminish its suppressive effect on immune responses in rats. Animals received TCP by gavage at 62.1 mg/kg (1/10th LD50) with or without ASX at 40 mg/kg, for 60 days. Intoxicated rats showed modulation of serum transaminases and protein profile. The hemagglutination antibody titer to sheep red blood cells (SRBC) and the number of plaque forming cells in spleen were reduced. The cell-mediated immunity and phagocytosis were suppressed, while serum interleukins IL-1β, IL-6 and IL-10 were elevated. Also, malondialdehyde, nitric oxide and 8-hydroxy-2'-deoxyguanosine levels were increased in the liver, spleen and thymus, with depletion of glutathione and suppression of superoxide dismutase and catalase activities. The expressions of inducible nitric oxide synthase and the high mobility group box protein 1 genes were upregulated with histomorphological alterations in the aforementioned organs. Co-treatment with ASX markedly ameliorated the toxic effects of TCP, and all markers showed a regression trend towards control values. Collectively our data suggest that the protective effects of ASX on the liver and immune system of TCP-treated animals depend upon improving the antioxidant status and relieving the inflammatory response, and thus it may be used as a promising therapeutic agent to provide superior hepato- and immunoprotection.
... Both eNOS and nNOS exhibit a mode of activation dependent on calmodulin binding to intracellular Ca +2 [126,127]. Therefore, an increase in cytoplasmic levels of this ion induced by NNs can lead to activation of both NOS isoforms and subsequent cytotoxic release of NO, as observed in the study by Duzguner and Erdogan [128]. ...
... Exposure to NNs has been associated with an increase in ROS levels and, consequently, LPO, oxidative damage to genetic material and protein oxidation [70,128,155,156]. In particular, an increase was observed in the levels of malondialdehyde (MDA), 8hydroxyguanosine and protein carbonyl, which were used as markers of LPO, DNA oxidation and protein oxidation, respectively [70,156]. ...
... It has been shown that exposure to NNs for approximately one month caused an increase in the activity of the enzymes catalase (CAT) and glutathione peroxidase (GSH-Px) in the brain [15,128]. However, a longer treatment with NNs decreased the antioxidant capacity, decreasing the activity of these two antioxidant enzymes [70,156]. ...
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.
... IMI, which is considered to be toxic to many systems, is known to upregulate pro-inflammatory cytokines such as TNF-α in the cerebral cortex, triggering inflammation (Duzguner and Erdogan, 2012). In the present study, TNF-α levels increased with acute IMI exposure, consistent with the previous literature (Duzguner and Erdogan, 2012). ...
... IMI, which is considered to be toxic to many systems, is known to upregulate pro-inflammatory cytokines such as TNF-α in the cerebral cortex, triggering inflammation (Duzguner and Erdogan, 2012). In the present study, TNF-α levels increased with acute IMI exposure, consistent with the previous literature (Duzguner and Erdogan, 2012). CAPE has been shown to have beneficial effects on a variety of processes such as neuroinflammation (Tsai et al., 2015) and neurotoxicity (Wei et al., 2008). ...
This study aimed to investigate the role of caffeic acid phenethyl ester (CAPE), a compound found in propolis, on imidacloprid (IMI), a nicotinic acetylcholine receptor agonist that causes cerebral toxicity. 60 adult rats were randomly divided into five groups: control, IMI (100 mg/kg), and IMI+CAPE (1, 5, 10 mg/kg). Cerebral cortex tissue was examined histopathologically, biochemically, spectrophotometrically and immunohistochemically. The results showed that IMI caused toxicity in the cerebral cortex. However, CAPE (5 and 10 mg/kg) attenuated the deteriorated histopathological score and normalized the apoptotic markers (Bax and Caspase-3). Additionally, CAPE dose-dependently normalized the levels of TNF-α, dopamin, GFAP and NGF, and at the highest dose (10 mg/kg) also normalized the balance of oxidative parameters (MDA, SOD, CAT, and GSH). In conclusion, the antioxidant, anti-inflammatory, and anti-apoptotic effects of CAPE may be a promising treatment for acute IMI-induced cerebral cortex toxicity.
... SOD and CAT play a critical role in scavenging of the superoxide anion ( (36) who stated that imidacloprid caused signi cant decrease in antioxidant enzymes activities and nonenzymes levels in rat brain. However, other studies revealed marked declines in glutathione levels in brain tissue with increases in enzymatic activities of SOD, CAT and GPx in male rats exposed to low doses of imidacloprid (2,37). Such increases in the intracellular enzymes may be endorsed for the compensatory mechanism of brain cells against imidacloprid exposure. ...
... In Our results also revealed noteworthy elevations in in ammatory cytokines as well as upregulations in the mRNA transcriptions of IL-1b, TNF-α, IL-6 and iNOS in TMX-exposed rats in respect to the controls. Oral administration of rats to imidacloprid for 30 days was reported to increase the mRNA transcriptions of TNFa, IL-6, IL-1b and IFN-c and decrease that of IL-12 in brain tissue (37). Further, in another study, imidacloprid enhanced the gene and protein expressions of IKKα, IKKβ, IL-1β, IL-6, and TNF-α in the liver of quails in a dosage-dependent manner (40). ...
Thiamethoxam, a neonicotinoid insecticide, is a widely used insecticide with neurotoxic potential. This study explored the neuroprotective effects of silymarin on thiamethoxam-triggered cortical injury in male rats. Animals were divided into four groups and treated daily either with SM (150 mg/kg), TMX (78.15 mg/kg), or both at the aforementioned doses for 28 days. Our results revealed marked declines in cortical SOD and CAT activities with elevations in MDA, IL-1b and TNF-α levels in thiamethoxam-treated rats. Further, thiamethoxam induced down-regulation in gene expressions of Sod, Cat, Gpx , and Nrf-2 genes, with up-regulation in the expression of IL-1b, IL-6, iNOS, TNF-α and NF-kB genes. Interestingly, pre-treatment with SM provided a notable neuroprotective action against TMX-mediated cortical damage that indicates its promising antioxidant and anti-inflammatory activities. This effect may be mediated by Nrf2/NF-kB/iNOS signalling and suppression of excess free radicals and production of inflammatory cytokines.
... On the contrary, addition of marjoram extract reflected its antiinflammatory effects via increase of IL-10 and decrease IL-1β, IL-6, TNF-α expressions. Regarding IMID induced inflammation, the present results were in line with a study done by Duzguner and Erdogan (2012) who reported upregulation of mRNA transcriptions of TNF-α, IL-6, IL-1β and IFNγ and IL-12 down regulation by effect of IMID. Moreover, our results were in agreement with previous studies on other neonicotinoid insecticides (Fathy and Abdelkader, 2021;Abou-Zeid et al., 2021) who reported imbalance between pro-inflammatory and anti-inflammatory cytokines. ...
... In the current work, the pretreatment with marjoram extract for 8 weeks revealed significant increase in spleen and thymus contents of catalase, SOD, and GSH and significant reduction of MDA after exposure to IMID when compared to IMID received group that increased MDA and decreased catalase, SOD, and GSH contents in the studying tissues. These results were consistent with the previous studies of Mohany et al. (2011), Duzguner andErdogan (2012), Mahajan et al. (2018) and Attia et al. (2021) who proved that exposure to IMID increased MDA with decreased catalase, SOD, and GSH contents in various vital organs. They interpreted the IMID induced oxidative stress by lipid peroxidation of cell membrane that was indicated by MDA elevation in tissues. ...
Imidacloprid (IMID), one of environmental persistent neonicotinoid insecticides, has been used a long time ago and categorized from insecticide induced moderate toxicity by World Health Organization (WHO). Marjoram, is one of the most worldwide used herbs in Egypt due to its antioxidant, anti-inflammatory, anti-genotoxic, anti-mutagenic, anticoagulant, and beneficial effects. This study aimed to evaluate the protective role of marjoram extract on the immunotoxic response and oxidative stress induced by IMID in the immune lymphoid organs (thymus and spleen) of rats. Fifty adult male albino rats were divided randomly into five groups; negative and positive (distilled water) control, marjoram extract (200 mg/kg/day), IMID (22.5 mg/kg/day), marjoram extract + IMID (200 mg/kg +22.5 mg/kg) orally for 8 weeks. Marjoram pretreatment reversed reduced animals body, thymus and spleen weights attributed to IMID. It amended the significantly elevated total leukocytes, neutrophils percentage, increased immunoglobulin G and the significantly reduction of lymphocytes percentage, phagocytic activity, phagocytic index and lysozyme activity induced by IMID. Moreover, marjoram administration significantly reduced thymic and splenic gene expression of interleukin-1β, interleukin-6, tumor necrosis factor-α and increased interleukin-10, in addition, it decreased thymic and splenic contents of malondialdehyde and restored the reduced antioxidant enzymes' activities following IMID exposure. Marjoram ameliorated IMID induced histopathological alterations in thymus and spleen and adjusted IMID immunomodulatory effects by increased the downregulation of CD4 and CD8 immune reactive cell expression. Conclusion, Marjoram has a protective role to reverse IMID immune toxic effects in thymus and spleen tissues of rats by its antioxidant, anti-inflammatory and immunomodulatory defense mechanisms.
... A new category of toxins are neonicotinoids, which are potent insecticides that can be used for crop safety and ectoparasite control in companion animals [1]. Because of their low toxicity to animals, they have been gradually used worldwide, sometimes replacing organophosphate and carbamate pesticides [2]. ...
... e generation of reactive oxygen (oxidative stress) and nitrogen (nitrosative stress) species appears to play a significant role in inducing the damage caused by the use of neonicotinoids on lipids, proteins, and DNA in vertebrates and invertebrates. In this regard, the role of oxidative stress and production of reactive species of oxygen and nitrogen on nerve, immune, liver, kidney, and reproductive damage has been investigated [1,25,26]. Neonicotinoids induce oxidative stress and produce free oxygen and nitrogen species, thereby causing toxic effects. CTD-induced oxidative stress has previously been observed in the liver of rainbow trout as elevated MDA levels [27]. ...
Clothianidin (CTD) is a member of the neonicotinoid group of insecticides. This study was performed to determine the effect of quercetin on clothianidin-induced liver injury (CTD) in rats. Rats were randomly assigned to a normal control (saline), a CTD control-treated group (20 mg/kg) every 3 days for 21 days, and CTD + quercetin-treated groups (2.5, 5, and 10 mg/kg) for 35 days intraperitoneally. Enzyme activity, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), was measured by spectrophotometry in serum samples by an automatic biochemical analyzer using commercial kits. Total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrate-nitrite were measured in homogeneous liver tissue samples of animals. A significant increase in ALT and AST enzyme activity was observed in the CTD group in comparison with that of the control groups. In the clothianidin + quercetin (10 mg/kg) group, the ALT and AST enzyme levels decreased compared to the clothianidin control group significantly P
... Several studies have reported that exposure to neonicotinoid insecticides increases ROS, activating inflammatory pathways in neuronal cells and producing pro-inflammatory cytokines (63). The present study showed a significant increase in proinflammatory mediators, including TNF-α, NF-κB and IL-1β in acetamipridexposed rats. ...
Acetamiprid is a class of neuroactive insecticides widely used to control insect pests. The current study aimed to investigate the potential neuroprotective effects of luteolin against acetamiprid-induced neurotoxicity in the rat cerebral cortex. Four equal groups of adult male rats (10 in each): control, acetamiprid (40 mg/kg for 28 days), luteolin (50 mg/kg for 28 days), and acetamiprid+luteolin cotreatment were used. Acetamiprid was shown to alter the oxidative state by increasing oxidant levels [nitric oxide (NO) and malondialdehyde (MDA)] and decreasing antioxidants [glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase-(CAT)], with increased activity of nuclear factor erythroid 2–related factor 2-(Nrf2). Likewise, acetamiprid increases the inflammatory response, as evidenced by increased interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nuclear factor kappa B-(NF-κB). In contrast, the treatment with luteolin brought these markers back to levels close to normal, showing that it protects neurocytes from oxidative damage and the neuroinflammation effects of acetamiprid-induced inflammation. Luteolin also demonstrated a neuroprotective role via the modulation of acetylcholinesterase (AChE) activity in the cerebral cortex tissue. Histopathology showed severe neurodegenerative changes, and apoptotic cells were seen in the acetamiprid-induced cerebral cortex layer, which was evident by increased protein expression levels of Bax and caspase-3 and decreased Bcl-2 levels. Histochemistry confirmed the neuronal degeneration, as proven by the change in neurocyte colour from brown to black when stained with a silver stain. Luteolin may have a neuroprotective effect against biochemical and histopathological changes induced by acetamiprid in the rat cerebral cortex.
... Oxidative stress is also a factor in dysbiosis (Weiss and Hennet, 2017) and exerts antibacterial effects on anaerobic bacteria; it also promotes the growth of certain bacteria (Winter et al., 2010) and disrupts the balance of the intestinal microbiota. Since NNs reportedly have oxidative stress-inducing effects (Kapoor et al., 2011;Duzguner and Erdogan, 2012;Tokumoto et al., 2013;Hoshi et al., 2014;Hirano et al., 2015;Kitauchi et al., 2021), it is assumed that CLO induced oxidative stress in the intestine and disrupted the balance of the intestinal microbiota. Furthermore, chronic administration of corticosterone has been reported to generate reactive oxygen species (Lin et al., 2004) and to induce oxidative damage (KV et al., 2018). ...
... NEOs exert their neurotoxic insecticidal action by binding to and activating nAchRs on the postsynaptic membrane of nerve cells (Duzguner and Erdogan 2012). They imitate the effect of Ach by opening ion channels, allowing cations such as Na + and Ca +2 to enter and cause excitatory neurotransmission in the central nervous system (Rose 2012). ...
Synthetic organic insecticides such as pyrethroids, organophosphates, neonicotinoids, and others have the potential to disrupt ecosystems and are often toxic to humans. Thiamethoxam (TMX), a neonicotinoid insecticide , is a widely used insecticide with neurotoxic potential. l-Carnitine (LC) is regarded as the “gatekeeper” in charge of allowing long-chain fatty acids into cell mitochondria. LC is an endogenous chemical that is renowned for its prospective biological activity in addition to its role in energy metabolism. This study investigated the protective effects of LC against TMX-induced neurotoxicity in male Wistar rats. For 28 days, animals were divided into four groups and treated daily with either LC (300 mg/kg), TMX (100 mg/kg), or both at the aforementioned doses. Our results revealed marked serum lipid profile and electrolyte changes, declines in brain antioxidants and neurotransmitters (acetylcholine, dopamine, and serotonin levels) with elevations in thiobarbituric acid reactive substances and proinflammatory cytokine levels, as well as acetylcholinesterase and monoamine oxidase brain activity in TMX-treated rats. TMX also increased the expression of caspase-3 and glial fibrillary acidic protein. In contrast, pretreatment with LC attenuated TMX-induced brain injury by suppressing oxidative stress and proinflammatory cytokines and modulating neurotransmitter levels. It also ameliorated the expression of apoptotic and astrogliosis markers. It could be concluded that LC has antioxidant, anti-inflammatory, anti-astrogliosis, and anti-apoptotic potential against TMX neurotoxicity.
Graphical abstract
... As reported in the literature, pesticide-induced oxidative stress can be induced by an increase in lipid peroxidation and a decrease in antioxidant capacity due to their ability to interact with plasma membranes [5]. There is indeed experimental evidence showing that exposure to IMID caused significant lipid peroxidation and alteration of antioxidant enzyme activities [45,46]. ...
The extensive use of agricultural pesticides to improve crop quality and yield significantly increased the risk to the public of exposure to small but repeated doses of pesticides over time through various routes, including skin, by increasing the risk of disease outbreaks. Although much work was conducted to reduce the use of pesticides in agriculture, little attention was paid to prevention, which could reduce the toxicity of pesticide exposure by reducing its impact on human health. Extra virgin olive oil (EVOO), a major component of the Mediterranean diet, exerts numerous health-promoting properties, many of which are attributed to oleuropein aglycone (OleA), the deglycosylated form of oleuropein, which is the main polyphenolic component of EVOO. In this work, three pesticides with different physicochemical and biological properties, namely oxadiazon (OXA), imidacloprid (IMID), and glyphosate (GLYPHO), were compared in terms of metabolic activity, mitochondrial function and epigenetic modulation in an in vitro cellular model of human HaCaT keratinocytes to mimic the pathway of dermal exposure. The potential protective effect of OleA against pesticide-induced cellular toxicity was then evaluated in a cell pre-treatment condition. This study showed that sub-lethal doses of OXA and IMID reduced the metabolic activity and mitochondrial functionality of HaCaT cells by inducing oxidative stress and altering intracellular calcium flux and caused epigenetic modification by reducing histone acetylation H3 and H4. GLYPHO, on the other hand, showed no evidence of cellular toxicity at the doses tested. Pretreatment of cells with OleA was able to protect cells from the damaging effects of the pesticides OXA and IMID by maintaining metabolic activity and mitochondrial function at a controlled level and preventing acetylation reduction, particularly of histone H3. In conclusion, the bioactive properties of OleA reported here could be of great pharmaceutical and health interest, as they could be further studied to design new formulations for the prevention of toxicity from exposure to pesticide use.
... Pesticides are a group of chemicals that are applied for the preclusion, destruction, repulsion, or elimination of insects, rodents, weeds and fungi (Ansari et al. 2021). Numerous mechanisms have been proposed for the lethal effects of pesticides on vertebrates, e.g., oxidative stress, intrusion on dopamine transporters, mitochondrial dysfunction and in ammation (Duzguner and Erdogan 2012). Neonicotinoids such as imidacloprid, acetamiprid, nitrosoguanidine, clothianidin and thiamethoxam possess substantial potency against various pests, in combination with their relatively reduced mammalian toxicity (Simon-Delso et al. 2015). ...
The purpose of the research was to assess the impacts of L-arginine (AR) on some biochemical indices and oxidative stress in male Wistar rats exposed to imidacloprid (IM) toxicity. Forty rats were used and they were randomly assigned to four groups. They received the treatments once daily by oral gavage for 14 days as follows: distilled water [DW group], imidacloprid (71 mg/kg) (IM group), imidacloprid (71 mg/kg) and L-arginine (100 mg/kg) [IM + AR100 group], imidacloprid (71 mg/kg) and L-arginine (200 mg/kg) [IM + AR200 group]. The rats were sacrificed after the study ended and the levels of serum proteins, urea and creatinine, oxidative stress parameters, as well as the activities of serum enzymes, were estimated. Significant reductions were recorded in the total protein concentrations of the IM and IM + AR100 groups relative to that of the DW group, respectively. Also, substantial declines were observed in the globulin levels of the IM and IM + AR100 groups compared to that of the DW and IM + AR200 groups respectively. There were significant elevations in the aspartate aminotransferase (IM, IM + AR100 and IM + AR200 groups) and creatinine (IM group) levels relative to that of the DW group correspondingly. Moreover, significant reductions were recorded in the activities of hepatic catalase and renal superoxide dismutase of the IM group compared to that of the IM + AR200 group respectively. It can be deduced that IM appreciably disrupted some serum biochemical indices probably through the induction of oxidative stress, while AR alleviated the undesirable effects of IM particularly at 200 mg/kg, perhaps through its antioxidant and bioprotective properties.
... Duzguner and Erdogan [78] 8 mg/kg b.w. ...
Recently, neonicotinoids have become the fastest-growing class of insecticides in conventional crop protection, with extensive usage against a wide range of sucking and chewing pests. Neonicotinoids are widely used due to their high toxicity to invertebrates, simplicity, flexibility with which they may be applied, and lengthy persistence, and their systemic nature ensures that they spread to all sections of the target crop. However, these properties raise the risk of environmental contaminations and potential toxicity to non-target organisms. Acetamiprid is a new generation insecticide, which is a safer alternative for controlling insect pests because of its low toxicity to honeybees. Acetamiprid is intended to target nicotinic acetylcholine receptors in insects, but its widespread usage has resulted in negative impacts on non-target animals such as mammals. This review summarizes in vivo and in vitro animal studies that investigated the toxicity of specific neonicotinoids. With summarized data, it can be presumed that certain concentrations of neonicotinoids in the reproductive system cause oxidative stress in the testis; spermatogenesis disruption; spermatozoa degradation; interruptions to endocrine function and Sertoli and Leydig cell function. In the female reproductive system, acetamiprid evokes pathomorphological alterations in follicles, along with metabolic changes in the ovaries.
... In rat livers treated with IM at higher doses, there was marked dilatation and congestion of the central vein and hepatocyte depletion. Other previous research supports the histological results of the current study in rats exposed to IM [113,114]. ...
Pesticides are widely used around the world to increase crop production. They also have negative impacts on animals, humans, and the ecosystem. This is the first report evaluating a novel pomegranate-extract-loaded clove-oil-based nanoemulsion (PELCN) and its potential for reducing oxidative stress and DNA damage, as well as its hepatoprotective effects against imidacloprid (IM) and chlorpyrifos (CPF) toxicity in male rats. The benchmark dose (BMD) approach was also used to study the dose–response toxicity of IM and CPF. IM and CPF were administered daily for 28 days at doses of 14, 28, and 54 mg/kg body weight (bw) of IM and 1, 2, and 4 mg/kg bw of CPF via drinking water. The PELCN was administered orally at a dose of 50 mg/kg bw/day of pomegranate extract, 500 mg/kg bw of the clove oil nanoemulsion, and IM or CPF at high doses in the drinking water. In male rats, IM and CPF caused a reduction in body weight gain and hepatotoxic effects as evidenced by increases in the liver enzymes AST, ALT, and ALP. They caused oxidative damage in the liver of male rats as indicated by the decreased liver activity of the GST, GPX, SOD, and CAT enzymes and decreased serum TAC. IM and CPF produced a significant dose-dependent increase in DNA damage in hepatocyte cells, resulting in moderate to severe liver damage with cells that are more inflammatory and have enlarged sinusoids and compacted nuclei. IM had a higher BMD than CPF for both body and liver weight, suggesting that CPF was more dose-dependently toxic than IM. Albumin was a highly sensitive liver biomarker for IM, while total protein was a biomarker for the CPF-treated rats. GPx was an extremely sensitive biomarker of oxidative stress in the IM treatment, while CAT and GPx were highly sensitive parameters in the CPF-treated rats. Therefore, at comparable doses, CPF has a higher potential to cause liver damage and oxidative stress than IM. The hepatotoxicity of IM and CPF can be mitigated by administering a nanoemulsion containing clove oil and pomegranate extract. The nanoemulsion acts as a protector against the oxidative stress caused by these insecticides, especially at high doses. The nanoemulsion based on clove oil increases the bioavailability and stability of the pomegranate extract, which has antioxidant properties.
... Tomizawa [12] reported that long-term exposure to imidacloprid (1 mg/kg/BW/day) may cause nAChR overexpression in the brain tissue of mammals, resulting in brain damage. In addition, Duzguner and Erdogan [13,14] reported that long-term exposure to 10 µM imidacloprid may induce inflammation and increase oxidative stress in the central nervous system of rats, eventually leading to neuronal apoptosis. ...
The neonicotinoid imidacloprid is a widely used insecticide worldwide. We assessed the effects of acute and chronic imidacloprid exposure on the social behavior of adult zebrafish. We assembled simple apparatus to detect 2D locomotion: a single camera capture system and two specially designed water tanks. We then used the tracking and heat maps of the behavior trajectories of zebrafish subjected to sham and imidacloprid exposure and compared their social behavior. Furthermore, histomorphology and immunohistochemistry of their brain tissue sections were performed to clarify possible neurotoxicity due to imidacloprid exposure in our adult zebrafish. Our results showed that imidacloprid exposure significantly reduced the zebrafish’s swimming speed, distance traveled, acceleration, and deceleration. The longer the imidacloprid exposure, the more severe the locomotor behavior disability. Furthermore, imidacloprid exposure significantly reduced heterosexual attractive behavior between the different sexes, as well as defensive alert behavior among males. Our histomorphology and immunohistochemistry evidence showed imidacloprid exposure may lead to neuronal oxidative stress, inflammation, apoptosis, and damage in the telencephalon of adult zebrafish. Thus, we suggested that neonicotinoid imidacloprid exposure can damage the telencephalon neurons of adult zebrafish through oxidative stress, inflammation, and apoptosis and then affect the social behavior of adult zebrafish.
... 64 ROS and free radicals participate significantly in the toxicity of pesticides and environmental chemicals, inducing oxidative stress and alterations in antioxidants or free radical scavenging enzymatic pathways. 65 The current study revealed a significant alteration in the brain redox status of the group exposed to IMI associated with a significant elevation of brain MDA level and a significant reduction in GSH and CAT activity in the rat brain. The same dysregulated brain redox status results associated with IMI were reported by Rawi et al. 63 Moreover, the oxidative damage of IMI was reported to be caused by increasing the protein oxidation and lipid peroxidation of the brain cells. ...
Imidacloprid (IMI) insecticide is rapidly metabolized in mammals and contributes to neurotoxicity via the blocking of nicotinic acetylcholine receptors, as in insects. Origanum majorana retains its great antioxidant potential in both fresh and dry forms. No data is available on the neuroprotective effect of this plant in laboratory animals. In this context, aerial parts of O. majorana were used to prepare the essential oil (OMO) and methanol extract (OME). The potential neuroprotective impact of both OMO and OME against IMI-induced neurotoxicity in rats was explored. Forty-two rats were divided into 6 groups, with 7 rats in each one. Rats were daily administered the oral treatments: normal saline, OMO, OME, IMI, IMI + OMO, and IMI + OME. Our results revealed the identification of 55 components in O. majorana essential oil, most belonging to the oxygenated and hydrocarbon monoterpenoid group. Moreover, 37 constituents were identified in the methanol extract, mostly phenolics. The potent neurotoxic effect of IMI on rats was confirmed by neurobehavioral and neuropathological alterations and a reduction of both acetylcholine esterase (AchE) activity and dopamine (DA), serotonin (5HT), and γ-aminobutyric acid (GABA) levels in the brain. Exposure of rats to IMI elevates the malondialdehyde (MDA) levels and reduces the antioxidant capacity. IMI could upregulate the transcription levels of nuclear factor-κB (NF-κB), interleukin-1 β (IL-1β), and tumor necrosis factor (TNF-α) genes and express strong caspase-3 and inducible nitric oxide synthase (iNOS) immunostaining in most examined brain areas. On the other hand, rats coadministered OMO or OME with IMI showed a marked improvement in all of the studied toxicological parameters. In conclusion, cotreatment of O. majorana extracts with IMI can protect against IMI neurotoxicity via their potent antioxidant, anti-inflammatory, and anti-apoptotic effects. Thus, we recommend a daily intake of O. majorana to protect against insecticide's oxidative stress-mediated neuroinflammatory stress and apoptosis. The molecular docking study of linalool, rosmarinic acid, γ-terpene, and terpene-4-ol justify the observed normalization of the elevated iNOS and TNF-α levels induced after exposure to IMI.
... Insecticides can disrupt cells' reactive oxygen species (ROS) metabolism (Nedzvetsky et al., 2021). This disruption leads to changes in enzymatic defenses and an increase in free radicals (Duzguner et al., 2012). As a result, this process can lead to apoptosis (Ge et al., 2015). ...
Studying the effects of neonicotinoids on non-target organisms is still an urgent task in today's world, where they are used in substantial quantities. Initially, it is interesting to find out the change in easy-to-detect parameters under insecticide exposure conditions that may indicate some exposure. Therefore, we investigated the parameters of oxidative changes (SOD, CAT, MDA, and total protein) in sexually mature marsh frogs caused by exposure to imidacloprid. Thirty frogs were selected for the experiment and divided into five groups of six individuals each. The exposure concentrations of imidacloprid were 10 µg/L and 100 µg/L. The duration of insecticide exposure was 7 and 21 days. After the finish of the experiment, the liver, kidney, and blood were taken from the animals under anesthesia. It was found that after 7 days of exposure, the group exposed to 100 µg/L imidacloprid solution had lower serum total protein than the control and 10 µg/L exposure groups (p<0.05). Also, after 21 days of imidacloprid exposure at a concentration of 100 µg/L, there was an increase in the SOD value in the frog liver compared to the control group (p<0.05). No significant differences were found in other parameters (p>0.05). The findings cast doubt on the unconditional use of common oxidative stress indices in adult marsh frogs as biomarkers of low-dose imidacloprid exposure. The obtained results for the adult marsh frog may support the possibility of using the liver SOD level only as a biomarker of imidacloprid exposure at environmentally significant concentrations.
... At the same time, it was observed that the INOS transcription level, protein level, and activity were all increased after abamectin exposure. INOS can produce NO, and studies have shown that NO can also be produced in response to stimulation by pollutants such as pesticides (Duzguner and Erdogan 2012), but excess NO will lead to oxidative stress (Wang et al. 2013). When the body fails to remove excess ROS (including NO), this may inactivate antioxidant enzymes and leads to a breakdown of the antioxidant system (Ray et al. 2012). ...
Abamectin is a commonly used pesticide in agriculture and fisheries and poses a risk to aquatic species. However, the mechanism of its toxic effects on fish remains to be discovered. In this study, we explored the effects of abamectin exposure at different concentrations on the respiratory system of carp. Carp were divided into three groups, namely the control group, low-dose abamectin treatment group, and high-dose abamectin treatment group. Gill tissue was collected after abamectin exposure for histopathological, biochemical, tunnel, mRNA, and protein expression analysis. Histopathological analysis indicated that abamectin damaged the gill structure. Biochemical analysis showed that abamectin triggered oxidative stress with lowered antioxidant enzyme activities and increased MDA content. Moreover, abamectin led to enhanced INOS levels and pro-inflammatory transcription, activating inflammation. Tunnel results demonstrated that exposure to abamectin induced gill cell apoptosis through an exogenous pathway. In addition, exposure to abamectin activated the PI3K/AKT/mTOR pathway, leading to inhibition of autophagy. Overall, abamectin caused respiratory system toxicity in carp via triggering oxidative stress, inflammation, and apoptosis and inhibiting autophagy. The study suggests that abamectin has a profound toxicity mechanism in the respiratory system of carp, contributing to a better understanding of pesticide risk assessment in aquatic systems.
... Activation of nitric oxide synthase by NEOs results in increase of nitric oxide. Consequently, excessive stimulation of nitric oxide synthase leads to massive production and accumulation of nitric oxide and peroxyl nitrite, which contributes greatly to oxidative stress [43]. ...
Thiamethoxam is one of the second-generation neonicotinoids, a new class of insecticides. The study was designed to investigate the effect of thiamethoxam on fertility in bucks. For this purpose, sixteen male adult male chinchilla rabbits were divided in two groups. Thiamethoxam intoxicated group was treated with thiamethoxam at dose of 250 mg/Kg body weight for 3 months. Semen analysis revealed distinct changes in sperm characteristics including significant decrease in sperm motility (both mass and individual) and sperm count. In addition, significant increase in dead spermatozoa and sperm deformities. Moreover, elevation in testicular concentration of MDA and GST was significant. GSH was significantly decreased. Degeneration and necrosis of spermatogenic cells with intertubular edema and vacuolations in seminiferous tubules were the major observed histopathological changes in the testis of intoxicated animals. In conclusion, thiamethoxam administration for 3 months induced significant decrease in fertility and oxidative stress in the reproductive system of adult male.
... Oxidative stress is caused by an imbalance between active oxygen species and the antioxidant capacity; such stress is exerted when the production of reactive oxygen species (ROS) exceeds the antioxidant capacity of the living body or when there is a decrease in the cellular antioxidant capacity. ROS damage cell nucleic acids, proteins, and lipids, causing cell death and damage to various organs [78]. ROS can be categorized as a singlet oxygen, superoxide, hydrogen peroxide, and hydroxyl radicals. ...
Neonicotinoid pesticides (NPs) are neurotoxic substances. They are highly effective as insecticides owing to their water solubility, permeability, and long-lasting activity. These molecules are structurally similar to nicotine and act as nicotinic acetylcholine receptor agonists. The administration of NPs to experimental animals reportedly causes neuromuscular and reproductive disorders. Moreover, recently reported problems caused by NPs include damage to land-dwelling creatures (such as mammals and birds), hydrobiology, and ecosystems. This review summarizes the recent reports on NP concentrations detected in river systems in several Japanese regions. These values were lower than the environmental standard values; however, seasonal variations were observed. Furthermore, reports on NP-induced testicular and ovarian toxicity were examined, revealing that the mechanism of injury is mainly driven by oxidative stress. The use of NPs is declining worldwide, except in Japan; therefore, continuous monitoring remains necessary.
... Previous studies have shown that IMD induces oxidative stress responses, such as catalase (CAT) and glutathione S-transferase (GST) activity [54] and induces three isoforms of nitric oxide synthases (iNOS, eNOS, nNOS) [55]. These oxidative stresses may cause damage to tissues and neurons, and we found that antioxidant osthole could rescue IMDinduced phenotypes, thus confirming that chronic IMD treatment with environmentalrelevant concentration impairs neuroplasticity and peripheral sensations by mediating oxidative stress. ...
Background:
Imidacloprid (IMD) is a widely used neonicotinoid-targeting insect nicotine acetylcholine receptors (nAChRs). However, off-target effects raise environmental concerns, including the IMD's impairment of the memory of honeybees and rodents. Although the down-regulation of inotropic glutamate receptor (iGluR) was proposed as the cause, whether IMD directly manipulates the activation or inhibition of iGluR is unknown. Using electrophysiological recording on fruit fly neuromuscular junction (NMJ), we found that IMD of 0.125 and 12.5 mg/L did not activate glutamate receptors nor inhibit the glutamate-triggered depolarization of the glutamatergic synapse. However, chronic IMD treatment attenuated short-term facilitation (STF) of NMJ by more than 20%. Moreover, by behavioral assays, we found that IMD desensitized the fruit flies' response to mechanosensitive, nociceptive, and photogenic stimuli. Finally, the treatment of the antioxidant osthole rescued the chronic IMD-induced phenotypes. We clarified that IMD is neither agonist nor antagonist of glutamate receptors, but chronic treatment with environmental-relevant concentrations impairs glutamatergic plasticity of the NMJ of fruit flies and interferes with the sensory response by mediating oxidative stress.
... The potential effect of IMI on the levels of GSH in Japanese quails showed a significant reduction in the GSH contents in all the tested tissues with levels of 94-61, 84-31, 84-53, 89-61, and 74-52% of the control in serum, brain, liver, heart, and wing muscles of quails, after dosing with IMI for 1-28 days every other day, respectively (Fig. 4a-b). The obtained results are in parallel with those reported by many investigators, where IMI reduced the levels of GSH in layer chickens (Sasidhar-Babu et al. 2014), red-legged partridge (Lopez-Antia et al. 2015), and rat (Bal et al. 2012;Duzguner and Erdogan 2012;Soujanya et al. 2013). The reduction in GSH levels in the present study indicated that quails suffered from serious damage due to reduction in their antioxidant capacity and could be related to the use of GSH itself in the metabolic processes and to compensate the increased production of free radicals ) and scavenge ROS which recovered again due to the inhibition of glutathione reductase by IMI (Halliwell and Gutteridge 2015). ...
The in vivo effect of the oral sublethal doses of 3.014 mg kg−1 of IMI (1/25 LD50) for 1, 7, 14, and 28 days every other day on Japanese quail was investigated. The results revealed that certain biomarkers in the selected tissues of the quail such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), aminotransaminases (alanine aminotransferase, ALT, and aspartate aminotransaminase, AST), phosphatases (acid phosphatase, ACP, and alkaline phosphatase, ALP), lactate dehydrogenase (LDH), adenosine-triphosphatase (ATPase), glutathione-S-transferase (GST), lipid peroxidation (LPO), and blood glucose showed significant inductions, while significant reductions in the levels of glutathione-reduced (GSH), deoxyribonucleic acid (DNA), and ribonucleic acid (RNA) were noticed. In this study, the molecular mechanisms of the toxic effects of imidacloprid on quails were elucidated regarding neurotoxicity, hepatotoxicity, oxidative stress, lipid peroxidation, antioxidant activity, and genotoxicity. Because IMI induced alterations in the levels of these biomarkers in Japanese quail; therefore, Japanese quail as a wild avian can be used as a suite bioindicator to detect imidacloprid toxicity.
... Imidacloprid, a neonicotinoid insecticide, induces oxidative stress and DNA damage on non-target organisms, namely various fish species such as Danio rerio (zebrafish) [13], Prochilodus lineatus [14], and Oreochromis niloticus (Nile tilapia) [15], affecting various organs (e.g., gills, kidney, brain, liver), as assessed by the levels of stress defence enzyme activity and by comet assay [13][14][15]. Imidacloprid was also reported to induce oxidative stress and inflammation in the hepatic and central nervous system of rats [16] and was associated with multiple neurobehavioral aberrations in adolescent and adult rats [17]. Moreover, using Drosophila melanogaster, imidacloprid at low doses promotes calcium influx into neurons triggering a fast increase in neuronal ROS level, affecting mitochondria, energy levels, and lipid environment, triggering metabolic and neurological impairments [18]. ...
In this work, three pesticides of different physicochemical properties: glyphosate (GLY, herbicide), imidacloprid (IMD, insecticide), and imazalil (IMZ, fungicide), were selected to assess their cytotoxicity against Caco-2 and HepG2 cells. Cell viability was assessed by the Alamar Blue assay, after 24 and 48 h exposure to different concentrations, and IC50 values were calculated. The mechanisms underlying toxicity, namely cellular reactive oxygen species (ROS), glutathione (GSH) content, lipid peroxidation, loss of mitochondrial membrane potential (MMP), and apoptosis/necrosis induction were assessed by flow cytometry. Cytotoxic profiles were further correlated with the molecular physicochemical parameters of pesticides, namely: water solubility, partition coefficient in an n-octanol/water (Log Pow) system, topological polar surface area (TPSA), the number of hydrogen-bonds (donor/acceptor), and rotatable bonds. In vitro outputs resulted in the following toxicity level: IMZ (Caco-2: IC50 = 253.5 ± 3.37 mM, and HepG2: IC50 = 94 ± 12 mM) > IMD (Caco-2: IC50 > 1 mM and HepG2: IC50 = 624 ± 24 mM) > GLY (IC50 > >1 mM, both cell lines), after 24 h treatment, being toxicity time-dependent (lower IC50 values at 48 h). Toxicity is explained by oxidative stress, as IMZ induced a higher intracellular ROS increase and lipid peroxidation, followed by IMD, while GLY did not change these markers. However, the three pesticides induced loss of MMP in HepG2 cells while in Caco-2 cells only IMZ produced significant MMP loss. Increased ROS and loss of MMP promoted apoptosis in Caco-2 cells subjected to IMZ, and in HepG2 cells exposed to IMD and IMZ, as assessed by Annexin-V/PI. The toxicity profile of pesticides is directly correlated with their Log Pow, as affinity for the lipophilic environment favours interaction with cell membranes governs, and is inversely correlated with their TPSA; however, membrane permeation is favoured by lower TPSA. IMZ presents the best molecular properties for membrane interaction and cell permeation, i.e., higher Log Pow, lower TPSA and lower hydrogen-bond (H-bond) donor/acceptor correlating with its higher toxicity. In conclusion, molecular physicochemical factors such as Log Pow, TPSA, and H-bond are likely to be directly correlated with pesticide-induced toxicity, thus they are key factors to potentially predict the toxicity of other compounds.
... On the contrary, the anti-inflammatory IL-10 mediator was negatively regulated in both organs [94]. The same effects were observed after oral treatment of rats with 1 mg/kg imidacloprid for 30 days [95]. Helper T cells regulate cellular and humoral immune responses. ...
People are exposed to pesticides through food, drinking water, and the environment. These compounds are associated with several disorders, such as inflammatory diseases, rheumatoid arthritis, cancer, and a condition related to metabolic syndrome. The immunotoxicants or immunotoxic compounds can cause a wide variety of effects on immune function, altering humoral immunity and cell-mediated immunity, resulting in adverse effects to the body. Here, immune system disorders are highlighted because they are closely linked to multiple organs, including the nervous, endocrine, reproductive, cardiovascular, and respiratory systems, leading to transient or permanent changes. Therefore, this study reviewed the mechanisms involved in the immunotoxicity of fungicides, herbicides, and insecticides in cells, animals, and humans in the past 11 years. According to the studies analyzed, the pesticides interfere with innate and adaptive immune functions, but the effects observed mainly on cellular and humoral immunity were highlighted. These compounds affected specific immune cells, causing apoptosis, changes in factor nuclear kappa B (NF-κB) expression, pro-inflammatory factors interleukin 6 (IL-6), interleukin 8 (IL-8), interferon-gamma (IFN-γ), chemokines (CXCL-c1c), and anti-inflammatory factor, such as interleukin 10 (IL-10). To verify the threats of these compounds, new evaluations with immunotoxicological biomarkers are necessary.
• Highlights
• Pesticides interfere with the innate and adaptive immune response.
• Cells, animals and human studies demonstrate the immunotoxicity of pesticides in the cellular and humoral immune response.
• Fungicides, herbicides, and insecticides alter the immune system by various mechanisms, such as pro-inflammatory and anti-inflammatory factors.
... Plasma urea and creatinine levels have been shown in human and animal studies to be useful indicators of renal function. An increase in plasma levels indicates that renal function is deteriorating [51]. Intoxication with P. hysterophorus increases the levels of liver enzymes ALT and ALP, which could be due to the generation of reactive oxygen species in the liver, which increases lipid peroxidation and toxic aldehydes, causing inflammation and necrosis [52]. ...
Parthenium hysterophorus L. is a poisonous Asteraceae weed. The phytochemical profile, antioxidant activity, total phenolic contents (TPC), total flavonoid contents (TFC), and cytotoxicity of Parthenium hysterophorus L. flower extract were evaluated in this study, and the toxic effects were assessed in rabbits. The HPLC-DAD system was used for phytochemical analysis. The hemolytic and DPPH assays were performed. The effects of orally administering the flower crude extract to rabbits (n = 5) at four different doses (10, 20, 40, and 80 mg/kg) for ten days on hematological and biochemical parameters were investigated. The crude extract of the flower contained phenolic compounds such as Gallic acid, Chlorogenic acid, Ellagic acid, and P Coumaric acid, which were detected at different retention times, according to the HPLC results. With a sample peak of 4667.475 %, chlorogenic acid was abundant. At concentrations of 80 µg, the methanolic extract of flowers had total phenolic contents (89.364 ± 4.715 g GAE/g) and total flavonoid contents (65.022 ± 2.694 g QE/g). In the DPPH free radical scavenging assay, 80 µg of extract had the highest cell inhibition of 76.90% with an IC50 value of 54.278 µg/µL, while in the hemolytic assay 200 µg of extract had the highest cell inhibition of 76.90% with an IC50 > 500. The biochemical and hematological parameters were altered in the flower extract-fed groups as compared to the control (p < 0.05). The toxic effects on the blood, liver, and kidneys were confirmed. The findings also confirmed the presence of phenolic and flavonoid content in the flower extract, both of which contribute to the plant’s antioxidant potential.
... Neonicotinoid insecticides are extensively utilized to protect the harvest and domesticated animals against the wide scope of pests (Matsuda et al., 2001, Tomizawa andCasida, 2005). The United States Environmental Protection Agency (US-EPA) enlisted the imidacloprid pesticide (IMI) [1-(6-chloro-3-pyridylmethyl)-N-nitr oimidazolidin-2-ylideneamine] in ''Group E" carcinogen, which implies that there is no proof of cancer-causing nature in people (Duzguner and Erdogan, 2012). Even though IMI is somewhat harmful to people and domesticated animals, it might in any case affect some organs like the brain, heart, kidney, testes and gastrointestinal organs causing severe disorders (Abbassy et al., 2014). ...
The neonicotinoid insecticide imidacloprid has been linked to significant reproductive damage in mammals. Origanum majorana essential oil (OME) is a natural herbal product used in the management of many diseases due to its strong antioxidant effects. The oil was hydrodistilled from O. Majorana and analyzed using GC/MS then its possible protective mechanisms against IMI-induced reprotoxicity in male rats were investigated. 28-adult male Wistar rats were divided into 4 groups as follows: group (1) control group, group (2) OME, group (3) IMI, and group (4) IMI+OME. The treatments were applied daily via oral gavage for 60 days. Remarkable abnormalities in both territorial aggressive and sexual behaviors were observed in IMI-treated rats with a significant elevation of serum FSH and LH as well as altered testicular redox status. Along with inhibition of the testicular expression of StAR and aromatase genes and serum total testosterone in addition to abnormal sperm count, viability, motility, and morphology. Histopathological examination showed severe degeneration and necrosis in both germ cells and Leydig cells with atrophy in most of the seminiferous tubules. Co-administration of OME with IMI notably improved all the above-mentioned studied parameters, and restored rats’ spermatogenesis, sexual behavior, and favorably modulates the levels of both testosterone and gonadotropic hormones via its potent antioxidant effect. These findings support the use of OME as a fertility enhancer and suggest that it could be used to manage pesticide-induced male infertility.
... Quantitative analyses of mRNA confirmed that IMI-induced mRNA transcriptions of three isoforms of nitric oxide synthases (iNOS, eNOS, nNOS) in brain and two isoforms (iNOS, eNOS) in liver. Evidence of chronic inflammation by IMI was observed as induction of proinflammatory cytokines TNF-α, IL-1β, IL-6, IL-12 and IFN-γ in liver and brain Duzguner and Erdogan (2012) Adult male Wistar Rats 28 days IMI 45 and 90 mg/kg BW/day alone and plus CUR 100 mg/kg BW/day oral gavage To investigate the neurotoxicity and biochemical changes as a result of IMI exposure and the potential protective role of CUR CUR restored the altered functions of biochemical markers and neurotoxicity in IMI exposed rats Lonare et al. (2014) may affect the developing mammalian nervous system, just as nicotine does (Kimura-Kuroda et al. 2012). EFSA also indicated that both ACE and IMI may affect neuronal development and function, although further good-quality in vivo data are needed to more properly characterize a developmental neurotoxicity potential and associated dose-response relationships; all dosed animals should be subjected to neuropathological analysis including histology of the brain, in accordance with OECD TG 426 (EFSA 2013d;OECD 2007). ...
Neonicotinoids are the most widely used pesticides in the world. However, research studies have shown that it can affect the cognitive abilities and health of non-target bees and other wild pollinators by inducing DNA damage, apoptosis and mitochondrial damage, injure to its central nervous system, and it is even developmentally neurotoxic to mammals and humans, with mitochondria being an important target of neonicotinoids. Therefore, this article reviews the role of mitochondrial morphology, calcium ions (Ca²⁺) homeostasis, respiratory function, apoptosis, and DNA damage in neonicotinoids-induced systemic toxicity. Additionally, it evaluates the protective effects of various active substances including vitamin C, N-acetylcysteine (NAC), curcumin (CUR), glutathione reduced (GSH), caffeic acid phenethyl ester (CAPE), resveratrol, and thymoquinone (TQ) on neonicotinoids-induced toxicity. This review manuscript found that mitochondria are important targets to neonicotinoids. Neonicotinoids can cause DNA damage, apoptosis, protein oxidation, and lipid peroxidation in non-target organisms by altering mitochondrial Ca²⁺ homeostasis, inhibiting mitochondrial respiration, and inducing reactive oxygen species (ROS) production. Several active substances (vitamin C, NAC, CUR, GSH, resveratrol, CAPE, and TQ) play a protective role against neonicotinoid-induced systemic toxicity by inhibiting ROS signaling pathways, apoptosis, and lipid peroxidation. This review manuscript emphasizes the importance and urgency of the development of neonicotinoid antidotes, emphasizes the prospect of the application of targeted mitochondrial antidotes, and prospects the development of neonicotinoid antidotes in order to provide some strategies for the prevention of neonicotinoid toxicity.
... These findings agreed with other reports that showed that lufenuron, belonging to the same hexaflumuron-family, was able to induce oxidative stress damage in the liver of rats (Basal et al. 2020). Also, chronic exposure to IM alters inflammation and oxidative stress markers in the liver and central nervous system of rats (Duzguner and Erdogan 2012). Increasing MDA levels suggest free O 2 overproduction that initiates DNA damage, protein degradation, lipid peroxidation and tissue damage particularly liver (organ of detoxification) and kidneys (organ of excretion) (Timoumi et al. 2019). ...
Pesticides are viewed as a major wellspring of ecological contamination and causing serious risky consequences for people and animals. Imidacloprid (IM) and hexaflumuron (HFM) are extensively utilized insect poisons for crop assurance on the planet. A few investigations examined IM harmfulness in rodents, but its exact mechanism hasn’t been mentioned previously as well as the toxicity of HFM doesn’t elucidate yet. For this reason, the present study was designed to explore the mechanism of each IM and HFM–evoked rat liver and kidney toxicity and to understand its molecular mechanism. 21 male Wistar albino rats were divided into 3 groups, as follows: group (1), normal saline; group (2), IM; and group (3), HFM. Both insecticides were orally administered every day for 28 days at a dose equal to 1/10 LD50 from the active ingredient. After 28 days postdosing, rats were anesthetized to collect blood samples then euthanized to collect liver and kidney tissue specimens. The results showed marked changes in walking, body tension, alertness, and head movement with a significant reduction in rats’ body weight in both IM and HFM receiving groups. Significant increases in MDA levels and decrease of GHS levels were recorded in liver and kidney homogenates of either IM or HFM groups. Liver and kidney tissues obtained from both pesticide receiving groups showed extensive histopathological alterations with a significant increase in the serum levels of ALT, AST, urea, and creatinine and a decrease in total proteins, albumin, and globulin levels. In addition, there was upregulation of the transcript levels of casp-3, JNK, and HO-1 genes with strong immunopositivity of casp-3, TNF-ὰ, and NF-KB protein expressions in the liver and kidneys of rats receiving either IM or HFM compared with the control group. In all studied parameters, HFM caused hepatorenal toxicity more than those induced by IM. We can conclude that each IM and HFM provoked liver and kidneys damage through overproduction of ROS, activation of NF-KB signaling pathways and mitochondrial/JNK-dependent apoptosis pathway.
... Our results revealed mice are treated with EMB produces a significant upregulation in the IL1b gene expression levels in the liver. These outcomes are in parallel to that reported by Liu (35). They found avermectin causes immune suppression by increasing the IL-1 β-mRNA levels in the pigeon. ...
Background:
Emamectin benzoate (EMB) is a biopesticide which used in agriculture as an insecticide. It is easier to reach ecologically and affects human health. This study aims to evaluate the protective effect of chitosan and chitosan nanoparticles against EMB-induced hepatotoxicity.
Methods:
Male mice were distributed into four groups: G1: the negative control, G2: EMB group (5 mg/kg diet), G3: EMB with Chitosan, (600 mg/kg diet), and G4: EMB with Chitosan nanoparticles (600 mg/kg diet). The experiment continues for 8 weeks, and the animals were sacrificed, and their organs were removed and immediately weighed after sacrifice. The liver was quickly removed and processed for histopathological and genetic studies.
Results:
Emamectin benzoate (EMB) treatment induced oxidative stress by increased levels of Malondialdehyde (MDA), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with inhibition of acetylcholinesterase (AChE), Superoxide dismutase (SOD) and Catalase (CAT) levels. EMB produced several histopathological changes in the liver. Relative expressions of studied genes elevated in the liver with increase in DNA damage. Co-treatment with chitosan and chitosan nanoparticles reduced EMB related liver toxicity that belong to biochemical, histopathological, gene expression, and DNA damage by increasing antioxidant capacity.
Conclusion:
This study offers insight into the potential for Chitosan and chitosan nanoparticles as a novel natural material against the oxidative stress induced by EMB.
... Currently, studies on the adverse effects of mNNIs exposure on human semen quality and the related mechanisms are scarce; the hypothesis of the underlying mechanism is mainly derived from animal experiments. Animal studies have shown that IMI can cause oxidative stress at 1 mg/kg bw/day (Duzguner and Erdogan, 2012). In addition, it has been demonstrated that steroid hormone synthesis could be interfered by low concentrations of IMI both in vitro (Caron-Beaudoin et al., 2018) and in vivo (Bal et al., 2012c). ...
Animal studies have revealed that exposure to neonicotinoid insecticides (NNIs) could compromise male reproductive function; however, related data on the occurrence of NNIs and their specific metabolites in human seminal plasma are scarce. To explore the potential effects of NNI exposure on male semen quality, we determined the presence of NNIs and some of their metabolites (collectively defined as mNNIs) in seminal plasma samples collected from men (n = 191) who visited a fertility clinic in Shijiazhuang, North China from 2018 to 2019. Associations between the mNNI concentrations and semen quality parameters were assessed using linear regression models, adjusting for important covariates. In the seminal plasma samples, desmethyl-acetamiprid (DM-ACE, detection frequency: 98.4%), imidacloprid-olefin (IMI-olefin, detection frequency: 86.5%), and desmethyl-clothianidin (DM-CLO, detection frequency: 70.8%) were frequently detected at median concentrations of 0.052, 0.003, and 0.007 ng/mL, respectively; meanwhile other compounds were detected at less than the method detection limits. In the single-mNNI models, the IMI-olefin concentration was associated with decreased progressive motility [IMI-olefin concentration: percent change (%Δ) = −17.0; 95% confidence interval (CI) = −30.3, −0.92; the highest tertile compared with the lowest tertile: %Δ = −21.1; 95% CI = −37.5, −0.23]. Similar results were found in the multiple-mNNIs models. No other inverse associations were found between the other mNNIs concentrations and semen quality parameters. This is the first study to identify the occurrence of mNNIs in the seminal plasma and the potential associations of their concentrations with human semen quality parameters. These findings imply an inverse association between the IMI-olefin concentration and semen quality.
... Experimental evidence demonstrates harmful effects of IMD at various concentrations and exposure times, as tested in rats, mice, bovines, and chickens; results of these experiments demonstrate hepatotoxic effects, including hepatocyte degeneration, hepatic sinus congestion, central venous dilation, hemorrhage (Kammon et al. 2010;Mohany et al. 2011;Toor et al. 2013), hypertrophied blood vessels, cytoplasmic lesions, pycnotic nuclei, leukocyte infiltration, hepatic necrosis and release of the enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) into the extracellular medium (Duzguner and Erdogan 2012;Desai and Parikh 2013;Soujanya et al. 2013;Arfat et al. 2014;Kapoor et al. 2014;Qadir et al. 2014). ...
Imidacloprid (IMD) is a neonicotinoid insecticide used in large quantities worldwide in both veterinary and agronomic applications. Several studies have shown adverse effects of IMD on non-target organisms, with the liver being identified as the main affected organ. This study aimed to evaluate the effects of IMD on human hepatoblastoma (HepG2) cells. HepG2 were exposed to IMD (0.25-2.0 mM) for 24 and 48 hours. IMD treatment resulted in cytotoxicity in the HepG2, inhibiting cell proliferation in a dose- and time-dependent manner, starting at concentrations of 0.5 mM (24 hours) and 0.25 mM (48 hours), and reducing cell viability from 0.5 mM onwards (24 and 48 hours). IMD significantly decreased the mitochondrial membrane potential at both time points investigated (2.0 mM), and also induced damage to the cell membrane, demonstrated by significant dose and time-dependent increases in lactate dehydrogenase (LDH) release from concentrations of 1.0 mM (24 hours) and 0.5 mM (48 hours) upwards. IMD treatment also increased the production of reactive oxygen and nitrogen species (ROS/RNS) at rates above 50% following 0.5 mM (24 hours) or 0.25 mM (48 hours) concentrations, and caused a significant decrease in reduced/oxidized glutathione ratio (GSH/GSSG), indicating oxidative stress. Furthermore, the antioxidant dithiothreitol, which reacts with ROS/RNS and acts as a thiol reducing agent, inhibited the cytotoxic effect of IMD. In addition, the metabolite IMD-olefin was more toxic than IMD. Our results indicate that IMD induces cytotoxicity in HepG2 cells and that this effect may be associated with an increase in the generation of ROS/RNS.
... This activity has been assumed to be relatively specific for the insect nervous system (Brown et al. 2006;Tan et al. 2007), as neonicotinoids have been developed to exhibit a higher affinity for insect nAChRs compared to vertebrate paralogs Tomizawa and Casida 2005;Casida 2018). However, some studies suggest adverse effects of neonicotinoids on mammals (Abou-Donia et al. 2008;Duzguner and Erdogan 2012;Burke et al. 2018;Berheim et al. 2019). A broad toxicological debate has been triggered by the observation that acetamiprid and IMI activated the nAChRs on neonatal rat neurons in the low µM range (Kimura-Kuroda et al. 2012). ...
Several neonicotinoids have recently been shown to activate the nicotinic acetylcholine receptor (nAChR) on human neurons. Moreover, imidacloprid (IMI) and other members of this pesticide family form a set of diverse metabolites within crops. Among these, desnitro-imidacloprid (DN-IMI) is of special toxicological interest, as there is evidence (i) for human dietary exposure to this metabolite, (ii) and that DN-IMI is a strong trigger of mammalian nicotinic responses. We set out here to quantify responses of human nAChRs to DN-IMI and an alternative metabolite, IMI-olefin. To evaluate toxicological hazards, these data were then compared to those of IMI and nicotine. Ca2+-imaging experiments on human neurons showed that DN-IMI exhibits an agonistic effect on nAChRs at sub-micromolar concentrations (equipotent with nicotine) while IMI-olefin activated the receptors less potently (in a similar range as IMI). Direct experimental data on the interaction with defined receptor subtypes were obtained by heterologous expression of various human nAChR subtypes in Xenopus laevis oocytes and measurement of the transmembrane currents evoked by exposure to putative ligands. DN-IMI acted on the physiologically important human nAChR subtypes α7, α3β4, and α4β2 (high-sensitivity variant) with similar potency as nicotine. IMI and IMI-olefin were confirmed as nAChR agonists, although with 2–3 orders of magnitude lower potency. Molecular docking studies, using receptor models for the α7 and α4β2 nAChR subtypes supported an activity of DN-IMI similar to that of nicotine. In summary, these data suggest that DN-IMI functionally affects human neurons similar to the well-established neurotoxicant nicotine by triggering α7 and several non-α7 nAChRs.
... These outcomes are in parallel agreed with that reported by Liu et al., (2014), who found that avermectin caused immune suppression by increasing the IL-1 β-mRNA levels in the pigeon. Also, Duzguner and Erdogan, (2014), found that imidacloprid stimulated IL-1b expressions in the liver. On the other hand, treatment with natural compounds led to a downregulation the expression of genes as a result of reducing the harmful effects of the insecticide. ...
Emamectin benzoate (EMB) is a biopesticide that is used in agriculture as an insecticide. Due to its wide range of use, it is easier to reach ecologically and affects human health. This study aims to evaluate the protective effect of natural compounds against EMB-induced hepatotoxicity. It is the first study quantifying the hepatoprotective effect of these extracts against EMB effects. Biochemical analysis includes MDA, CAT, SOD, ALT and AST analysis. However, genetic studies include the gene expression of Mgst1, CYP2E1, caspase3, IL-1β and DNA fragmentation, as well as, histopathological investigations were performed. Male mice were distributed into five groups: G1: the negative control, G2: EMB group (5mg/kg diet), G3: EMB+Boswellia serrata (90 mg/kg diet), G4: EMB+Cinnamomum zeylanicum (600mg/kg diet), G5: EMB+ powder of the snail (600mg/kg diet), and the experiment continues for eight weeks. The results appeared that EMB induced oxidative stress in the liver by increase the activity of MDA. The biomarker of liver injury ALT and AST were elevated with antioxidant enzymes inhibition. EMB produced several histopathological changes in the liver. Relative expressions of Mgst1, CYP2E, caspase-3 and IL-1β genes elevated in the liver. The increase in DNA damage was noticed as recorded by an increase in tail length, tail DNA% and tail moment. Co-treatment with natural compounds reduced the toxicity of EMB. They reduce the abnormal biochemical, histopathological, gene expression and DNA damage by increasing antioxidant capacity. Therefore, the natural compounds used in this study act as potent hepatoprotective agents against EMB induced hepatotoxicity in mice.
... Owumi and Dim (2019) reported in the study that there was a significant increase in MPO enzyme activity at 14 days of exposure to chlorpyrifos (5 mg/kg) in adult male Wistar rats liver and kidney tissues compared to the control group. Duzguner and Erdogan (2012) reported that the increase in MPO enzyme activity in 30 days chronic period of exposure to imidacloprid (1 mg/kg b. wt.) in the liver and brain tissues of Wistar rats is evidence that the effect of intense oxidative stress. ...
The study of the toxic effects of emamectin benzoate (EMB) was conducted in male mice. Mice were randomly divided into 4 groups; control group, EMB25 group (1/30 LD50 = 25 mg/kg/day), EMB50 group (1/15 LD50 = 50 mg/kg/day), and EMB100 group (1/7.5 LD50 = 100 mg/kg/day). Control group received water (placebo), and EMB groups were administered by oral gavage for 14 days. The superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) enzyme activities, thiobarbituric acid reactive substance (TBARS) and protein carbonyl (PC) levels, and adenosine triphosphatase (ATPases) enzymes, which are ion transport enzymes (Na+/K+ ATPase, Ca+2 ATPase, Mg+2 ATPase), acetylcholinesterase (AChE, neurotoxicity biomarker), and myeloperoxidase (MPO) enzyme activities (inflammatory biomarker), were measured by spectrophotometric methods. 8-Hydroxy-2′-deoxyguanosine level (8-OHdG, DNA oxidation biomarker) was measured by enzyme-linked immunosorbent analysis (ELISA) technique. The results showed a decrease in SOD, CAT and GPx enzyme activities in the brain tissue and an increase in GST enzyme activity in the EMB groups compared to the control group. Meanwhile, the enzyme activities of the ion transport enzymes Na+/K+ ATPase, Ca+2 ATPase, and Mg+2 ATPase, and AChE enzyme activity showed significant inhibition. In addition, MPO enzyme activity, 8-OHdG, PC, and TBARS levels were increased. The results showed that dose-dependent EMB exposure induced different physiological processes with enzymatic and biomolecular multi-biomarkers in the brain tissue of male mice and caused neurotoxic effects.
... These ndings agreed with other report showed that lufenuron, belonging to the same hexa umuron-family, was able to induce oxidative stress damage in the liver of rats (Basal et al. 2020). Also, chronic exposure to IC alters in ammation and oxidative stress markers in the liver and central nervous system of rats (Duzguner and Erdogan 2012). Increasing MDA levels suggest free O 2 overproduction that initiates DNA damage, protein degradation, lipid peroxidation and tissue damage particularly liver (organ of detoxi cation) and kidneys (organ of excretion) (Timoumi et al. 2019). ...
Pesticides are considered the main source of environmental pollution and causing severe hazardous effects on humans and livestock. Imidacloprid (IC) and hexaflumuron (HFM) are broadly used insecticides for crop protection in the world. Some studies discussed IC toxicity in rats, but the toxicity of HFM doesn’t elucidate yet. So that, the current study aimed to investigate the pathogenesis and the mechanistic way of both IC and HFM induced hepatorenal toxicity in rats with comprehensive insight into its molecular mechanism. 21 male Wistar albino rats were divided into 3 groups as the following: group (1), normal saline; group (2), receiving IC; and group (3), receiving HFM. All the following materials were orally administered every day for 28 days. At the end, all rats were euthanized to collect blood and organ samples (liver and kidneys). The results revealed behavioral alterations in walking, body tension, alertness, and head movement as well as a decrease in body weight of rats receiving either IC or HFM. In addition to increasing the levels of MDA with decreasing GHS levels in liver and kidney homogenates. Both liver and kidney tissues showed extensive histopathological alterations associated with increasing the serum levels of ALT, AST, urea, and creatinine as well as reduction in total proteins, albumin, and globulin levels. Furthermore, there was upregulation of m-RNA levels of caspase-3, JNK, and HO-1 genes with strong positive reaction of caspase-3, TNF-ὰ and NF- K B proteins in both liver and kidneys of rats receiving either IC or HFM compared with the control group. We can conclude that both IC and HFM induced oxidative hepatorenal damage via ROS overproduction that activate NF- K B signaling pathways and mitochondrial and JNK dependent apoptosis pathway.
Imidacloprid (IMID) is one of the most widely used neonicotinoid insecticides globally and, consequently, a probable widespread environmental contaminant. The potential neurotoxic effects of IMID have been previously reported. This study aimed to investigate the possible beneficial effect of thymol (TML) in relieving IMID-induced harmful effects on the brain of male Sprague-Dawley rats. For this aim, four groups (10 rats/group) were orally administered corn oil, TML (30 mg/kg b.wt), IMID (22.5 mg/kg b.wt), or TML + IMID for 56 days. The brain tissues were biochemically, histopathologically, and immunohistochemically evaluated. The results displayed that TML significantly restored the IMID-induced depletion of the total antioxidant capacity of the brain tissues. At the same time, the IMID-associated increased levels of lipid peroxidation in terms of malondialdehyde content were markedly suppressed in the TML + IMID group. Also, TML oral dosing markedly reduced the release of inflammatory elements, including nitric oxide and myeloperoxidase, resulting from IMID exposure. Furthermore, the IMID-induced decrease in gamma-aminobutyric acid but the increase in acetylcholinesterase was considerably reversed by TML oral dosing. Additionally, TML oral administration significantly counteracted the IMID-induced hepatic DNA damage, as revealed by the comet assay. Besides, a significant downregulation in hepatic Caspase-3 was evident in the TML + IMID group compared to the IMID group. However, TML oral dosing has not significantly altered the IMID-induced nuclear factor (NF-κB p65) increase. Therefore, TML could be a protective agent against IMID-induced detrimental impacts on brain tissue, possibly through its antioxidant, antiapoptotic, and anti-inflammatory activities.
Since neonicotinoids (NNIs) are widely used around the world, they are extensively distributed in the environment and frequently occurred in humans. This study was conducted to assess the risk of NNIs residues in vegetables and fruits in Henan province, and evaluate the associations of NNIs single and mixed exposure with glucose metabolism, and further explore whether testosterone mediated these relationships in Henan rural population. The data of vegetables and fruits were collected from Henan Province in 2020-2021, and participants were drawn from the Henan Rural Cohort study. Hazard quotient (HQ) and hazard index (HI) were used to assess the risk of exposure to the individual and combined NNIs through vegetables or fruits intake. Relative potency factor (RPF) method was utilized to normalize each NNIs to imidacloprid (IMIRPF). Generalized linear models were used to explore the effects of each NNIs and IMIRPF on glucose metabolism. Weight quartile sum (WQS) regression and Bayesian kernel machine regression (BKMR) model were applied to estimate the effect of NNIs mixtures on glucose metabolism. Mediation analysis was employed to explore whether testosterone mediated these relationships. The HQs and HI in both vegetables and fruits were much lower than 1, which indicated that NNIs in vegetables and fruits were not expected to cause significant adverse effects. However, plasma natural logarithm nitenpyram (Ln_NIT), Ln_thiacloprid-amid (Ln_THD-A), and Ln_IMIeq were positively associated with type 2 diabetes mellitus (T2DM) (odds ratio (OR) (95% confidence interval (CI)): 1.12 (1.05, 1.19), 1.21 (1.10, 1.32), and 1.48 (1.22, 1.80)). Both WQS regression and BKMR models observed significantly positive associations between NNIs mixture exposure and T2DM. Testosterone partially mediated these associations among women (PE = 6.67%). These findings suggest that human NNIs exposure may impair glucose metabolism and could contribute to rising rates of T2DM, and it's necessary to regulate the use of pesticides in rural areas.
The co-exposure of microplastics (MPs) and other contaminants has aroused extensive attention, but the combined impacts of MPs and pesticides remain poorly understood. Acetochlor (ACT), a widely used chloroacetamide herbicide, has raised concerns for its potential bio-adverse effects. This study evaluated the influences of polyethylene microplastics (PE-MPs) for acute toxicity, bioaccumulation, and intestinal toxicity in zebrafish to ACT. We found that PE-MPs significantly enhanced ACT acute toxicity. Also, PE-MPs increased the accumulation of ACT in zebrafish and aggravate the oxidative stress damage of ACT in intestines. Exposure to PE-MPs or/and ACT causes mild damage to the gut tissue of zebrafish and altered gut microbial composition. In terms of gene transcription, ACT exposure triggered a significant increase in inflammatory response-related gene expressions in the intestines, while some pro-inflammatory factors were found to be inhibited by PE-MPs. This study provides a new perspective on the fate of MPs in the environment and on the assessment of the combined effects of MPs and pesticides on organisms.
The neonicotinoid imidacloprid was promoted in the market because of widespread resistance to other insecticides, plus its low mammalian impact and higher specific toxicity towards insects. This study aimed to evaluate the immunomodulatory effect of imidacloprid on macrophages. RAW 264.7 cells were incubated to 0-4000mg/L of imidacloprid for 24 and 96h. Imidacloprid presented a concentration-dependent cytotoxicity after 24h and 96h incubation for MTT reduction (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide) (EC50 519.6 and 324.6mg/L, respectively) and Neutral Red (3-amino-7-dimethylamino-2-methylphenazine hydrochloride) assays (EC50 1139.0 and 324.2mg/L, respectively). Moreover, imidacloprid decreased the cells' inflammatory response and promoted a mitochondrial depolarization. The complex II and succinate dehydrogenase (SDH) activities in RAW 264.7 cells incubated with imidacloprid increased more at 24h. These results suggest that imidacloprid exerts an immunomodulatory effect and mitochondria can act as regulator of innate immune responses in the cytotoxicity mediated by the insecticide in RAW 264.7 cells.
Introduction
Although excessive use of pesticides and unsafe agricultural practices may contribute to numerous intoxications, the role of PPE (personal-protective-equipment) in the minimization of toxicological effects due to pesticide exposure has not been addressed so far. The present study aimed to assess the impact of the use of PPE on the minimization of effects of exposure to pesticides among farm-workers.
Methods
A community-based follow-up study with questionnaire-based survey and field observations was undertaken among farm-workers (n = 180) of Rangareddy district, Telangana, India. Biomarkers of exposure such as cholinesterase activity, inflammatory markers (TNF-α, IL-1β, IL-6, cortisol, and hs-C reactive protein), nutrients (vitamins A, E), liver function (total protein and A/G ratio, AST and ALT levels) were investigated in the laboratory by following the standard protocols.
Results
Farm-workers who had a mean farming exposure of 18 years of and who neither followed safe pesticide handling practices nor used PPE and also showed reluctance to obey good agricultural practices (GAPs). Inhibition of AChE (acetylcholine esterase) with increased inflammation was found among farm-workers as compared to their respective normal values when they have not used PPE. Linear regression statistical analysis revealed a profound effect on inhibition in the AChE activity and various inflammatory markers with the increase in the duration of pesticide exposure. Further, there was no effect of the duration of pesticide exposure on the levels of vitamins A, E, ALT, AST, total protein, and A/G ratio. Further, intervention studies carried out on the use of PPE provided (commercially available and cost-effective) for 90 days showed a significant reduction in the biomarker levels (p < 0.01).
Conclusion
This study demonstrated the importance of the use of PPE during pesticide applications and other agricultural tasks to minimize pesticide-associated adverse health effects.
Neonicotinoid insecticides, known for their selectivity and low mammalian toxicity, have been widely used in recent years as alternatives to organophosphate insecticides. Although neonicotinoids are generally considered to be safe, data show that they can cause harmful effects on human and environmental health. Due to the lack of information on their mechanism of toxicity, the effects of imidacloprid and thiamethoxam on DNA methylation as the most used marker for epigenetic effects were investigated in human neuroblastoma (SH-SY5Y) cells. The cells were exposed to imidacloprid and thiamethoxam in concentrations of 100, 200, and 500 μM for 24 hours, then global DNA methylation and expression of genes involved in global DNA methylation (DNMT1, DNMT3a and DNMT3b) were investigated. Global DNA methylation significantly increased after imidacloprid exposure at 100 μM, and thiamethoxam exposures at 200 µM and 500 μM (>1.5-fold). Imidacloprid significantly decreased the expression of DNMT1 and DNMT3a, whereas thiamethoxam did not cause any significant changes in the expression of DNMT genes. Our findings suggested that alteration in global DNA methylation may be involved in the toxic mechanisms of imidacloprid and thiametoxam.
Imidacloprid (IMI), the main component of neonicotinoid insecticides, promotes oxidative stress and genotoxicity in mammals. The aim of this experiment is to assess oxidative stress in liver cells and genotoxicity of erythrocytes for rats exposed to sub-lethal doses of IMI and the protective effects for Rhodophyta as antioxidant material versus imidacloprid. A total of 30 adult male albino rats (average body weight, 190-200 g) were divided into six groups (n=5) as follows: group 1 served as the control, group 2 received 200 mg/kg red algae, group 3 received 45 mg/kg IMI (high-dose group), group 4 received 22.5 mg/kg IMI (low-dose group), group 5 received 200 mg/kg red algae +45 mg/kg IMI, and group 6 received 200 mg/kg red algae +22.5 mg/kg IMI. After 28 d of treatment, the antioxidant activity of the crude extract of red algae was assessed in terms of free radical scavenging activity and found to be higher in TCA (75.57%) followed by DPPH (50.08%) at concentration 100 μg extract and a significant increase in lipid peroxidation and reductions in glutathione were observed in liver cells were intoxicated with high and low doses of IMI. Moreover decreases in catalase and glutathione peroxidase parameters in same previous groups which indicated oxidative stress. In addition significant increases in micronucleus frequency (MN) in the bone marrow of the rats as a genotoxicity marker which indicated DNA damage in erythrocytes cells with alterations in the histopathology of liver cells were also noted such as necrosis, inflammatory cells, infiltration, and necrobiotic changes. Whereas Rhodophyta succeeded in alleviation the oxidative damage and genotoxicity induced by the insecticide. In conclusion, IMI demonstrates hazardous effects, such as alterations in antioxidant status and mutagenicity of erythrocytes and polysaccharides from Rhodophyta has good antioxidant activity in vivo model systems against imidacloprid.
Wastewater effluent-dominated streams are becoming increasingly common worldwide, including in temperate regions, with potential impacts on ecological systems and drinking water sources. We recently quantified the occurrence/ spatiotemporal dynamics of...
Background
An increasing number of studies have reported neonicotinoid insecticides (NEOs), the emerging alternatives to conventional insecticides, may increase oxidative stress and cause adverse health effects, but limited is known about the prenatal NEOs exposures and their impact on birth outcomes.
Objectives
We investigated the levels of prenatal exposure to NEOs/metabolites, to assess their associations with birth outcomes, and investigate whether these associations could be mediated by oxidative stress using 8-OHdG as the biomarker.
Methods
We studied 296 mother-infant pairs recruited from Laizhou Wan Birth Cohort in 2010 – 2013. Two NEOs (IMI and ACE), three metabolites (6-CN, ND-ACE, and 2CTCA), and 8-OHdG were measured in maternal urine collected before delivery. Birth outcomes including birth weight, birth length, ponderal index (PI), head circumference, and gestational age, were acquired. We examined the associations between NEOs/metabolites and birth outcomes using multivariable linear regression. Mediation analysis was conducted to clarify the role of 8-OHdG on the association of NEOs/metabolites exposure and birth outcomes.
Results
Highest detection rate was observed for ACE (100.0%), followed by IMI (98.3%) and 6-CN (98.0%), suggesting the common exposure of pregnant women. The highest median concentration was observed for 6-CN with creatinine-adjusted median levels of 9.58 μg/g creatinine. A decrease in newborns’ head circumference was observed with a 10-fold increase in IMI (β = -1.83; 95% CI = -3.04, −0.62) and ACE (β = -2.27; 95% CI = -3.56, −0.98). An increase in newborns’ PI was observed with a 10-fold increase in IMI (β = 0.40; 95% CI = 0.03, 0.75). Maternal 8-OHdG demonstrated 38.5–65.5% mediating effects in the negative association of IMI, ACE, 2-CTCA with head circumference. These associations might differ between boys and girls.
Conclusions
Pregnant women were widely exposed to NEOs/metabolites in China. Results suggested the potential impacts of prenatal exposure to certain neonicotinoid insecticides on head circumference. Urinary 8-OHdG may partly mediate these associations.
Since the past few decades, various chemicals and termed pesticides have been used to protect the crops from pests. The pesticides are mostly used in large quantities in agriculture and toxic exposure to such chemicals is reported to impact human health by causing morbidity and severe disabilities. The indiscriminate use of different pesticides is reported to cause neurotoxicological problems at different stages of human lives. Most of the pesticides are reported to raise the oxidative stress level in the human system. This elevated level of reactive oxygen species is known to exhibit severe damage to different cellular systems. Neuron cells are highly sensitive toward the elevation of oxidative stress and thus pesticide-mediated toxicity leads to different neurological disorders in humans. This chapter elaborates upon different classes of pesticides and their effect on oxidative stress. Following this, the association between pesticide exposure and the development of different neurological disorders are also discussed in this chapter.KeywordsPesticidesOxidative stressNeurological disordersReactive oxygen speciesNervous system
Probiotics have been shown to have positive effects when it comes to combating various health issues when consumed, preventing even the absorption of environmental toxins. One of the main environmental toxins encountered today is pesticide residues. Neonicotinoids, widely applied today in countries that have approved of them, are a known class of insecticides with an excellent and effective potency. Neonicotinoids have been shown to cause various toxic effects, either acutely or chronically, on human health and on beneficial insects when exposed. To clarify the assumption that probiotics could counteract these toxic effects, especially on vital organs, the probiotic yeast “Saccharomyces boulardii” (S. boulardii) was tested against the neonicotinoids, acetamiprid (ACE) and imidacloprid (IMI), as it has outstanding physiological and metabolic properties. The results obtained from the studies indicated that although ACE and IMI induced liver, kidney, brain and bowel damage, there was a considerable level of protection by the dietary supplementation of S. boulardii, as it reduced the absorption of these insecticides.
The aim of this study was to investigate whether vitamin E (VitE) and selenium (Se) or VitE plus Se have any the protective and/or augmented effects on cypermethrin (CYP)-induced oxidative stress in liver, brain, kidney and blood in rats. Rats were treated orally with daily 50 mg/kg (∼ 1/4 ED50) of CYP in corn oil for five days after administrations of VitE (100 mg/kg sc.), Se (0.1 mg/kg, sc.) and VitE plus Se for three days. Malondialdehyde (MDA) concentrations, glutathione peroxidase (GSH-Px) and catalase (CAT) activities were measured in tissues and blood samples. MDA concentrations in all tissues except plasma, and GSH-Px activities in liver and erythrocytes were significantly increased, but CAT activities in all tissues except erythrocytes were decreased in CYP treated group when compared with the control group. Treatment with VitE prior to CYP reduced sensitivity on CYP-induced oxidative stress. The use of Se was observed to increase both MDA concentrations and antioxidant systems such as GSH-Px and CAT activities. On the other hand, VitE plus Se caused complex alterations in the antioxidant system on the oxidative stress induced by CYP. The results suggest that CYP can induce oxidative stress and VitE can modify CYP metabolism and play a protective role against CYP-induced oxidative stress.
The actions of neonicotinoid insecticides on nicotinic acetylcholine receptors (nAChRs) in the terminal abdominal ganglion neurons of the American cockroach were investigated using whole-cell patch-clamp electrophysiology. Neonicotinoids possessing a nitromethylene group showed higher agonist affinity than the corresponding nitroimine analogues, whereas compounds with an acyclic guanidine moiety showed greater agonist efficacy than the corresponding cyclic compounds. Imidacloprid showed the lowest agonist efficacy of all neonicotinoids and low concentrations of imidacloprid attenuated acetylcholine-induced currents. However, such blocking actions were minimal with other neonicotinoids. The diverse actions of neonicotinoids on nAChRs, combined with target accessibility based on hydrophobicity, appears to account for their insecticidal potency on cockroaches measured in the presence of metabolic inhibitors.
The neurotoxic effects and acetylcholinesterase inhibition induced by endosulfan, and the amelioration of these effects by Vitamin C (Vit C), were studied in the brains of New Zealand white rabbits. The cerebrum and cerebellum of each rabbit was examined grossly and histopathologically, and caspase-3 activity was determined by immunohistochemical methods. Twenty-four rabbits were divided into four groups (n = 6). Rabbits in Group I (END) were given a sublethal dose of endosulfan (1 mg/kg bw) in corn oil daily by oral gavage for 6 weeks. Group II (END + C) received the same dose of endosulfan and also Vit C (20 mg/kg bw) every second day during the 6 week period. Group III (OIL + C) received oral corn oil daily and Vit C every second day for 6 weeks. Group IV (OIL) received corn oil daily by oral gavage throughout the experiment. A significant reduction in acetylcholinesterase activity was observed in the END group, which was ameliorated in the END + C group. Hyperemia and slight hemorrhages in brains and cerebellums were seen in some rabbits in the END group. There were no gross cerebral or cerebellar lesions in the other groups. Hemorrhages, degenerations and slight gliosis were the marked histopathological findings of some rabbits belonging to the END group. A positive caspase-3 reaction was more severe in the END group than in the others. An ameliorating effect of Vit C on gross, histopathological, and immunohistochemical findings was observed in the END + C group. Thus, although endosulfan could cause neurotoxic effects in rabbits, this toxicity was decreased by Vit C treatment, which increased serum acetylcholinesterase activity.
Imidacloprid is a neonicotinoid insecticide and has been extensively used as a crop pest and pet flea control programme because it’s high specificity as an insecticide. Imidacloprid toxicity on mammalian tissues has not been adequately evaluated. In the present study, potential acute neuro and liver toxic effects of imidacloprid were analyzed in rats as a model of mammalian using antioxidant–oxidant and inflammatory system. 10 μM imidacloprid was administrated intravenously and 2 h post-administration, the rats were sacrificed, liver and brains were surgically removed. Exposure to imidacloprid led to significant increases in nitric oxide concentrations in brain, liver and plasma samples. The quantitative mRNA transcriptional analyses demonstrated that imidacloprid-elevated production of NO levels due to the induction of iNOS in liver, but neither nNOS nor iNOS were induced in brain. The oxidant-generating enzymes xanthine oxidase and myeloperoxidase activities in both tissues were elevated and significant lipid peroxidation in liver and plasma was observed. The antioxidant catalase, superoxide dismutase and glutathione peroxidase activities were differently responded to imidacloprid administration. Significant intracellular glutathione depletion was also measured in both tissues. Imidacloprid treatment up-regulated inflammatory cytokines TNF-α, IL-6 and IL-1β mRNA transcriptions by 2.5- to 5.2-fold increases in both brain and liver. Conversely, anti-inflammatory mediator IL-10 mRNA was down-regulated in both organs. These results suggest that imidacloprid cause oxidative stress and inflammation in central nervous system and liver in non-target organisms in rats.
One,1-dichloro-2,2 bis(p-chlorophenyl) ethylene (p,p′-DDE), the major metabolite of 2,2-bis(4-Chlorophenyl)-1,1,1-trichloroethane (DDT), is a known persistent organic pollutant and male reproductive toxicant. It has antiandrogenic effect. However, the mechanism by which p,p′-DDE exposure causes male reproductive
toxicity remains unknown. In the present study, rat Sertoli cells were used to investigate the molecular mechanism involved in p,p′-DDE-induced toxicity in male reproductive system. The results indicated that p,p′-DDE exposure at over 30 μM showed the induction of apoptotic cell death. p,p′-DDE could induce increases in FasL mRNA and protein, which could be blocked by an antioxidant agent, N-acetyl-l-cysteine (NAC). In addition, caspase-3 and -8 were activated by p,p′-DDE treatment in these cells. The activation of NF-κB was enhanced with the increase of p,p′-DDE dose. Taken together, these results suggested that exposure to p,p′-DDE might induce apoptosis of rat Sertoli cells through a FasL-dependent pathway.
This study investigated the effects of paraquat, a widely used herbicide, on the aquatic unicellular alga Chlorella vulgaris through short-term toxicity tests at the physiological and gene transcriptional levels. Exposure to 0.5 microM paraquat increased the activities of the antioxidant enzymes superoxide dismutase, peroxidase, and catalase to levels 4.93, 3.19, and 3.09 times higher, respectively, than those of the control. Furthermore, exposure to 0.75 microM paraquat increased the activities of these antioxidant enzymes to even higher levels. The decrease in chlorophyll content and the increases in reactive oxygen species (ROS) and malondialdehyde content following exposure to paraquat suggest that the alga was severely damaged and cell growth was greatly inhibited. Real-time PCR showed that paraquat reduced the transcript abundance of psaB and rbcL to 7.09 and 29.83% of the control, respectively. Our results demonstrate that paraquat inhibited electron transport and CO2 assimilation, and also triggered the synthesis of ROS that disrupt cellular structure and inhibit cell growth.
Current risk assessment practices do not consider possible synergistic or antagonistic interactions of compounds to which persons may be exposed during the same period of time. This may simply reflect the minimal amount of data available on such interactions, particularly with regard to immunotoxicology. Therefore, this study was conducted to determine if such interactions occur between the most abundantly used conventional pesticide in the United States (atrazine) and a legacy pesticide that is still present in the United States food supply at levels greater than recognized as safe (dieldrin). The results provide evidence that greater than additive effects on signaling and cytokine production occur and suggest that evaluation of common mixtures for such effects may be needed. The compounds both separately and together directly inhibited cytokine production induced by polyinosinic-polycytidylic acid (poly I:C) by macrophages in cell culture. Subcutaneous administration of dieldrin (10-20 mg/kg, daily for 7 d) and atrazine (one dose on Day 7, 100-200 mg/kg) inhibited the production of IL-6 and IL-12 in the peritoneal cavity in a dose-dependent manner, but IL-10 was either increased or not affected. The suppression of IL-6 production and inhibition of NF-kappa B activation was greater than additive when comparing animals given both compounds to those given either compound separately. However, at lower dosages of both compounds (10 mg/kg dieldrin and 50 mg/kg atrazine), the effect was much greater than additive on IL-6 production (adding the individual effects of atrazine and dieldrin on IL-6 production indicates 20% suppression, whereas the combination yields 80% suppression) and essentially additive for inhibition of the activation of c-JUN (a component of the transcription factor, AP-1). Previously published results indicate that atrazine induces a neuroendocrine stress response, and results reported here indicate that dieldrin at 20 mg/kg increases serum corticosterone concentrations, indicating a stress response. This and other possible mechanisms of the greater than additive effects on cytokine production are discussed. Dieldrin and atrazine administered orally (as opposed to subcutaneously as in the other experiments) also effectively suppressed IL-6 production. These results suggest that interactions other than additive effects for compounds with similar mechanisms of action should be considered in risk assessment. Finally, a molecular mechanism for the greater than additive inhibition of IL-6 production is proposed and a mathematical model incorporating that mechanism is presented.
The role of nitric oxide (NO) in inflammation represents one of the most studied yet controversial subjects in physiology. A number of reports have demonstrated that NO possesses potent anti-inflammatory properties, whereas an equally impressive number of studies suggest that NO may promote inflammation-induced cell and tissue dysfunction. The reasons for these apparent paradoxical observations are not entirely clear; however, we propose that understanding the physiological chemistry of NO and its metabolites will provide a blueprint by which one may distinguish the regulatory/anti-inflammatory properties of NO from its deleterious/proinflammatory effects. The physiological chemistry of NO is complex and encompasses numerous potential reactions. In an attempt to simplify the understanding of this chemistry, the physiological aspects of NO chemistry may be categorized into direct and indirect effects. This type of classification allows for consideration of timing, location, and rate of production of NO and the relevant targets likely to be affected. Direct effects are those reactions in which NO interacts directly with a biological molecule or target and are thought to occur under normal physiological conditions when the rates of NO production are low. Generally, these types of reactions may serve regulatory and/or anti-inflammatory functions. Indirect effects, on the other hand, are those reactions mediated by NO-derived intermediates such as reactive nitrogen oxide species derived from the reaction of NO with oxygen or superoxide and are produced when fluxes of NO are enhanced. We postulate that these types of reactions may predominate during times of active inflammation. Consideration of the physiological chemistry of NO and its metabolites will hopefully allow one to identify which of the many NO-dependent reactions are important in modulating the inflammatory response and may help in the design of new therapeutic strategies for the treatment of inflammatory tissue injury.
Effects of nicotine on arterial endothelium-dependent relaxations mediated by nitric oxide are controversial. Experiments were designed to test the hypothesis that nicotine can directly alter activity of endothelial nitric-oxide synthase (eNOS). NOS from aortic endothelial cells of untreated dogs and recombinant eNOS, neuronal NOS, and inducible NOS were used for these experiments. NOS activity was determined as conversion of L-[(3)H]arginine to L-[(3)H]citrulline in the absence or presence of nicotine (10(-7)-10(-3) M) in vitro. In separate assays, concentrations of cofactors NADPH, FAD, and tetrahydrobioprotein were reduced by half to assess for possible interaction with nicotine. With enzyme from aortic endothelial cells, total and calcium-dependent accumulation of citrulline increased by 30% in the presence of 10(-5) M nicotine. Nicotine dose dependently also increased citrulline accumulation by recombinant eNOS and neuronal NOS but not inducible NOS. Effects of nicotine on accumulation of citrulline by isolated eNOS and recombinant eNOS were further modulated by changes in the concentration of NADPH in the incubation solution. Our data demonstrate a significant effect of nicotine on eNOS-mediated citrulline accumulation. These results suggest that effects of nicotine on production of nitric oxide may depend on NADPH or oxygen radical interactions with NOS and thus may explain, in part, inconsistent findings of changes in production of endothelium-derived nitric oxide with nicotine administration.
The effect of the cyclodiene organochlorine pesticides aldrin, dieldrin and endosulfan was assessed on CHO-K1 cultures at fractions of their lethal doses, determined by the neutral red (NRI) incorporation assay (NRI6.25, NRI12.5 and NRI25). Glutathione peroxidase, reductase and S-transferase, and total and oxidised glutathione were evaluated along the standard growth curve of the cultures. After a 24-h incubation with each insecticide, glutathione peroxidase incurred a large increase, while glutathione reductase and S-transferase activities were slightly higher than untreated controls. Unlike oxidised glutathione, the content of total glutathione declined significantly after exposure to cyclodiene insecticides. Changes in cell membrane integrity were assessed by the lactate dehydrogenase (LDH) release assay and lipid peroxidation for a wide range of pesticide concentrations. Membrane leakage and peroxide production were significantly enhanced at concentrations of aldrin and as low as 12.5 microg/ml, whereas dieldrin and endosulfan increased membrane fragility at much higher concentrations.
We have recently reported that nicotine has angiogenic effects, which appear to be mediated through non-neuronal nicotinic acetylcholine receptors (nAChRs). Here, we describe the endogenous cholinergic pathway for angiogenesis. In an in vitro angiogenesis model, increasing concentrations of the nonselective nAChR antagonist mecamylamine completely and reversibly inhibited endothelial network formation. Although several nAChR isoforms are expressed on endothelial cells (ECs), a similar inhibition was only obtained with the selective alpha7-nAChR antagonist alpha-bungarotoxin, whereas other selective antagonists did not result in significant inhibition of network formation. alpha7-nAChR was upregulated during proliferation, by hypoxia in vitro, and by ischemia in vivo. The nAChR-induced network formation was partially dependent on VEGF, was completely dependent on the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, and finally resulted in NF-kappaB activation. In vivo, pharmacological inhibition of nAChR as well as genetic disruption of alpha7-nAChR expression significantly inhibited inflammatory angiogenesis and reduced ischemia-induced angiogenesis and tumor growth. Our results suggest that nAChRs may play an important role in physiological and pathological angiogenesis. To our knowledge, this is the first description of a cholinergic angiogenic pathway, and it suggests a novel avenue for therapeutic modulation of angiogenesis.
Tobacco smoking has been causally linked to the development of chronic obstructive pulmonary disease. It has been reported that the reactive oxygen species (ROS)- generating enzyme xanthine dehydrogenase/oxidase (XO) is increased in smoking-related stomach ulcers and that gastric mucosal damage caused by tobacco smoke can be blocked by the XO inhibitor allopurinol. In order to test the hypothesis that tobacco may cause the upregulation of XO in the lung, cultured rat pulmonary microvascular endothelial cells were exposed to tobacco smoke condensate (TSC). TSC at a concentration of 20 microg/mL significantly upregulated XO activity after 24 h of exposure. Longer exposure (1 week) to a lower concentration of TSC (2 microg/mL) also caused an increase in XO activity. Unlike hypoxia, TSC treatment did not alter the phosphorylation of XO. However, TSC treatment increased XO mRNA expression and the XO gene promoter activity. Furthermore, actinomycin D blocked the activation of XO by TSC. In conclusion, our results indicate that tobacco smoke condensate causes upregulation of XO transcription and activity.
Use of the real-time polymerase chain reaction (PCR) to amplify cDNA products reverse transcribed from mRNA is on the way to becoming a routine tool in molecular biology to study low abundance gene expression. Real-time PCR is easy to perform, provides the necessary accuracy and produces reliable as well as rapid quantification results. But accurate quantification of nucleic acids requires a reproducible methodology and an adequate mathematical model for data analysis. This study enters into the particular topics of the relative quantification in real-time RT-PCR of a target gene transcript in comparison to a reference gene transcript. Therefore, a new mathematical model is presented. The relative expression ratio is calculated only from the real-time PCR efficiencies and the crossing point deviation of an unknown sample versus a control. This model needs no calibration curve. Control levels were included in the model to standardise each reaction run with respect to RNA integrity, sample loading and inter-PCR variations. High accuracy and reproducibility (<2.5% variation) were reached in LightCycler PCR using the established mathematical model.
The role of nitric oxide (NO) in inflammation represents one of the most studied yet controversial subjects in physiology. A number of reports have demonstrated that NO possesses potent anti-inflammatory properties, whereas an equally impressive number of studies suggest that NO may promote inflammation-induced cell and tissue dysfunction. The reasons for these apparent paradoxical observations are not entirely clear; however, we propose that understanding the physiological chemistry of NO and its metabolites will provide a blueprint by which one may distinguish the regulatory/anti-inflammatory properties of NO from its deleterious/proinflammatory effects. The physiological chemistry of NO is complex and encompasses numerous potential reactions. In an attempt to simplify the understanding of this chemistry, the physiological aspects of NO chemistry may be categorized into direct and indirect effects. This type of classification allows for consideration of timing, location, and rate of production of NO and the relevant targets likely to be affected. Direct effects are those reactions in which NO interacts directly with a biological molecule or target and are thought to occur under normal physiological conditions when the rates of NO production are low. Generally, these types of reactions may serve regulatory and/or anti-inflammatory functions. Indirect effects, on the other hand, are those reactions mediated by NO-derived intermediates such as reactive nitrogen oxide species derived from the reaction of NO with oxygen or superoxide and are produced when fluxes of NO are enhanced. We postulate that these types of reactions may predominate during times of active inflammation. Consideration of the physiological chemistry of NO and its metabolites will hopefully allow one to identify which of the many NO-dependent reactions are important in modulating the inflammatory response and may help in the design of new therapeutic strategies for the treatment of inflammatory tissue injury.
A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
Following the discovery of the insecticidal properties of the heterocyclic nitromethylenes (Soloway et al. 1978), chemists of Nihon Bayer Agrochem started in 1979 to optimize these structures. In 1985 the coupling of the chloropyridyl moiety to the N-nitro substituted imidazolidine ring system enabled the synthesis of the highly active insecticide imidacloprid (Fig. 1). Imidacloprid is the first commercial example of the chloronicotinyl insecticides acting on nicotinic acetylcholine receptors (Leicht 1993). It is now registered in more than 60 countries as a compound with a new or non-conventional mode of action to combat highly resistant insect pests (Elbert et al. 1991; Elbert et al. 1996; Nauen et al. 1996a). Chloronicotinyl insecticides will grow in importance in the coming years because other close analogues of imidacloprid, such as Takeda’s and Nippon Soda’s open chain derivatives nitenpyram and acetamiprid, respectively, have been described (Tomizawa et al. 1995; Yamamoto et al. 1995). During recent years several studies have demonstrated the excellent activity of imidacloprid on pest species of different orders. The present chapter gives an overview of the biological activity of imidacloprid on different target pests, its selectivity even at the molecular level, its physicochemical properties which led to good systemicity and its agricultural importance.
Neuronal nicotinic acetylcholine (nACh) receptors in the brain are more commonly associated with modulatory events than mediation of synaptic transmission. nACh receptors have a high permeability for Ca2+, and Ca2+ signals are pivotal in shaping nACh receptor-mediated neuromodulatory effects. In this review, we consider the mechanisms through which nACh receptors convert rapid ionic signals into sustained, wide-ranging phenomena. The complex Ca2+ responses that are generated after activation of nACh receptors can transmit information beyond the initial domain and facilitate the interface with many intracellular processes. These mechanisms underlie the diverse repertoire of neuronal activities of nicotine in the brain, from the enhancement of learning and memory, to addiction and neuroprotection.
Deltamethrin and thiachloprid are an α-cyano class pyrethroid and neonicotinoid insecticide, respectively. Recently, a pesticide combining deltamethrin and thiacloprid has also been released. In the present study, the acute and subacute toxic effects of deltamethrin, thiachlopride, and a combination of these insecticides, on the lymphoid organs (spleen, thymus and bone marrow), polymorphonuclear leukocytes (PMNs) and plasma of rats, were determined to better understand mammalian antioxidant–oxidant and inflammatory system responses. For this purpose, rats were treated orally with different doses of thiacloprid (single acute dose of 112.5mg/kg); subacute dose of 22.5mg/kg/day for 30days; deltamethrin (single acute dose of 15mg/kg); subacute dose (3mg/kg/day for 30days), or a combination of these pesticides. Results were compared with those from a comparable dosing regimen with the known immunosuppressive drug cyclophosphamide. Pesticide treatments caused significant changes in the levels of liver and kidney injury markers. Antioxidant enzyme (catalase and glutathione peroxidase), glutathione and plasma antioxidant levels decreased but lipid peroxidation increased in all lymphoid organs and the plasma. Glutathione-S-transferase and especially DT-diaphorase activity, decreased after thiacloprid treatment. Myeloperoxidase activity, carbonyl content, lipid peroxidation and total nitrite levels increased in PMNs and plasma. When evaluated as a whole, the oxidative and inflammatory stresses seen in the pesticide combination groups were not much more pronounced than in the groups treated with a single pesticide. In terms of the evaluated biochemical parameters, the pesticides showed similar effects to cyclophosphamide.
Neonicotinoids are the only major new class of insecticides introduced in the past three decades. They act as selective agonists at the insect nicotinic acetylcholine receptor and are therefore highly toxic towards important insect pests but relatively safe to mammals. However, the excellent selective toxicity may not be evident with their metabolites or analogous compounds. The aim of this paper is to consider the effects of neonicotinoids and derivatives in mammalian cells and mice involving up-regulation of nicotinic receptor levels and activation of the intracellular signal integration cascade elicited by chronic or sustained exposure and analgesic and toxic effects in mice.
The favorable selective toxicity of imidacloprid (IMI) to insects versus mammals is attributed to differences in their binding affinity or potency in the nicotinic acetylcholine receptor (nAChR), a proposal tested here by studies on the mechanism of toxicity of IMI metabolites and analogs to mammals. IMI, its desnitro metabolite (DN-IMI), its nitromethylene analog (CH-IMI), and 26 other analogs and metabolites were examined for intraperitoneal toxicity to mice and potency forin vitroinhibition of the binding of [3H]nicotine (the classical nAChR probe) in mouse brain membranes. IMI and 7 analogs with LD50values of 7–50 mg/kg (or intoxication signs at 50 mg/kg) inhibited [3H]nicotine binding by 50% (IC50) at 12–800 nM whereas 21 other analogs that were not toxic at 50 mg/kg gave an IC50of >1000 nM, thereby correlating the toxicity with interaction at the [3H]nicotine binding site. The most potent compounds were DN-IMI and CH-IMI (and its tetrahydropyrimidine analog) with LD50s of 7–24 mg/kg and IC50s of 12–33 nM compared with values for IMI of 39–49 mg/kg and 806 nM, respectively. DN-IMI is therefore a candidate bioactivation product for IMI in mammals. Scatchard analyses indicated that CH-IMIin vitroand possibly DN-IMIin vitroandex vivocompete for the nicotine site (which is at or near the ACh site). When used directly as radioligands, single, saturable, high-affinity binding sites were observed for [3H]DN-IMI (Kd13 nM,Bmax51 fmol/mg protein) and [3H]CH-IMI (Kd16 nM,Bmax20 fmol/mg protein) using the conditions of [3H]nicotine binding (Kd7.8 nM,Bmax87 fmol/mg protein). [3H]DN-IMI also binds to kidney membranes at a site where it is displaced by atropine (ki0.5 μM). [3H]CH-IMI is particularly useful for comparative studies because of high-affinity sites in both insect and mammalian brain.
A laboratory feeding test was conducted on queenless micro-colonies of three bumblebee workers (Bombus terrestris L) to study the effects of low doses of imidacloprid on pollen and syrup consumption, worker survival, brood size and larval development. Two doses were used: D1 = 10 µg AI kg−1 in syrup and 6 µg AI kg−1 in pollen; D2 was 2.5 times higher in syrup and 2.7 higher in pollen. During 85 days 27, 30 and 29 micro-colonies were reared for control, D1 and D2 treatments respectively.Food consumption was not affected by either dose. During the 5-day pre-oviposition period the mean insecticide intake was 4.8 ng per day per worker in treatment D2. Both doses slightly but significantly affected worker survival rate by 10% during the first month, without any dose-effect relationship. Brood production was significantly reduced in D1 treatment and larval ejection by workers was significantly lower in D1 and D2 than in control. No significant effect of D1 and D2 treatments on the duration of larval development was revealed. No residue could be detected in workers still alive after 85 days.It was concluded that the survival rate and reproductive capacity of B terrestris was not likely to be affected by prolonged ingestion of nectar produced by sunflower after seed-dressing treatment with imidacloprid (Gaucho), since honey or pollen collected by honeybees foraging treated sunflower never revealed concentrations of imidacloprid higher than 10 µg kg−1.© 2000 Society of Chemical Industry
The recognition that intracellular free calcium serves as a ubiquitous intracellular signal has motivated efforts to elucidate
mechanisms by which cells regulate calcium influx. One route of entry that may offer both spatial and temporal fine resolution
for altering calcium levels is that provided by cation-permeable, ligand-gated ion channels. Biophysical measurements as well
as calcium imaging techniques demonstrate that neuronal nicotinic acetylcholine receptors as a class have a high relative
permeability to calcium; some subtypes equal or exceed all other known receptors in this respect. Activation of nicotinic
receptors on neurons can produce substantial increases in intracellular calcium levels by direct passage of calcium through
the receptor channel. When multiple classes of nicotinic receptors are expressed by the same neuron, each appears capable
of increasing calcium in the cell but may differ with respect to location, temporal response, agonist sensitivity, or regulation
in achieving it. As a result, nicotinic receptors must be considered strong candidates for signaling molecules through which
neurons regulate a diverse array of cellular events.
Organophosphate (OP) pesticides such as dimethoate and malathion intoxication has been shown to produce oxidative stress due to the generation of free radicals and alter the antioxidant defense system in erythrocytes. It is possible that vitamin E being present at the cell membrane site may prevent OP-induced oxidative damage. In the present study, rats were pretreated orally with vitamin E (250 mg/kg body wt, twice a week for 6 weeks) prior to oral administration of a single low dose of dimethoate and/or malathion (0.01% LD50). The result showed that treatment with OP increased lipid peroxidation (LPO) in erythrocytes, however, vitamin E pretreated rats administered OP’s showed decreased LPO in erythrocytes. The increase in the activities of superoxide dismutase (SOD) and catalase (CAT) and total-SH content in erythrocytes from dimethoate and/or malathion treated rats as compared to control appears to be a response towards increased oxidative stress. Vitamin E pretreated animals administered OP’s showed a lowering in these parameters as compared to OP treated rats which indicates that vitamin E provide protection against OP-induced oxidative stress. The glutathione-S-transferase (GST) activity in erythrocytes was inhibited in OP intoxicated rats which partially recovered in vitamin E pretreated animals administered OP’s. Inhibition in erythrocyte and serum acetylcholinesterase (AChE) activity was not relieved in vitamin E pretreated rats administered OP’s probably due to the competitive nature of enzyme inhibition by OP’s. The results show that vitamin E may amelierate OP-induced oxidative stress by decreasing LPO and altering antioxidant defense system in erthrocytes.
Polymorphonuclear neutrophils are professional phagocytes whose efficacy depends on a multicomponent NADPH oxidase for generating superoxide anions and bacterial killing. They can be primed and activated by different agents that can impair oxidative burst and phagocytosis with opposite effects: reduced capability to destroy bacteria or hyperactivation that induces the generation of large quantities of toxic reactive oxygen species, which can damage surrounding tissue and participate in inflammation. The present study was designed to evaluate the effect of sub-chronic (60 days) permethrin treatment (1/10 DL(50)) on rat polymorphonuclear neutrophils respiratory burst. The results show that permethrin treatment increases superoxide anion production (33 times) and the activity of hydrogen peroxide-myeloperoxidase system (67 times). In vitro experiments suggest that this effect can be related to permethrin priming and to physico-chemical changes at the plasma membrane level of neutrophils. The antioxidant supplementation with Vitamin E and coenzyme Q(10) can protect against the abnormal respiratory burst in rat treated with permethrin. The in vitro studies show that neutrophil apoptosis begins soon after 1h of incubation with permethrin (0.725% of total cells) or its metabolites (3-phenoxybenzyl alcohol, 3-phenoxybenzaldehyde and 3-phenoxybenzoic acid 1.36, 2.26 and 1.3 of total cells, respectively) and that the level of apoptotic cells is very low. In conclusion, immunotoxicity of permethrin measured in rats could prompt future studies on the consequences of chronic insecticide exposure.
Comparative Effects of Calcium Channel Blockers, Autonomic Nervous System Blockers, and Free Radical Scavengers On Diazinon-Induced Hyposecretion Of Insulin From Isolated Islets of Langerhans in Rats
Hyperglycaemia has been observed with exposure to organophosphate insecticides. This study was designed to compare the effects of calcium channel blockers, alpha-adrenergic, beta-adrenergic, and muscarinic receptor blockers, and of free radical scavengers on insulin secretion from diazinon-treated islets of Langerhans isolated from the pancreas of rats using standard collagenase digestion, separation by centrifugation, and hand-picking technique. The islets were then cultured in an incubator at 37 °C and 5 % CO 2 . In each experimental set 1 mL of 8 mmol L ⁻¹ glucose plus 125 μg mL ⁻¹ or 625 μg mL ⁻¹ of diazinon were added, except for the control group, which received 8 mmol L ⁻¹ glucose alone. The cultures were then treated with one of the following: 30 μmol L ⁻¹ atropine, 100 μmol L ⁻¹ ACh + 10 μmol L ⁻¹ neostigmine, 0.1 μmol L ⁻¹ propranolol, 2 μmol L ⁻¹ nifedipine, 50 μmol L ⁻¹ phenoxybenzamine, or 10 μmol L ⁻¹ alphatocopherol. In all experiments, diazinon significantly reduced glucose-stimulated insulin secretion at both doses, showing no dose dependency, as the average inhibition for the lower dose was 62.20 % and for the higher dose 64.38 %. Acetylcholine and alpha-tocopherol restored, whereas atropine potentiated diazinon-induced hyposecretion of insulin. Alpha-, beta- and calcium channel blockers did not change diazinon-induced effects. These findings suggest that diazinon affects insulin secretion mainly by disturbing the balance between free radicals and antioxidants in the islets of Langerhans and by inducing toxic stress.
DDT (bis[4-chlorophenyl]-1,1,1-trichloroethane) is responsible for many immuno-dysregulatory functions in exposed animals, but data particularly on complement system and macrophages are limited. In this study we have shown that DDT activates the complement system through the alternative pathway in the absence of any pathogen. A significant (p<0.05) increase in C3b, C3d and C3a generation, and decline in complement hemolytic activity was observed in insecticide exposed sera. The uncontrolled complement consumption reduces the lytic activity of the complement, which enhances the susceptibility to pyogenic infection if the exposure to DDT remains unabated. Further, DDT induced the significant (p<0.05) production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) in macrophages and thus contributes inflammatory reactions, cytokine imbalance and immune-dysregulation. These molecular changes in macrophages lead to structural aberrations like heterochromatin condensation, loss of pseudopodia, cytoplasmic vacuolization, DNA fragmentation and hypodiploid nuclei as seen in our study, suggesting apoptosis. However, in presence lipopolysaccharide, DDT induced significant (p<0.05) suppression of TNF-alpha and NO generation, suggestive of impairment of macrophage microbiocidal effects. This study concludes that the functional and structural derangements of macrophages in association with uncontrolled and excessive complement consumption by DDT are perhaps one of the major mechanisms contributing to the immunosuppressive effects of insecticide.
Xanthine oxidase was decreased 2- to 10-fold in all examined rat hepatomas irrespective of the malignancy; growth rate and degrees of histological differentiation of the neoplasms. The affinity to substrate (KM=6-8 muM) and the pH optimum (8.0) of the liver and hepatoma enzymes were the same. The reprogramming of gene expression, as manifested in the decreased activity of this key purine metabolizing enzyme, appears to be specific to neoplastic transformation. Since glutamine PRPP amidotransferase activity was increased but the opposing enzyme, xanthine oxidase, was decreased in all the hepatomas, the reprogramming of gene expression results in an imbalance that favors synthesis against catabolism. This enzymatic imbalance should confer selective advantages to the cancer cells.
Concentrations of a peroxidation product (malondialdehyde), fluorescent chromophores, lipofuscin-like fluorescent products, superoxide dismutase, catalase, glutathione peroxidase, and vitamin E in the maternal blood and the cord blood were determined and the results obtained were related to the estimation of lipid peroxidation and protective mechanism against uncontrolled oxidative processes in late pregnancy. Serum levels of fluorescent products were higher in the maternal blood than in the cord blood, indicating less frequent lipid peroxidation in the fetus than in the mother. In support of this assumption, the three protective enzymes and vitamin E were present in relatively lower concentrations in the cord blood. Sudden exposure of the newborn infant to a normobaric atmosphere after beginning breathing seems, therefore, to cause oxidation of red blood cell membrane, denaturation of the membrane, inducing hemoglobin breakdown, and consequently hemolysis.
A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
Nitrate in serum and urine was assayed by a modification of the cadmium-reduction method; the nitrite produced was determined by diazotization of sulfanilamide and coupling to naphthylethylene diamine. After samples were deproteinized with Somogyi reagent, the nitrate was reduced by Cu-coated Cd in glycine buffer at pH 9.7 (2.5 to 3 g of Cd granules for a 4-mL reaction mixture). The reduction followed pseudo-first-order reaction kinetics, a convenient time interval for assay being 75 to 90 min. Maximum reduction (85%) occurred at about 2 h. Detection limits in urine or serum were 2 to 250 mumol/L. This method does not require the reaction to go to completion, does not require expensive reagents or equipment, and can assay several samples simultaneously. Repeated assays of two serum pools gave CVs of 9.0% and 4.7% for nitrate concentrations of 31.4 and 80.2 mumol/L, respectively (n = 20 each). The mean concentration of nitrate was 1704.0 +/- 1294 (SD) mumol/L (n = 21) in untimed normal urine, 81.8 +/- 50.1 mumol/L in serum of 38 renal dialysis patients, and 51.2 +/- 26.4 mumol/L in serum of 38 controls.
This assay for superoxide dismutase (SOD, EC 1.15.1.1) activity involves inhibition of nitroblue tetrazolium reduction, with xanthine-xanthine oxidase used as a superoxide generator. By using a reaction terminator, we can determine 40 samples within 55 min. One unit of activity of pure bovine liver Cu,ZnSOD and chicken liver MnSOD was expressed by 30 ng and 500 ng of protein, respectively. The mean concentrations of Cu,ZnSOD as measured by this method in blood from normal adults were 242 (SEM 4) mg/L in erythrocytes, 548 (SEM 20) micrograms/L in serum, and 173 (SEM 11) micrograms/L in plasma. The Cu,ZnSOD concentrations in serum and plasma of patients with cancer of the large intestine tended to be less and greater than these values, respectively, but not statistically significantly so.
An assay procedure is described in which blood cell glutathione peroxidase may be accurately measured by a direct spectrophotometric procedure. Glutathione peroxidase activity is found to be associated with a relatively stable, nondialyzable, heat-labile, intracellular component which is separable from hemoglobin, by gel filtration and ammonium sulfate precipitation. The activity appears to be dependent upon active sulfhydryl groups and is unaffected by low concentrations of azide, cyanide, or ferricyanide.
Tetramethylbenzidine, a noncarcinogenic, nonmutagenic derivative of benzidine, has been used as a substrate to assay myeloperoxidase. The assay is sensitive to 0.1 μg of enzyme and can be used to quantitate myeloperoxidase over a pH range of 4.4 to 7.4.
Paradoxical sleep deprivation was performed on rats using platform technique to investigate the oxidative process associated with it. Levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), total glutathione (GSH) and malondialdehyde production were measured in brain of rats under control conditions (C) and those on single large platforms (SLP), multiple large platforms (MLP), single small platforms (SSP) and multiple small platforms (MSP) groups. SOD, CAT and GPx brain activity and malondialdehyde production were not modified by any of the procedures. Brain GSH, however, was significantly reduced in both SSP and SLP groups. These results suggest that paradoxical sleep deprivation per se is not associated with oxidative damage. The observed alterations could be attributed to factors such as immobilization and social isolation present in the single platform techniques.
This study is the first to examine and characterize the testicular apoptosis which might be induced due to exposure of male rats to deltamethrin. Furthermore, the role which might be played by nitric oxide (NO), as well as the other reactive oxygen species (ROS) in controlling this testicular apoptosis was assessed. Apoptosis was evaluated by DNA fragmentation detected by agarose gel electrophoresis and cellular morphology on testicular tissue sections. It was found that administration of deltamethrin (1 mg/kg daily for 21 days) to animals resulted in characteristic DNA migration patterns (laddering), thereby providing evidence that apoptosis is the major mechanism of cell death in the testicular tissues. In addition, histopathological examination of testicular tissue sections showed that apoptosis was confined to the basal germ cells, primary and secondary spermatocytes. These changes, in addition to the appearance of Sertoli cell vacuoles in deltamethrin-intoxicated animals, indicates the suppression of spermatogenesis. At the same time, the plasma levels of both NO and lipid peroxides measured as malondialdehyde (MDA) were found to be significantly increased in deltamethrin-treated animals. Administration of NO synthase (NOS) inhibitors such as N(G)-nitro monomethyl L-arginine hydrochloride (L-NMMA, 1 mg/kg) to rats 2 h before exposure to deltamethrin was effective in the reduction of the typically testicular apoptotic DNA fragmentation pattern and the associated histopathological changes. These findings may suggest that deltamethrin-induced testicular apoptosis is mediated by NO. Therefore, the pharmacological manipulation of apoptosis by selective NOS inhibitors such as L-NMMA may offer new possibilities for the control of deltamethrin-induced testicular dysfunction and infertility in the future.
Oxidative stress was studied in blood samples obtained from lindane, malathion and propoxur poisoning cases admitted to the Guru Teg Bahadur Hospital, Delhi and evaluated for lipid peroxidation, oxygen free radical (OFR) scavenging enzymes, and glutathione (GSH) and related enzymes. Acetylcholine esterase (AChE), gamma glutamyl transpeptidase (GGT) and GSH level were also assayed in lymphocytes. The level of thiobarbituric acid reacting substances and activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and GGT were increased and GSH level was decreased in pesticide poisoning. Apparently lindane (at the concentration examined) was more potent than malathion and propoxur in producing alteration in lipid peroxidation, GSH related parameters and OFR scavenging enzymes. However, AChE activity and GSH level in lymphocytes of malathion poisoning cases were reduced and GGT activity was enhanced in comparison to control subjects. The present results suggest that OFR scavenging enzymes were induced while combating oxidative stress in a differential manner in organochlorine, organophosphate and carbamate poisoning. Increased lipid peroxidation, coupled with altered levels of GSH and OFR scavenging enzymes in the blood are discussed in the light of oxidative stress.
This study developed a bioassay with the isopod Porcellio dilatatus based on the activity of the enzymes acetylcholinesterase (AChE) and lactate dehydrogenase (LDH). The in vivo effects of the insecticides parathion-ethyl and endosulfan-sulfate on AChE and LDH activities of P. dilatatus under laboratory conditions were investigated. The route of uptake of the pesticides was through the food (alder leaves). Isopods were exposed to a wide range of concentrations of parathion or endosulfan (0.1, 1, 10, 25, 50, 100, 250, and 500 microg/g of food) for 21 days. After this period, the activity of AChE and LDH was determined. Parathion induced significant depression of both AChE and LDH activities. Animals fed with endosulfan-contaminated food exhibited lower LDH activities than control animals, while AChE activity was similar in all treatments. The results of the present investigation suggest that the isopod. P. dilatatus is a suitable species for use in toxicity tests and indicate that the enzymes AChE and LDH could be used as effect criteria both in laboratory and in field studies with this species.
Pesticide chemicals may induce oxidative stress leading to generation of free radicals and alterations in antioxidants or oxygen free radical (OFR) scavenging enzymes. Hence, the effect of subchronic malathion (O,O-dimethyl-S-1,2, bis ethoxy carbonyl ethyl phosphorodithioate) exposure was evaluated on lipid peroxidation, glutathione and related enzymes and OFR scavenging enzymes in albino rats. Administration of malathion (20 ppm) for 4 weeks increased the malondialdehyde (MDA) levels in serum, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in erythrocytes and glutathione reductase (GR) and glutathione S-transferase (GST) in serum. However, it decreased the glutathione (GSH) level in whole blood. Concomitant dietary feeding of Zingiber officinales Rosc (ginger 1%, w/w) significantly attenuated malathion induced lipid peroxidation and oxidative stress in these rats. These results indicate the possible involvement of free radicals in organophosphate-induced toxicity and highlight the protective action of ginger, an indigenous medicinal plant product.
Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities were determined in rat tissues after dermal exposure to pesticides. Two experiments were conducted in male SD rats, 190-210 g body weight. Acephate (ACP), methamidophos (MAP) and nicotine (NIC) were dissolved either individually or together in 0.25 mL of 50% ethanol, which contained: AP = 12.6 or MAP 1.3 or NIC = 9.6 mg; EXP 1--individual pesticide exposure; 64 rats, 16/group; EXP 2--mixture of AP + MAP + NIC at levels of 1X, 2X, 3X; 48 rats, 12/group; 0.25 mL of solution or ethanol (Controls) was applied to 25 mm2 area of shaved skin 3 times a week. Half the rats were terminated after 4 weeks and the rest after 4 weeks of stopping exposure. Single pesticides decreased erythrocyte (RBC) SOD by 17% after exposure and in the NIC group after post exposure (P#0.05). Increasing concentrations of AP + MAP + NIC mixture elevated RBC SOD by 22% in the 2X and 3X groups and CAT by 13% in the 3X group (P#0.05); post exposure increased RBC SOD by 2-3 fold and CAT activity by 13% in all 3 groups. Liver GPX increased by 30-40% and CAT decreased by 12% in all exposed and post exposed groups (P#0.05). The results suggest that dermal exposure to mixtures of pesticides can selectively induce SOD, CAT and GPX activities in RBC and liver.
Nicotinic acetylcholine receptors (nAChRs) are expressed in the midbrain ascending dopaminergic system, a target of many addictive drugs. Here we assessed the intracellular Ca2+ level by imaging fura-2-loaded cells in substantia nigra pars compacta in mouse brain slices, and we examined the influence on this level of prolonged exposures to nicotine using mice lacking the nAChR beta2-subunit. In control cells, superfusion with nicotine (10-100 microM) caused a long-lasting rise of intracellular Ca2+ level which depended on extracellular Ca2+. This nicotinic response was almost completely absent in beta2-/- mutant mice, leaving a small residual response to a high concentration (100 microM) of nicotine which was inhibited by the alpha7-subunit-selective antagonist, methyllycaconitine. Conversely, the alpha7-subunit-selective agonist choline (10 mM) caused a methyllycaconitine-sensitive increase in intracellular Ca2+ level both in wild-type and beta2-/- mutant mice. Nicotine-elicited Ca2+ mobilization was reduced by the Na+ channel blocker tetrodotoxin (TTX) and by T-type Ca2+ channel blocking agents, whereas the choline-elicited Ca2+ increase was insensitive to TTX. Neither nicotine nor choline produced Ca2+ increase following inhibition of the release of Ca2+ from intracellular stores by dantrolene. These results demonstrate that in nigral dopaminergic neurons, nicotine can elicit Ca2+ mobilization via activation of two distinct nAChR subtypes: that of beta2-subunit-containing nAChR followed by activation of Na+ channel and T-type Ca2+ channels, and/or activation of alpha7-subunit-containing nAChR. The Ca2+ influx due to nAChR activation is subsequently amplified by the recruitment of intracellular Ca2+ stores. This Ca2+ mobilization may possibly contribute to the long-term effects of nicotine on the dopaminergic system.
Nicotine exerts its central actions by regulating cationic fluxes through nicotinic acetylcholine receptors (nAChRs). By this effect, the drug likely also modifies events occurring beyond the nAChR, including the regulation of nitric oxide (NO) synthesis. The present study was undertaken to assess the effects of acute and chronic nicotine administration (0.4 mg/kg, s.c.) on levels of NO(-)(2)+NO(-)(3), stable metabolites of NO, in brain regions of male and female rats. Nicotine increased levels of the metabolites, and therefore presumably of NO, with sex differences in the degree of stimulation, the brain regions affected, and the variance between the effects of acute and chronic administration. Prior inhibition of NO synthase eliminated the effect of nicotine in all regions studied. While nicotine appeared to increase NO indirectly via glutamate receptors in the cortex and hippocampus, this was not true of the corpus striatum, where blocking NMDA-type glutamate receptors with MK-801 had no effect. The findings support the view that NO is likely involved in some of the central effects of nicotine.
Use of the real-time polymerase chain reaction (PCR) to amplify cDNA products reverse transcribed from mRNA is on the way
to becoming a routine tool in molecular biology to study low abundance gene expression. Real-time PCR is easy to perform,
provides the necessary accuracy and produces reliable as well as rapid quantification results. But accurate quantification
of nucleic acids requires a reproducible methodology and an adequate mathematical model for data analysis. This study enters
into the particular topics of the relative quantification in real-time RT–PCR of a target gene transcript in comparison to
a reference gene transcript. Therefore, a new mathematical model is presented. The relative expression ratio is calculated
only from the real-time PCR efficiencies and the crossing point deviation of an unknown sample versus a control. This model
needs no calibration curve. Control levels were included in the model to standardise each reaction run with respect to RNA
integrity, sample loading and inter-PCR variations. High accuracy and reproducibility (<2.5% variation) were reached in LightCycler
PCR using the established mathematical model.
Imidacloprid (IMI) is the principal neonicotinoid (the only major new class of synthetic insecticides of the past three decades). The excellent safety profile of IMI is not shared with a metabolite, desnitro-IMI (DNIMI), which displays high toxicity to mammals associated with agonist action at the alpha4beta2 nicotinic acetylcholine receptor (nAChR) in brain. This study examines the hypothesis that IMI, DNIMI, and (-)-nicotine activate the extracellular signal-regulated kinase (ERK) cascade via primary interaction with the alpha4beta2 nAChR in mouse neuroblastoma N1E-115 cells. These three nicotinic agonists induce phosphorylation of ERK (p44/p42) in a concentration-dependent manner with an optimal incubation period of 30 min. DNIMI (1 microM)-induced ERK activation is blocked by nicotinic antagonist mecamylamine but not by alpha-bungarotoxin and muscarinic antagonist atropine. This activation is prevented by intracellular Ca(2+) chelator BAPTA-AM but not by removal of external Ca(2+) using EGTA and Ca(2+)-free medium. 2-Aminoethoxy-diphenylborate, a blocker for inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) release from intracellular stores, inhibits DNIMI-induced ERK activation but a high level of ryanodine (to block ryanodine receptor-mediated Ca(2+) release) does not. The inhibitor U-73122 for phospholipase C (to suppress IP(3) production) prevents ERK activation evoked by DNIMI. Inhibitors for protein kinase C (PKC) (GF109203X) and ERK kinase (PD98059) block this activation whereas an inhibitor (H-89) for cyclic AMP-dependent protein kinase does not. Thus, neonicotinoids activate the ERK cascade triggered by primary action at the alpha4beta2 nAChR with an involvement of intracellular Ca(2+) mobilization possibly mediated by IP(3). It is further suggested that intracellular Ca(2+) activates a sequential pathway from PKC to ERK.
The effect of oral administration of acephate (360 mg/kg body weight), for 15 days, daily, was investigated on the erythrocytes of male rats. Activities of acetyl cholinesterase and glucose-6-phosphate dehydrogenase decreased, while those of glutathione-s-transferase and glutathione reductase increased. Decreased glutathione content and increased lipid peroxidation suggest that there was increased oxidative stress in the erythrocytes of treated animals. Increased cholesterol/phospholipid ratio in the erythrocyte membranes and morphological changes in RBCs (scanning electron microscopy studies) were observed in acephate treated animals. The results clearly suggest that acephate induced oxidative stress in erythrocytes leads to morphological changes.
Epidemiological studies have reported that cigarette smoking may protect from neurodegenerative diseases such as Parkinson's disease. These protective effects are thought to be mediated by nicotine. Recent data showed that nicotine significantly decreases respiratory control ratio (RCR) and superoxide anion generation of brain mitochondria. Thus, we investigated nicotine effects on rat brain in two experimental models: first, an in vitro anoxia/reoxygenation experiment and secondly, an in vivo rotenone-induced Parkinson-like syndrome. Anoxia/reoxygenation impaired mitochondrial respiration by 43.68% whereas in the presence of nicotine, it was less impaired, by 31.1% at 10(-7) M. In rats chronically administered rotenone (3 mg/kg/day), we observed profound mitochondrial damage: the RCR decreased by 50.36% and the superoxide anion generation and the membrane anisotropy increased by 56.03 and 13.43%, respectively. All of these indications of mitochondrial damage were limited by chronic administration of nicotine. Nicotine developed mitochondrial effects in vivo and in vitro at very low concentration. All these results were in accordance with epidemiological studies, which report a protective effect of nicotine in neurodegenerative diseases. Thus, we propose that one effect of nicotine is to preserve mitochondrial functions of the rat central nervous system.