**6.2 Carbaryl**

Recent studies on the neurotoxic effects associated with carbaryl are scarce. However, it has been reported that in bees, it can inhibit carbonic anhydrase [104] and decrease acetylcholinesterase levels [103], as well as its negative effect on isopod growth and survival (**Table 5**) [146]. In aquatic organisms, it has been discovered that carbaryl can cause embryonic deformities and growth inhibition in crustaceans [147], affect hatching speed in shrimp [62], locomotives alterations in blue crabs [66], mussels [68], and zebrafish [69]. Besides, in this same species, it has been associated with alterations in exploratory, social, and feeding behavior [67]. Likewise, in tadpoles, it causes hypoactivity, reduction in escape swimming, and feeding behavior (**Table 4**) [65]. Regarding the effects on brain chemistry, it has been reported that carbaryl may be related to the decrease in the levels of acetylcholine, GABA, choline, tryptophan, and phenylalanine in zebrafish [108]. Additionally, it inhibits acetylcholinesterase in shrimp [62], in some species of tropical fish [109], and also in mollusks (**Table 5**) [107]. On the other hand, it has been documented that in broilers, acute poisoning can cause walking difficulty, weakness in the legs, dizziness, frequent defecation, less food consumption, and a decrease in aggressive behavior (**Table 4**) [79]. Overall, acetylcholinesterase inhibition has been reported, particularly in the vulture [114]. Simultaneously, in experimental rodents, it has been associated with deficits in memory and learning. As well as alterations in habitual behavior [90] and hypoactivity [91]. Furthermore, in a supposed carbaryl poisoning in bats, signs such as hypersalivation, miotic pupils, lethargy, and coma were reported [92]. This substance can also inhibit acetylcholinesterase in Norwegian gray rats [91] and in experimental rodents. The above has been related to neurodevelopmental alterations [90], as depicted in the visual and frontal cortex electroencephalogram [133] and hippocampal neuroinflammation [134]. In humans, it has been linked to a semi-conscious state and acetylcholinesterase inhibition after acute poisoning in a 3-year-old child, without further details on other associated neurological signs (**Table 4**) [99]. Moreover, in an in vitro study, it was observed that carbaryl could bind to human melatonin receptors [122]. Carbaryl was recently associated with meningiomas in people agriculturally involved in an epidemiological investigation [141].

While, acute poisonings are associated with signs of piloerection, tremors, seizures, and hypoactivity, among other neurological manifestations [88]. Regarding brain neurochemistry in experimental rodents, it has been reported that chlorpyrifos can alter the activity of acetylcholinesterase [86, 87, 117, 118]. It participates in the downregulation of genes related to Parkinson's disease [117], causes oxidative stress [86] and decreases dopamine and serotonin levels [87, 118]. Overall, it has also been associated with neurodegeneration in rodents for experimentation [131, 132]. In humans, it has been reported that chlorpyrifos can alter social and motor function in children [96, 97]. As well as having fallout related to neurobehavioral deficits in workers exposed to the insecticide [98]. At the neurochemical level, in an in vitro study with human cells, it was shown that it can decrease intracellular levels of ATP and cause mitochondrial dysfunction [121]. Finally, at the cellular level, it has been reported to cause inhibition of activated calcium channels by voltage [137], alter morphology [138], and induce apoptosis in vitro [139]. In human cells exposed to chlorpyrifos, a recently published study reported that it may be associated with

alterations in the morphology of different brain regions in children exposed to the substance (**Table 6**) [140].

#### **6.3 Imidacloprid**

Despite being considered harmless for most living organisms, neonicotinoid insecticide have been the focus of extensive investigation, as their toxicity has been proven to extend beyond insects [148], to humans. Imidacloprid poisoning in bees has been associated to neurological symptoms such as paralysis and tremors [56], and fire ant exposure has been linked to decreased consumption, foraging, and digging behavior, as well as parasitic wasps with alterations in host-seeking behavior (**Table 4**) [57, 58]. Reduced visual mobility and degradation in in-flight behavior in lobsters, in addition to influencing queen selection behavior in stingless bees have been other reported consequences of the exposure to this insecticide [59, 60]. Imidacloprid has been linked to a decrease in the density of synaptic units in fungiform bodies [125] and a decrease in driving speed in lobsters [103]. It can also increase acetylcholinesterase levels [103] and induce apoptosis and neuronal autophagy [60, 124]. In edaphic invertebrates, imidacloprid causes diverse effects on the survival, growth, and reproduction of earthworms, springtails, mites, and isopods based on LC50, EC50, and EC20 toxicity tests [149]. In aquatic organisms, a decrease in acetylcholinesterase levels in mollusks has been reported [150], as well as varied effects on exploratory behavior, swimming activity, and sensorimotor response to startling stimuli in zebrafish (**Tables 4** and **5**) [70].

Moreover, exposure to imidacloprid has been associated with alterations in swimming behavior in tadpoles [71] and shrimp [73], decreased response to predators in frogs [72], and locomotor alterations in crabs [74], zebrafish [75] and tadpoles (**Table 4**) [76]. At the neurochemical level, it has been proposed that imidacloprid can alter acetylcholinesterase activity and cause oxidative stress in fish [75, 105, 110]. It also inhibits brachial acetylcholinesterase in oysters [111] and in fish muscles (**Table 5**) [112]. At the cellular level, it has been documented that the above may be associated with increased expression of BNDF and c-fos in the brain tissues of zebrafish (**Table 6**) [126]. In birds, it has been reported that exposure to imidacloprid can cause hypoactivity, decreased flight behavior, spasms, drooping wings, ataxia, and prostration in pigeons [80]. It has also been stated that it can alter the migratory orientation and delay the time of starting migration in the white-crowned sparrow [151]. In one of the most recently published studies, it was reported that in chickens, it can generate neurological signs such as muscle tremors, ataxia and depression (**Table 4**) [82]; in quail, it can increase monoamine levels in the cerebral cortex [115] and alter the activity of acetylcholinesterase in the muscles and brain of the gray laurel wing bird (**Table 5**) [116]. At the cellular level, it has been associated with neurodegeneration in chicken embryos' cerebellum [129] and pigeons [130]. In experimentation rodents, it has been associated with hypoactivity, increased grooming behavior, and conduct associated with anxiety and depression [93, 94]. While in bats, it may be associated with alterations in the vocal, auditory, orientation, and memory systems (**Table 4**) [95]. Also, in rodents, it can increase acetylcholinesterase activity [119], adrenaline, norepinephrine, and cortisone levels [93], and reduce serotonin, GABA, dopamine, and glutathione (**Table 5**) [120, 152]. Regarding the cellular effects, exposure to imidacloprid can also cause neurodegeneration, an increase in the expression of GFAP [152], and DNA damage in neurons [136]. In bats, it has been related to a decrease in proteins related to echolocation in different brain regions [95]. Moreover, in humans, acute imidacloprid poisonings have been associated with neurological signs such as dyspnea, coma, sweating, drowsiness, confusion, incoherence, lack of orientation, and miotic pupils, among others [100–102].

*Neurotoxic Effects of Insecticides Chlorpyrifos, Carbaryl, Imidacloprid, in Different Animal… DOI: http://dx.doi.org/10.5772/intechopen.100527*

In an in vitro study with LUHMES and SH-SY5Y cells, an increase in intracellular calcium levels was found [123] (**Table 5**) On the other hand, after acute poisoning, cerebral edema has been reported as a necropsy finding [101], while in an in vitro study it was revealed that it can cause the death of SH-SY5Y cells [135].

On the other hand, acute poisonings are linked to piloerection, tremors, seizures, and hypoactivity, among other neurological manifestations. Regarding brain neurochemistry in experimental rodents, it has been reported that chlorpyrifos can alter the activity of acetylcholinesterase [86, 87, 117, 118]. It participates in the downregulation of genes related to Parkinson's disease [117], causes oxidative stress [86] and decreases dopamine and serotonin levels [87, 118]. Overall, it has also been associated with neurodegeneration in rodents for experimentation [85, 132]. In humans, it has been reported that chlorpyrifos can alter social and motor function in children [96, 97]. As well as having fallout related to neurobehavioral deficits in workers exposed to the insecticide [98]. At the neurochemical level, in an in vitro study with human cells, it was shown that it can decrease intracellular levels of ATP and cause mitochondrial dysfunction [121]. Finally, at the cellular level, it has been reported to cause inhibition of activated calcium channels by voltage [137], alter morphology [138], and induce apoptosis in vitro [139]. In human cells exposed to chlorpyrifos, a recently published study reported that it may be associated with alterations in the morphology of different brain regions in children exposed to the substance [140].

## **7. Conclusions and perspectives**

Insecticides are pesticides commonly associated with neurotoxic effects [153] and although the general population is exposed on a daily basis to low doses through water and food [154–156] the highest risk is presented by agricultural workers, their families and people who live in the areas surrounding the fields, unfortunately, these people are the most exposed and also the least informed about the toxic effects, which leads to bad practices of use, handling and disposal of these substances, which put wildlife and the environment at risk. Since the effects that cause the greatest impact are usually those that directly affect human health, in conclusion some neurotoxic effects associated with the use of insecticides are revealed. In epidemiological studies in humans, organophosphates have been linked to effects such as cholinergic syndrome, polyneuropathy and neuropsychiatric disorders such as cognitive deficits, anxiety, depression, peripheral neuropathy, extrapyramidal symptoms such as dystonia, tremor at rest, bradykinesia, postural instability and rigidity of facial muscles, among others, and have even been associated with neurodegenerative diseases such as Parkinson's and Alzheimer's disease [157, 158]; neonicotinoids have been linked to developmental diseases such as autism and anencephaly and in acute poisonings with neurological signs such as memory loss, finger tremors, muscle spasms, coma and dilated pupils [159–161]; On the other hand, with regard to epidemiological studies on neurotoxicity of carbamates in humans, the literature is limited, however, in the most recently published article, it has been reported that after acute poisoning, these pesticides can cause signs such as coma, drowsiness, seizures, disorientation, tremors and fasciculations, among others [157]. However, although there are epidemiological studies in which the possible relationship between exposure to pesticides and neurological disorders has been determined, to date they remain limited and in fact most of the toxic effects of many pesticides used in the field are unknown. agriculture and therefore it is difficult to determine how we can protect ourselves from them, although there are studies in which the neuroprotective effect of various substances has been experimentally demonstrated, which could counteract the neurotoxic effects of pesticides, for example in the case of pesticides.

Organophosphates it has been documented that the flavonoid kaempferol may have protective effects on chlorpyrifos-induced neurotoxicity [162] and that crocin and citric acid may also have the same effect on malathion-induced toxicity [163, 164]; in the case of neonicotinoids, reduced glutathione, curcumin, resveratrol, ascorbic acid, and aqueous ginger extract have been shown to act as neuroprotectors against imidacloprid-induced toxicity [165–168], as well as curcumin and N-acetylcysteine can protect against acetamiprid-induced neurotoxicity [169, 170]; In the case of carbamates, it has been described that naringenin can combat oxidative stress induced by exposure to carbaryl [171]. Previous studies offer alternatives as possible neuroprotectors, therefore, it is necessary to continue investigating the mechanisms of toxicity and target species of pesticides that exist on the market, before thinking of creating new, more powerful and, of course, more toxic pesticides ; In addition to banning those that pose a high risk to living beings and the environment and making strict policies to control their distribution and sale, since it is clear that it is difficult to live without pesticides, however, it is our duty to use them responsibly.
