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Vinayagam Magendira Mani, et al., BAOJ Pathol 2017, 1: 21: 008

BAOJ Pathology

Review

BAOJ Pathol, an open access journal Volume 1; Issue 2; 005

*Corresponding author: Abdul Majeeth Mohamed Sadiq, Principal & Head, PG and Research Department of Biochemistry, Adhiparasakthi College of Arts and Science (Autonomous), Kalavai -632 506 Tamil Nadu, India, Tel: +91 9443449881; E-mail: [email protected]

Sub Date: June 15, 2017, Acc Date: June 19, 2017, Pub Date: June 19, 2017.

Citation: Vinayagam Magendira Mani, Adikesaven Gokulakrishnan and Abdul Majeeth Mohamed Sadiq (2017) Molecular Mechanism of Neu-rodevelopmental Toxicity Risks of Occupational Exposure of Pyrethroid Pesticide with Reference to Deltamethrin - A Critical Review. BAOJ Pathol 1: 008.

Copyright: © 2017 Vinayagam Magendira Mani, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Molecular Mechanism of Neurodevelopmental Toxicity Risks of Occupational Exposure of Pyrethroid Pesticide with Reference to Deltamethrin - A Critical Review

Vinayagam Magendira Mani1, Adikesaven Gokulakrishnan1 and Abdul Majeeth Mohamed Sadiq2*

1PG and Research Department of Biochemistry, Islamiah College (Autonomous), Vaniyambadi- 635 751, Tamil Nadu, India2 Principal & Head, PG and Research Department of Biochemistry, Adhiparasakthi College of Arts and Science (Autonomous), Kalavai -632 506 Tamil

Nadu, India

Abstract

Deltamethrin (DLM) is a type II α - cyano group containing synthetic pyrethroid insecticide that is used extensively for controlling arthropods worldwide and is at forefront of efforts to fight against malaria and other mosquito-borne diseases. Humans are exposed to DLM via direct exposure to the vapors, inhalation, epidermal contact and ingestion due to occupational exposure in the environment through contaminated food, water and consumption on suicidal attempt. Acute and chronic exposure of DLM leads to pathophysiology of a broad spectrum of cerebrovascular and neurodegenerative disorders like Parkinson disease, Lou Gehrig’s disease, Alzheimer disease, developmental deficits, birth defects, low IQ, pervasive developmental disorder, attention problems and learning disabilities. In this work, we review the molecular mechanisms involved in the neurotoxic actions of pyrethroid pesticide deltamethrin during acute and chronic exposure on experimental animals.

Keywords: Pyrethroids; Deltamethrin; Neurotoxicity

Pesticides

The United Nations Food and Agricultural Organization (UNFAO) has defined the “Pesticide as some element or mixture of elements used for controlling, preventing, destroying any pest, including vectors of human and animal disease, or undesirable species of plants and animals causing harm during or otherwise interfering with the storage, production, processing, transport, marketing of food, agricultural commodities, wood and wood products or animal foodstuffs, or elements which can be administered to animals and plants for the control of insects, arachnids or other pests in or on their bodies”. The term pesticide also includes substances intended for use as a plant growth regulator, desiccant, defoliant, agent for thinning fruit, preventing the premature fall of fruit and substances applied to crops either before or after harvest to protect the commodity from worsening during storage and transport [1].

Exposure of Pesticides

Over the last few eras agricultural pesticides have become a common household item in rural areas of the developing world. Due to their easy availability, pesticides have become commonly used for intentional self-poisoning [2]. The widespread use of pesticides in agriculture, public health and household environments results in continuous exposure of human populations. Pesticide residues may enter into the environment as a result of spray drift, vaporization, surface run-off, unlawful acts, spills, drainage discharges and through leaching or soil dusts [3].

Exposure to pesticides can arise through several pathways (e.g. food, drinking water, residential, occupational) and routes (oral, inhalation, epidermal contact, respiratory and conjunctival routes). The type, severity and adverse health effects of pesticides are determined by the individual chemical composition, the dose and the duration of exposure and the exposure route [4,5]. The majority of foods purchased in supermarkets have detectable levels of pesticide deposits. For example, of several thousand samples of food, the overall assessment in 8 fruits and 12 vegetables is that 73% have pesticide residues [6,7]. In five crops (apples, strawberries,

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Citation: Vinayagam Magendira Mani, Adikesaven Gokulakrishnan and Abdul Majeeth Mohamed Sadiq (2017) Molecular Mechanism of Neurodevelopmental Toxicity Risks of Occupational Exposure of Pyrethroid Pesticide with Reference to Deltamethrin - A Critical Review. BAOJ Pathol 1: 008.

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peaches, pears and celery) pesticide content were found in 90% of the crops of interest is the fact that 38 different pesticides were identified in apples [8,9]. Population researches on biomonitoring of pyrethroid pesticides have been carried out to evaluate the risk of human exposure [10]. Children have been found to have greater exposure of pesticides than adolescent and adults as indicated by the existence of pesticide metabolites in the urine [11]. Metabolites of pyrethroids have also been found in the urine of pre-school and elementary stage children as a result of residential exposure [12]. Detection of pyrethroid metabolites in the breast milk and urine of pregnant women has further raised health concern to the risk of exposure of fetus and developing children [13]. Pesticide exposure has been implicated in the etiopathogenesis of neuro degenerative disorder particularly PD, now pyrethroid pesticides also believed to be associated with PD.

Pesticide Poisoning

On 3rd December, 1984, more than 40 tons of methyl isocyanate (MIC) gas leaked from a pesticide plant Union Carbide Corporation (UCC) in Bhopal, India, immediately killing at least 3,800 people and causing significant morbidity and 20,000 premature deaths reportedly occurring in the subsequent two years [14]. Pesticide poisoning is an important problem in India. The Indian pesticide industry, with an estimated 79,800 metric tons [15] of production for 2007 - 2008, is ranked second in Asia and twelfth globally. In worth terms, the size of the Indian pesticide industry was estimated at US$ 1500 million, including exports of US$ 622 million. WHO, (2009) [16] estimate that 6,00,000 cases and 60,000 deaths occur in India annually, with the most vulnerable to children, women, workers in the informal sector and poor farmers. According to the National Crime Records Bureau (NCRB), Ministry of Home Affairs, India, the total number of farmers having allegedly committed suicide by ingesting pesticides totaled 1, 83,000 in the decade 1997-2007. That is the equal of one suicide every 30 minutes. Among the worst-affected States, the main cotton growing states are Andhra Pradesh, Madhya Pradesh, Maharashtra, and Tamilnadu. India suffers from dual burden of pesticides acute as well as chronic. Annually about 8,000-10,000 cases and 1,000 plus fatality are in India [17].

Pyrethroids

Pyrethroids are artificial chemical analogues of pyrethrins, which are naturally occurring insecticidal compounds formed in the flowers of chrysanthemums (Chrysanthemum cinerariaefolium and Chrysanthemum cineum) [18]. First generation pyrethroids (e.g., allethrin, prallethrin, resmethrin, imiprothrin, phenothrin, and tetramethrin) were developed by the early 1970’s and typically destroys quickly in sunlight, so they are chiefly applied indoors or found in products like flea collars, aerosol sprays and foggers [19]. The pyrethroids were therefore developed to yield more

environmentally stable and commercially viable pesticides. In the late 1970’s, the second generation pyrethroids [e.g., deltamethrin, cypermethrin, bifenthrin, cyhalothrin, cyfluthrin, esfenvalerate, fenpropathrin, and permethrin] were intended to be more photo stable and are frequently used in products to control for several types of insects and pests on agricultural crops, in and around residential dwellings and on pets [20]. Pyrethroids may become the only increased pesticide type in China, with the annual demands in 2016 being expected to be approximately 3800 tons, increased by 8.4% than last year [21]. Pyrethroid pesticides are considered to be one of the most important causes of pollution in agricultural production, and may be a potential hazard to public health [22].

Pyrethroids can be classified as Type I and type II compounds [23]. Type I pyrethroids are esters of primary and secondary alcohols. Type II pyrethroids are esters of secondary alcohols with α- cyano group at the carbon of the alcohol moiety. The signs of acute toxicity in rats differ between Type I and Type II pyrethroids [24]. Type II pyrethroids are generally more potent than Type I pyrethroids. Symptoms in rats exposed with Type I pyrethroids include aggression and hypersensitivity, general and fine tremor, convulsive twitching, coma and death. Type II pyrethroids produce salivation, coarse tremor, increased extensor tone, writhing convulsions, pawing and burrowing finally death. The site of action of pyrethroids is the voltage dependent sodium channel, chloride, calcium channels also be targets [25,26,27]. Pyrethroids consist of cyclopropane carboxylic acid moieties linked to aromatic alcohols through a central ester and ether bond. Modifications to this basic pyrethroid structure are designed to increase insecticidal effectiveness and photo stability, but it results in changes in pyrethroid activity in non-target species [23]. One such modification is the addition of α-cyano group to the alcohol moiety, considered a milestone in the development of synthetic pyrethrin analogs due to its critical role in providing greater insecticidal activity [28].

Figure -1: Structure of Deltamethrin

Pyrethroids are neurotoxicants [29,26,18]. Pyrethroid compounds can cross the placental barrier, blood brain barrier are known to interfere with hormonal and neurological development, the immune system and other physiological functions [30,31]. They have also shown immune toxic effects [32] and mammalian reproductive toxicity [33,34] and they are mutagenic and


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carcinogenic to humans [35], allergy and immunosuppression [36], cardiovascular toxicity [37], reproductive side effects [38] endocrine related diseases [39], hepatotoxicity and nephrotoxicity [40].

Deltamethrin

Deltamethrin [DLM] is one of the most type II neurotoxic pyrethroid insecticides. This insecticide was first produced in 1974 and marketed in 1978. The IUPAC name of DLM is [S]-α-cyano-3-phenoxybenzyl [1R, 3R]-3- [2, 2-dibromovinyl] - 2, 2-dimethyl cyclopropane carboxylate Roth: [S]-α cyano-3-phenoxybenzyl [1R] – cis -3 - [2,2 -dibromovinyl] 2,2 dimethyl cyclopropane carboxylate and its molecular formula is C22H19Br2No3. DLM is a synthetic insecticide, which is structurally based on natural pyrethrins, which quickly paralyze the insect nervous system giving a quick knockdown effect. DLM is globally used in crop protection including cotton, corn, cereals, soybeans, fruits and vegetables for pests such as mites, ants, weevils, beetles and control of malaria and other vector borne diseases [41]. DLM also used on areas such as golf courses, ornamental gardens, lawns, outdoor perimeter treatments, indoors as spot, crack, crevice treatments and pet collars. The illegal, unregistered products known as “Miraculous Chalk” or “Chinese Chalk” can also contains DLM as the active ingredient.

DLM characterize an industrial and environmental pollutant that is toxic to birds, animals, fishes and human living in the same ecosystem and direct or indirect exposure leads to the risk of substantial hazards [42]. The mechanism of action of pyrethroids, including DLM, is the same for target and non-target organisms. DLM mode of action is thought to be mainly CNS in action, or at least originate in higher nerve centers of the brain. Death of insects

appears to be due to irreversible damage to the nervous system occurring when poisoning lasts more than a few hours. Anand et al., [43] reported that DLM was rapidly distributed in nerve tissues with a distribution half-time of 2.1 hrs in rats after inducing single oral dose, showing that DLM has potency to accumulate in brain due to its relatively high blood flow and lipid content. It is neurotoxic to humans and has been found in human breast milk [44]. Recently, in South Africa, residues of DLM were found in breast milk and urine, together with DDT, in an area they use DDT as treatment for malaria control, as well as pyrethroids in small-scale agriculture [44]. DLM was reported most significantly present in the milk samples [45], fruits and vegetables [46] and even in soft drinks [47]. Recent studies have found potential hazards of DLM to fetuses, infants and children [48]. Therefore a great and urgent demand to quickly detect accidental or deliberate contamination by DLM, due to its potentially severe consequences to the environment and human health. The LD50 value for DLM (128 mg/kg BW) is based on the administration of the compound in corn oil and it is lower than that in aqueous solutions [49].

Deltamethrin Half-Life

Half-lives can vary extensively based on environmental factors. The amount of chemical remaining after a half-life will always depends on the quantity of the chemical originally applied. It should be noted that some chemicals may degrade into compounds of toxicological significance. Half-life is the measurement of time it takes for half of the applied amount of compound to break down. The half-life period can change based on solubility, soil chemistry, temperature, water content and the quantity of organic matter in the soil. DLM does not break down as quickly in soil with a high clay or organic matter content. DLM is broken down by microbes, light and water.

Table

S. No Deltamethrin Half-life References

1 Soil 5.7 - 209 days USEPA, 1999 [50]

2 Sandy /silt loam soil 11 - 72 days WHO, 1990 [51]

3 Plant surfaces 5.9 - 17 days Hill and Johnson, 1987 [52]

4 Anaerobic Half-life 31 - 36 days Tomlin, 2006 [53]

5 Hydrolysis Half-life 33 days USEPA, 1999 [50]

6 Aquatic half-life 8 - 48 hrs Erstfeld, 1999 [54]

7 Direct aqueous photolysis 30 days USEPA, 1999 [50]

8 pH 9 2.5 days USEPA, 1999 [50]

9 Pond sediment 306 days Muir et al., 1985 [55]

10 Pond surface 14 hrs Muir et al., 1985 [55]

11 Vegetative surfaces 5.9 - 17 days Hill and Johnson, 1987 [52]

12 Brain 1 - 2 days Soderlund et al., 2002 [23]

13 Fat 5 days Marei et al., 1982 [56]


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Its two major breakdown products move more easily in the soil than DLM itself.

Pharmacokinetics, Distribution, Metabolism and Absorp-tion of DLM

The detoxification of a xenobiotic, whose parent form is the primary toxicant, can occur via a number of different pathways including phase I biotransformation pathways and/or phase II conjugation pathways. The initial biotransformation of pyrethroids follows one of two phase I pathways, cytochrome P450 [P450] oxidation, or esterase hydrolysis and takes place primarily in the liver of mammals. These processes result in the production of numerous metabolites. Thiocyanate was the primary metabolite after rats were administered DLM orally or intraperitoneally. Other metabolites include PBA (3-phenoxybenzoic acid), 4’-OH-PB acid sulfate (4’-hydroxy-3-phenoxybenzoic acid sulfate), Br2CA (3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylic acid). The terminal phase of pyrethroid metabolism is the formation of glucuronide and glycine conjugates [57,58].

DLM is rapidly absorbed when administered orally or intraperitoneally and enters the central and peripheral nervous systems [59]. DLM is metabolized and its metabolites excreted over a period of days in rats. Ana`don et al., [1996] [59] reported the elimination half-life of DLM to be 38.5 hrs after an oral dosage of 26 mg/kg, while Mirfazaelian [2006] [60] found that DLM and its metabolites were largely excreted within 4 days. Many pharmacokinetic and dynamic studies have elucidated that a portion of orally administered DLM partition into fatty tissues, in which they persist for at least 3 weeks [23]. DLM can also be detected in the adipose tissue of rats with a half-life of 5-6 days and is most persistent in the body fat of animal models [56]. Ester cleavage and oxidation, primarily at the 4V position, are the two major means of DLM metabolism. Esterase catalyze hydrolysis of the ester bond to form relatively non-toxic acid and alcohol moieties, whereas CYP450s catalyze aromatic hydroxylation of DLM at various positions, notably the 4V position, followed by conjugation [58].

Molecular Mechanism of Pyrethroid Deltamethrin Induced Neurotoxicity

Lipophilic nature of the Pyrethroids have an easy as well as rapid access to the tissues, including the central nervous system [CNS] and thus even very small doses are able to produce significant biological and pathophysiological effects. Recently, many studies have reported exposure to pyrethroid pesticides in humans may cause subtle to severe neuro-physiological and neurobehavioral abnormalities [61]. The mechanism by which deltamethrin are thought to exert neurotoxicity is by prolonging the opening of

Na+ channels. This prolonged opening of Na+ channels results in persistent depolarization, leading to repetitive firing and if the exposure is high enough, seizures, paralysis and finally death occurs [18]. Specifically, research evidences have suggested possible roles for voltage-gated calcium channels, chloride channels, GABA receptors, modulation in the release of neurotransmitters especially acetylcholine, dopamine (DA) and serotonin or proteins involved in signal transduction and the mitochondrial electron transport chain (ETC), oxidative stress, microgliosis, astrogliosis, neuronal inflammation, neuronal apoptosis in the acute and chronic manifestation of neurotoxicity elicited by pyrethroid pesticides [62,23].

ROS & Oxidative Stress

Pesticides act as pro-oxidants and provoke effects in multiple organs [63]. Oxidative stress is defined by organ and tissue damage is caused by reactive oxygen species (ROS), reactive nitrogen species (RNS) and other oxidizing agents [64,65]. The acute and chronic exposure to DLM causes increase in lipid peroxide, TBA reactive products. Oxidative damage induced by DLM might be due to their lipophilic nature, whereby they could easily penetrate the cell membrane. DLM also generates various radicals as superoxide radical, hydroxyl radical, nitrogen species such as nitric oxide, peroxynitrite thus causing damage consistent with oxidative stress. These free radicals attack the cell membrane and lead to destabilization and degeneration of cell membrane as a result of LPO. Increased free radical accumulations are directly associated with oxidative damage to membrane carbohydrates, proteins, lipids, DNA and RNA of neuronal, glial and vascular brain tissue [66].

The brain is vulnerable to oxidative stress damage because of its high energy usage, high metabolic demands, low levels of endogenous scavengers [e.g., superoxide dismutase, catalase, vitamin C etc.], extensive axonal and dendritic networks and high cellular content of proteins and lipids [67]. Mammalian brains have a high tendency to generate reactive oxygen and nitrogen species (ROS/RNS) including hydrogen peroxide, superoxide, nitric oxide and peroxynitrite [68]. The high level of O2 consumption by mitochondrial metabolism in the brain and the continuous supply of oxygen allow for ROS/RNS to be generated from a variety of sources including nitric oxide synthases and mitochondrial respiratory chain [69]. These processes are further enhanced by neuro inflammation in which microglial cells become an additional source of ROS from NADPH oxidases [70]. The brain also contains high levels of polyunsaturated fatty acids which are targets for the initiation of lipid peroxidation which can proliferate the formation of reactive lipid species such as 4-hydroxy nonenal (HNE) and malondialdehyde (MDA) which in turn are capable of modifying proteins and lipids [71]. These modifications of proteins appear to


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accumulate in the brain during aging in AD and PD [72]. Several postmortem reports shows that markers for lipid peroxidation, oxidative DNA, protein damage and mitochondrial dysfunction [73] are significantly associated with the substantianigra [SN] of PD patients [74], indicating that oxidative stress plays an important role in the pathogenesis of PD in DLM induced neurotoxicity [75].

Acetylcholinesterase Inhibition

Acetylcholinesterase [AChE] represents a biomarker of neurotoxicity [76]. AChE is an important cholinesterase enzyme found in many types of conducting tissue, nerve, muscle, central and peripheral tissues, motor, sensory fibers, cholinergic and non cholinergic fibers, neuromuscular junctions, synapses in the CNS. AChE hydrolyzes acetylcholine into choline and acetate after activation of acetylcholine receptors at the postsynaptic membrane [77]. The choline released is recycled in the presynaptic nerve cell. The activity of AChE is greater in motor neurons than in sensory neurons. During neurotransmission, ACh is released from the pre-synaptic neuron into the synaptic cleft then it binds to ACh receptors on the post-synaptic membrane, transmitting the signal to the post-synaptic neuron. AChE, also located on the postsynaptic membrane, terminates the signal transmission by hydrolyzing the ACh. The liberated choline is engaged again by the pre-synaptic neuron and ACh is synthetized by joining with acetyl-CoA through the action of choline acetyl transferase [78]. For a cholinergic neuron to get another impulse, ACh must be released from the ACh receptor. This happens only when the concentration of ACh in the synaptic cleft is very low. AChE activity is a standard biomarker of pyrethroid pesticide poisoning. Pyrethroids have been demonstrated to cause a decrease in activities of AChE in erythrocytes and CNS of living organisms [79]. The inhibition of AChE enzyme was attributed to the occupation of its active sites by DLM exposure that could leads to decrease the cellular metabolism, disturb metabolic, nervous activity and lead to ionic refluxes and differential membrane permeability in addition to increase in LPO [80]. Extreme inhibition of AChE leads to nervous system malfunction, metabolic dysfunction, behavioral deficits, learning and memory deficiencies [81], which can leads to anxiety, fear, emotion and stress finally to neurodegenerative disorders [79]. Inhibition of AChE leads to accumulation of ACh in the synaptic cleft and results in delayed neurotransmission. Irreversible inhibitors of AChE lead to muscular paralysis, convulsions, bronchial constriction and death by asphyxiation.

Microgliosis

Microglia is the resident innate immune cells in the brain, have been implicated as active contributors to neuronal damage in neurodegenerative diseases including AD [82], multiple sclerosis (MS) [83], amyotrophic lateral sclerosis (ALS) [84], PD [85], and

Huntington’s disease [86] in which higher activation and dys-regulation of microglia might result in disastrous and progressive neurotoxic concerns [87]. A Microglial cell derived from myeloid cells in the periphery and comprises approximately 12% of cells in the brain. Microglia density varies in the brain region of adult human (0.5-16.6%) [88] and in adult rats, they dominate in the grey matter, with the uppermost concentrations being found in the hippocampus, basal ganglia, olfactory telencephalon, and substantianigra. In mature brain, microglia typically exists in a resting state characterized by ramified morphology and monitors the brain environment [89]. In response to certain signs of brain injury or immunological stimuli, microglia cells are readily activated [90]. Activated microglia undergo a dramatic transformation from their resting ramified state into an amoeboid morphology and present an up-regulated catalogue of surface molecules [91]. Activated microglia are involved in regulating brain progress by enforcing the programmed elimination of neural cells [92] and seem to improve neuronal survival through the release of trophic and anti-inflammatory elements [93]. In fact, neuronal inflammation, microglial activation and the peripheral immune system are intricately linked and PD has been linked with peripheral immune dys-regulation [94]. More specifically, pro-inflammatory cytokines are raised in PD patient [95] and up-regulated by circulating white blood cells, both at basal level and in response to pro-inflammatory stimuli [94], indicating that these peripheral cells are biologically altered during the development of CNS pathology.

Astrogliosis

Astrogliosis is a hallmark of damaged CNS tissue [96]. This term refers to progressive modifications in gene expression and altered cellular morphology, often including inflammation of neuronal cells. Astrocytes play important role in the appropriate functioning of the human brain [97]. They are essential for maintaining ion and pH homeostasis, for the elimination of neurotransmitters, for providing glucose supply to the brain and blood brain barrier. Further, recent evidence indicates that astrocytes regulate synaptic activity, synaptogenesis, and neurogenesis [98] also plays significant role in neuronal protection. Inflammatory activation of astrocytes or astrocyte dysfunction is supposed to be associated with several chronic neurological disorders, including prion, AD, PD and dementia [99,100]. Undoubtedly, astrocyte dysfunction causes neurological problems in adults. Astrocyte dysfunction also causes neurological problems in children because the developing nervous system is even more sensitive to environmental insults in children’s than adults.

Astrogliosis is characterized by the increased expression of GFAP, characterizes the response of astrocytes to all types of


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injuries of nervous system and has been reported in experimental toxicological studies using several pesticides including pyrethroids [101]. Astrocyte activation is an essential feature during acute brain inflammation [102]. Astrocytic and microglial activation occurs in response to a group of toxins that contribute to the pathogenesis of neuroinflammation and neurodegeneration [103].

GFAP a marker for reactive gliosis, increased expressions of GFAP in immunostaining and immunoblot were observed in the DLM-induced rats support the astrogliosis and microgliosis involved in the molecular mechanism of DLM-induced neurotoxicity. In this study, hypertrophied GFAP with rosenthal fiber like structures indicates DLM-induced astrogliosis. An increase in the GFAP expression is associated to the neuro developmental pathology such as AD or non-specific gliosis [104,105]. Little and O’Callagha, [2001] [106] reported that micro-anatomical analysis of DLM exposure leads to a selective loss of nerve cells in frontal cortex and hippocampus and the development of astrogliosis that represents a sign of sufferance of nervous tissue/system. Thus reactive gliosis cause increase expression of pro-inflammatory cytokines leads to neuronal injury thereby influencing learning and memory deficits.

Behavioral Changes

Exposure to pyrethroid pesticides has been found to affect the neurobehavioral performance, neurotransmitter systems in humans and experimental models [107]. Alterations in the motor activity, open field behavior, catalepsy and operant behavior have been reported after exposure to pyrethroids [108]. It could affect all the three phases of development, i.e., prenatal, postnatal and perinatal period and exert oxidative stress on brain involving all the four major brain region under study, i.e., frontal cortex (FC), hippocampus (HP), cerebellum (CB), and corpus striatum (CS) which are responsible for regulating essential functions such as learning, memory and locomotor activity in the adult brain leading to increased anxiety and depression. Delay in development of physical milestone and reflexes, diminishing in motor activity, grip strength and other behaviors associated with neurochemical modifications has been reported following pyrethroid exposure [18,108,109] Studies show that in brain, DLM exposure can interact with neurotransmitter receptors and can alter blood-brain barrier (BBB) permeability [110] leading to neurobehavioral alterations in infants and adults [111]. DLM exposure causes reduced recognition memory, impaired discrimination for the objects, anxiety that express fear behavior on open spaces into which they are forced. It may be due to the inhibitory effects of DLM on GABA and AChE, producing an indirect augmentation of excitatory neuronal transmission [112]. DLM exposure also causes increased freezing, grooming and rearing behaviors, suggesting that the DLM disturb the CNS cause increases emotionality and

exploratory activities of rat. In this respect, the most important response to increased emotionality in the open field is freezing behavior, with a consequential decrease in locomotion frequency parallel to an increase in immobility indicates a motor deficiency related to dopaminergic blockage function. Alterations in open field behavior, catalepsy, motor activity and operant behavior have been reported to the following exposure of pyrethroid pesticides [108,113].

DLM exposure causes gait disturbances like decreased walking speed, altered foot angle, overlapping patterns of foot, inability to walk on grid runway, narrow beam, inclined plane and staircase runways. Gait disturbances are commonly observed in subjects with PD resulting from a degeneration of dopaminergic (DA) neurons in the substantianigra (SN) [114]. Typically, the hallmark changes of walk following PD comprise temporal asymmetry, which manifests as an inability to maintain internal step rhythm [115], reduced walking speed, increased rhythm and increased double standpoint time [115]. In addition, PD subjects exhibit irregular longitudinal indices of step patterns, which typically include short steps [116], freezing gait [117] and decreased stride length [118]. DLM-induced the altered locomotion behavior is due to the inhibition of AChE and accumulation of acetylcholine (ACh), a neurotransmitter at synaptic junctions, which disturbs the coordination between the nervous and muscular junctions cause neurotoxicity.

Mitochondrial Dysfunction

Mitochondria play an important function in energy metabolism within the cell, and mitochondrial dysfunction, oxidative stress leads to various neurodegenerative disorders. Mitochondria are found in all eukaryotic cells and role to produce cellular energy in the form of adenosine triphosphate [ATP] by oxidative phosphorylation and are thought to be derived evolutionarily from the fusion of prokaryotic and eukaryotic organisms [119]. They are also involved in regulation of cell death through apoptosis, calcium homeostasis, haem biosynthesis and the formation and export of iron-sulphur [Fe-S] clusters [120,121] and function in the control of cell division and growth. Following excitotoxicity and other neurodegenerative insults, mitochondria will take up calcium which leads to an increased production of ROS. As a result, neuronal cells face excessive amounts of ROS [122]. This ROS leads to reduce mitochondrial ATP production, increased mitochondrial deoxyribonucleic acid (DNA) mutations, increase in the abnormal mitochondrial cristae structures and impairs intracellular calcium level [123]. Increased ROS production with mitochondrial dysfunction ultimately affects neurons and accelerates neurodegenerative process [124]. Mitochondrial dysfunction with complex I deficiency and impaired electron


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transfer in the substantianigra in PD have been reported [125]. Furthermore, mutations in several mitochondrial proteins have been associated with hereditary forms of PD [126], as well as the presence of deletions in mitochondrial DNA identified in aging and substantianigra in PD [127].

DLM exposure caused impairment in mitochondrial enzyme complex activity as indicated by decrease in the activities of (complex-I) NADH dehydrogenase (NADH-DH), (complex-II) Succinate dehydrogenase (SDH), (complex-III) Cytochrome-C-oxidase, Isocitrate dehydrogenase (ICDH), α-Ketoglutarate dehydrogenase (KGDH), and Malate dehydrogenase (MDH). It is well known that these enzymes are involved in energy production (ATP), by oxidative phosphorylation occurs in mitochondria. In DLM-induced mitochondrial injury, free radicals and oxidative stress are major implication, thus free radicals induced ROS toxicity shuts down mitochondrial oxidative phosphorylation and the TCA cycle, blocking mitochondrial ATP production [122]. DLM also enhances the level of LPO of mitochondrial phospholipids bilayer in which the respiratory chain is embedded. Thus, the respiratory cycle enzymes could have been affected by the free radicals formed by DLM. Formation of ROS induces a loss of mitochondrial permeability transition, which leads to the release of cyt-C from mitochondria [128]. Decrease in the concentration of cyt-C leads to a decrease in the uptake of oxygen, resulting in low respiratory rate. Thus, reduction in mitochondrial cytochrome content, results in a loss of activities of oxidative phosphorylation capacity. The DLM-induced decrease in the activities of NADH dehydrogenase enzymes is due to depletion of reducing equivalents like NADH and NADPH, which are utilized for the production of reduced glutathione to counter oxidative damage of mitochondrial components [129]. DLM-induced mitochondrial impairment also results in Ca2+dys-regulation and activation of NOS. This could be one of the potential mechanisms for enhancement of nitric oxide (NO) in aging brain. NO and oxygen free radicals reacts to form peroxynitrite (ONOO-) which causes oxidative damage in mitochondria [130]. DLM-induced mitochondrial dysfunction leads to vulnerability of oxidative stress and thus stress triggers a downstream cell death pathway that leads to neuronal apoptosis [131]. Recently, Kumar et al., also reported that chronic exposure to DLM-caused damage of mitochondrial energy metabolism in different regions of rat brain [132].

Neuronal Inflammation

Neuronal inflammation is actively involved in the pathological process of neurodegenerative diseases such as AD, PD and MS [133]. Cytokines, which include chemokines, interferons (IFNs), interleukins (ILs), growth factors and tissue necrosis factors (TNF-α), are a major element of a highly complex system that

controls immune and inflammatory responses in the peripheral nervous system and CNS [134]. Oxidative damage from free radical and other oxidants trigger inflammation via a cytokine mediated immune response [135] that involves release of anti-inflammatory and pro-inflammatory cytokines (e.g., TNF-α, IL-1, IL-6) by peripheral and CNS cells (e.g., microglia and astrocytes) [134]. Increased pro-inflammatory cytokine levels are associated with cerebral oxidative stress and apoptosis through generation of ROS and other inflammatory mediators in the brain (and peripheral organ systems) by immune cells, microglia and astrocytes [136,137]. Therefore, oxidative stress and inflammation often occur in tandem in many diseases and disorders, including AD, PD, smoking and pesticide exposure [138,139].

DLM cause direct cellular damage, oxidative stress and free radicals that activate the transcription of multiple inflammatory genes. DLM-induced astrocytic and microglial activation has also been associated with the production of pro-inflammatory toxic cytokines [140]. Inflammation in DLM-induced neuronal degeneration is mediated by soluble pro-inflammatory molecules such as cytokines, prostaglandins and NO. DLM induced increased expression of iNOS produces toxic aggregates of NO is associated with neuronal cell death by inhibiting mitochondrial respiration and excitotoxicity and has been implicated in DLM-induced neurotoxicity [141]. Further, increase in the expressions of TNF-α and COX-2 has been observed in DLM-induced rats and is indicative of enhanced neuroinflammation. DLM exposure causes increased expression of TNF-α, alters mitochondrial integrity by reduction in membrane potential and ATP depletion [142]. Thus TNF-α induced activation of NF-κB expression together with generation of ROS, as being responsible for DLM-induced neuronal apoptosis.

Neuronal Apoptosis

Apoptosis plays an important role in the development and mainte-nance of homeostasis in most of the multicellular organisms [143]. This kind of cell death can be triggered by the activation of certain death receptors or by cellular stress [144] and implicates a cascade of biochemical events that are tightly regulated. Some of these cascade molecules involve in the activation of the cysteine pro-teases called caspases and the release of mitochondrial death fac-tors, such as cyt C. Bcl-2 gene families are recognized as cell death regulating genes. Of these genes, Bax and Bcl-2 associated proteins (Bad) stimulate cell death, whereas, Bcl-2 prevent cell death and promote cell survival [145]. The Bcl-2 proteins bind to the outer membrane of mitochondria and block cyt C activation [146].

DLM exposure causes the up-regulation of Bax expression in rat brain may be associated with the increased expression of P53 [147], which functions in a pathway to stimulate the transcription and


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translation of Bax, on the other hand, increase expression of p53 down-regulate the expression of Bcl-2, subsequently apoptosis occurs in rat brain [147,148,149]. The higher level of cytoplasmic p53 protein interacts with mitochondria, thereby promoting mito-chondrial membrane permeability [150], and plays an important role in the regulation of apoptosis during DLM exposure [151].

The level of cyt C in the cytosol, serve as a marker of mitochondrial damage. DLM-exposure showed intense expression of Bax and regulate apoptosis by increasingly release of cyt C from mitochondria into the cytosol. Release of cyt-C activates caspase-9 which ultimately results in cell death through the cleaving of the executioner caspase, such as caspase-3. Activated caspase-3 plays a key role in triggering the catabolic caspase cascade [152]. Caspase cascade is activated through binding of procaspase-9 with Apaf-1 to form the apoptosome complex following the release of cyt-C from damaged mitochondria triggering caspase activation, and ultimately causes cell death [153]. DLM-exposure causes increase expression and activation of cyt C, caspase 3, 9 evident apoptosis plays important role DLM neurotoxicity. DLM-induced neurotoxicity is mediated by intrinsic apoptosis pathway triggered by P53 and the extrinsic pathway of apoptosis initiated by inflammatory activators such as TNF, COX2, NFκB, IL1β also results in activation of caspase-3, 9, which is known to activate endonuclease and induce DNA fragmentation.

Previous studies reported that the acute exposure of type II pyrethroid causes apoptosis both in vivo [147] and in-vitro studies [154,155] . Recent works shown that DLM-induced apoptosis in in-vitro was through activation of the endoplasmic reticulum (ER) stress pathway [152]. Persistent activation of the ER stress pathway is connected to progressive loss of neurons leading to neurodegeneration and cognitive dysfunction [156,157], which may be the result of reduced synaptic plasticity and neuronal viability in the cortex and hippocampus [158]. Several in- vivo and in- vitro studies have reported that the toxic effects of DLM in a variety of cell types, including neuronal cells, thymocytes and adrenal pheochromocytoma cells. In neuronal cells, Wu and Liu (2000) [147] detected apoptotic cells in the cortex and hippocampus after DLM treatment (in-vitro and in-vivo). DNA fragmentation has also been observed by DLM in neuroblastoma cells [152], glioblastoma cells [159], thymocytes, Enan et al., [1996] [160], thymocytes of male mice [161]. In testicular tissues of rats, DLM (in-vivo) also induces apoptosis as observed by El-Gohary et al. [1999] [162].

Conclusion

Deltamethrin-induced neurotoxicity is a matter of concern, as humans are exposed to it, in their day-to-day life. Deltamethrin- induced neurotoxicity is depends on number of factors such as

doses, time and routes of exposure. The review summarizes the molecular mechanism of DLM induced neurotoxicity. More experimental and prospective clinical studies are needed, so that the management of severe pesticide poisoning may be optimized and more attention to the reduction of pesticide usage in the environment is suggested.

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