The Association between Pesticide Exposure and the Development of Fronto-Temporal Dementia-Cum-Dissociative Disorders: A Review

Pesticides are chemicals used in agricultural fields for the prevention or destruction of pests. Inappropriate use of these substances, as well as handling them without using personal protective equipment, may result in serious health problems such as neurodegenerative diseases and mental disorders. Previous studies have demonstrated the adverse effects of pesticides on brain function. However, some researchers have associated pesticide poisoning with the development of disorders such as dissociative amnesia, multiple personality disorders, and depersonalization disorder. The objective of this work was to perform a bibliographic review of the relationship between pesticide poisoning and the development of dissociative disorders. Previous studies suggest that the duration of pesticide exposure is a major determinant in the development of dissociative diseases and disorders. The information obtained in this review suggests that there is no specific relationship between dissociative disorders and pesticide poisoning. However, these results point to associating the most representative symptoms of dissociative disorder (such as amnesia and memory loss) with pesticide exposure. Based on the bibliographic search, possible mechanisms of action were suggested in an attempt to explain a possible association between exposure to pesticides and the appearance of dissociative disorders.


Introduction
Pesticide poisoning represents a great risk to the health of the global population. A study carried out by the ONU in 2017 showed that 200,000 deaths from poisoning are recorded annually, especially in developing countries [1]. Farmers are highly vulnerable to pesticide poisoning due to direct contact with these chemicals. Among the most widely used pesticides in the world are organophosphates (OPs), carbamates, and pyrethroids [2]. Speaking specifically of OPs, worldwide it is estimated that around 3 million people are exposed to this type of pesticide each year, which represents approximately 300,000 deaths [3].The mechanism of action of OPs is through the inhibition of acetylcholinesterase (AChE) in the synapse, which leads to an accumulation of acetylcholine (ACh) from cholinergic receptors (muscarinic and nicotinic) in the central and autonomic nervous system and in the neuromuscular junctions, causing different clinical manifestations [4]. The degree of poisoning Worldwide, it is estimated that fifty million people undergo dementia, a figure that has increased to ten million cases each year, ranking among the ten main causes of death, with a negative impact on the psychological, physical, and social level that affects the quality of life of patients and represents one of the main causes of dependency and disability [7]. The most relevant types of cortical dementias are dementia with Lewy bodies, Alzheimer's disease, and FTD [8].
FTD is a neurodegenerative disease characterized by progressive changes in personality and behavior and/or early and progressive language impairment [9]. It is the second most common cause of dementia in people under 65 years of age [10]. Due to the heterogeneity of cognitive alterations, FTD comprises three clinical variants: behavioral/frontal, primary progressive aphasia, and semantic dementia [11]. These variants are shown in Table 1. Bilateral or left inferolateral temporal cortex Modified from [12].

Front Variant
The frontal variant represents 90% of FTD cases, and it presents very varied alterations depending on the affected prefrontal area. If it affects the orbitofrontal area, it causes a lack of social sensitivity, aggressiveness, inattentiveness, and changes in personality. On the

Primary Progressive Aphasia
In primary progressive aphasia, syntactic and phonological language alterations occur, which at the initial stages produce an inability to remember names of people or objects, followed by agrammatism, which may end in mutism [13]. This aphasic syndrome is divided into two variables: fluent (affects semantic processing, but syntax and phonology are preserved) and non-fluent, i.e., grammatical errors and phonological paraphasia [14,15]. In advanced stages of the disease, when all aspects of language are severely affected, memory deficits and behavioral changes may also manifest ( Figure 1) [15].

Semantic Dementia
Semantic dementia is characterized by an inability to recognize facts, objects, or the meaning of words. In addition, the ability to perceive visual stimuli, smells, tastes, and non-verbal sounds is progressively lost. People with semantic dementia may present behavioral changes that are different from the frontal variant since they concentrate most of

Primary Progressive Aphasia
In primary progressive aphasia, syntactic and phonological language alterations occur, which at the initial stages produce an inability to remember names of people or objects, followed by agrammatism, which may end in mutism [13]. This aphasic syndrome is divided into two variables: fluent (affects semantic processing, but syntax and phonology are preserved) and non-fluent, i.e., grammatical errors and phonological paraphasia [14,15]. In advanced stages of the disease, when all aspects of language are severely affected, memory deficits and behavioral changes may also manifest ( Figure 1) [15].

Semantic Dementia
Semantic dementia is characterized by an inability to recognize facts, objects, or the meaning of words. In addition, the ability to perceive visual stimuli, smells, tastes, and non-verbal sounds is progressively lost. People with semantic dementia may present behavioral changes that are different from the frontal variant since they concentrate most of their time on a single activity in contrast to loss of interest, which is a characteristic of the frontal variant ( Figure 1) [16].

Relationship FDT Variants with Pesticides
There are highly toxic pesticides for dopaminergic neurons [17]. The loss of dopamine in the connections between the prefrontal cortex and caudate nucleus leads to inhibition of Brain Sci. 2023, 13, 1194 4 of 14 response and planning. This results in the inability to sustain directed activities to achieve a set goal or objective and the inability to correctly perform motor actions associated with complex movement [18]. This may be associated with the frontal variant of FTD since if the mesiofrontal area is affected, there is loss of movement in the same way. An alteration in the dorsolateral zone leads to the inability to make decisions, which could explain the lack of planning and response due to a decrease in the level of dopamine in the connection between the prefrontal cortex and caudate nucleus [12,13,18]. It should be noted that the decrease in the amount of dopamine is also related to the use of chemical herbicides such as Paraquat, Diquat, and the fungicide MANEB, which are toxic to nigrostriatal dopaminergic neurons [17].

Parkinson's Disease (PD)
PD is the second most frequent neurodegenerative disease after Alzheimer's disease [18]. The main signs of PD are akinesia, postural rigidity, and tremor at rest, which are the consequences of impairment in dopaminergic activity. Neuronal death, mainly in the substantia nigra, leads to a reduction in dopamine levels, which is responsible for the characteristic signs of the disease. In addition, the degeneration of the substantia nigra causes deficits in balance [19]. Epidemiological data suggest that there is an increased risk of developing PD after exposure to pesticides [20]. Pesticides such as paraquat, rotenone, and dieldrin induce apoptosis of dopaminergic neurons [21].
On the other hand, the presence of α-synuclein (a protein that forms Lewy bodies) in the enteric nervous system, submandibular gland, dorsal motor nucleus of the vagus nerve, and olfactory bulb may cause these peripheral areas to act as receptors for environmental factors that trigger the onset of PD, such as the pesticides rotenone and paraquat [18]. Heiko et al. (2003) described the progression of PD in 6 stages related to the presence of α-synuclein in different locations, and its clinical correlation. Stages 1-3 correspond to the preclinical phase of the disease. At these stages, α-synuclein aggregates are found at the level of the sympathetic and parasympathetic pre-and post-ganglionic fibers of the enteric nervous system connected to the olfactory bulb, dorsal nucleus of the vagus nerve, and at the level of the spinal cord. In stage 4, there is neurodegeneration in the zona pars compacta of the substantia nigra. Finally, in stages 5-6, the α-synuclein aggregates are distributed in sensory association areas corresponding to the premotor and motor prefrontal cortex [22]. Table 2 shows different pesticides related to the development of PD. Organochlorines (dieldrin and lindane) have been associated with PD. Various studies have shown the toxic effects of dieldrin and lindane on dopaminergic neurons, resulting in ROS-induced apoptosis of these neurons. In addition, postmortem studies have found high concentrations of organochlorine pesticides in the substantia nigra [21,23,24].
Animal studies have shown the involvement of organophosphates (OPs) in the development of PD. For example, chronic exposure to dichlorvos caused nigrostriatal dopaminergic degeneration and a 60-80% decrease in levels of tyrosine hydroxylase and dopamine in the striatum, while malathion increased the concentration of α-synuclein in the striatum. Moreover, OPs induce damage to the dopaminergic system through the production of ROS [24][25][26]. The pyrethroids cypermethrin and deltamethrin interfere with dopaminergic mechanisms involved in the production of dopamine, thereby decreasing the level of this neurotransmitter in the brain [27].
Several studies have demonstrated that paraquat is absorbed by the dopamine transporter, thereby resulting in toxicity and apoptosis due to oxidative stress [27][28][29]. Moreover, in an animal study, Drolet et al. (2009) reported that rotenone administration caused loss of striatal dopamine and accumulation of α-synuclein in the other dopaminergic neurons, in addition to the appearance of PD characteristics such as rigidity, postural instability, and bradykinesia [30]. Table 2. Pesticides associated with pathogenesis of PD.

Type of Pesticide Relationship with PD Type of Study References
Organochlorines Dieldrin Acted as dopaminergic toxin in mesencephalic cultures. Review [27] Reduced brain dopamine levels, increased ROS in nigral dopaminergic neurons, inhibited mitochondrial oxidative phosphorylation, altered mitochondrial membrane potential, and caused cytochrome C release.
Review [21] There were increased concentrations of these insecticides in the substantia nigra, which may be directly related to reduced dopamine concentrations Post mortem study [23] Lindane There were increased concentrations of these insecticides in the substantia nigra, which may be directly related to reduced dopamine concentrations Post mortem study [23] Others They were neurotoxic, produced oxidative stress, and damaged the dopaminergic system.
Animal model [24] OPs Dichlorvos Produced nigrostriatal dopaminergic degeneration, reduced levels of striatal dopamine and tyrosine hydroxylase.
Animal model [25] Malathion Increased levels of α-synuclein protein and mRNA in striatal tissue Animal model [26] Others Were neurotoxic, and produced oxidative stress and damage to the dopaminergic system Animal model [24] Pyrethroids Cypermethrin Interfered with cholinergic and dopaminergic neurotransmission mechanisms Review [27] Deltamethrin Reduced dopamine levels Review [27] Others

Rotenone
Were selectively toxic to dopaminergic neurons Human brain spheroid model from induced pluripotent stem cells [31] Mitochondrial toxin Case-control studies [32,33] Reduced tyrosine hydroxylase-positive neurons in the substantia nigra, induced loss of striatal dopamine, and accumulation of α-synuclein and polyubiquitin-positive aggregates in the remaining dopaminergic neurons Animal model [30] Paraquat Damaged dopaminergic neurons due to oxidative stress Case-control studies [27] Caused cellular toxicity due to oxidative stress to dopaminergic neurons. Animal model [28] Led to loss of dopaminergic neurons due to oxidative stress. Review [29] 1.1.

Dissociative Disorders
These disorders refer to mental disorders that involve disconnection and a lack of continuity of thoughts, memory, environments, actions, and identity. A person with a dissociative disorder is disconnected from reality in involuntary and unhealthy ways, leading to problems with daily functioning [34]. In the general population, the prevalence of dissociative disorders is 5% to 10%, while in psychiatric patients it is 10.2% to 41.4% [35]. Three main types of dissociative disorders are recognized: dissociative amnesia, dissociative identity disorder, and de-personalization/de-realization disorder [34].

Dissociative Amnesia
Dissociative amnesia (DA) is a disorder characterized by disruptions in the proper functioning of consciousness, memory, identity, and behavior. The affected person is unable to remember moments of their own life. In DA, there are alterations in brain sections such as the frontal cortex, hippocampus, temporal lobes (medial, right and left), hypothalamus, and thalamus. These structures are crucial in the processing of memory and emotional content, and they are activated in response to stress. However, certain neurotransmitters are also released, but in situations of minimal stress, the concentrations of dopamine, serotonin, acetylcholine, and norepinephrine are altered in the amygdala, hippocampus, and prefrontal cortex. Acute stress produces variations in levels of corticosterone, a hormone that regulates the release and activities of the aforementioned neurotransmitters and, under normal conditions, consolidates long-term memory. Consequently, changes in the action of corticosterone cause alterations in the activities of the different neurotransmitters. These changes are associated with an inability to remember events, the development of disruptive behaviors, and, ultimately, the development of DA [36,37].

Dissociative Identity Disorder (DID)
Formerly known as multiple personality disorder, it is a condition in which two or more different personalities coexist, with each one of them having its own criteria for perceiving and thinking about itself and the external environment. In this disease, there are serious changes in the way a person feels about himself, in addition to important alterations in behavior, memory, perception, cognition and functioning of sensorimotor [38].
Currently, it is more acceptable to refer to this condition as discontinuity in memory and identity. Dissociative identity disorder (DID) has the characteristic symptoms of other dissociative disorders (AD and de-personalization/de-realization). It is important to point out that for the diagnosis of DID, DA must be present. This explains the amnesia that the other personalities manifest. Patients with DID may present transient psychotic symptoms, e.g., hallucinations [39].

Depersonalization/De-Realization (DD)
This is a psychiatric condition characterized by permanent feelings of unreality about the outside world as well as self-detachment. Depersonalization is an experience in which the person affected does not control his thinking. Consequently, he feels alienated, distant, and unable to identify himself. In contrast, de-realization is the feeling of strangeness towards the outside world. Both experiences are related. However, the patient may suffer episodes of de-realization without having experienced de-personalization, and vice versa. Due to their inability to describe experiences clearly, these patients often resort to metaphors, and since they never lose contact with reality and are able to identify sensations during DD episodes, this disorder is considered a type of neurosis [40,41]. Depersonalization may be due to alterations in the levels of different neurotransmitters, for example, glutaminergic N-methyl-D-aspartate (NMDA) receptors distributed throughout the amygdala, hippocampus, and cerebral cortex. These neurotransmitters are involved in associative functions in long-term memory. In cholinergic overstimulation, the activation of these receptors induces the release of nitric oxide, which causes neurotoxicity and neuronal degeneration by interacting with the superoxide radical to form nitric superoxide [42,43].
The neurotoxicity of some types of pesticides affects the synthesis, release, absorption, and degradation of different neurotransmitters. The OPs affect the central nervous system by inhibiting AChE, which catalyzes the hydrolysis of ACh into choline and acetate. Because of AChE inhibition, an excessive accumulation of ACh occurs in the synaptic cleft, causing overstimulation of nicotinic and muscarinic receptors located both in the central nervous system and at the neuromuscular junction, hence the importance of the dose, exposure time, and severity of the poisoning [6,44] (Figure 2). ide [42,43].
The neurotoxicity of some types of pesticides affects the synthesis, release, absorption, and degradation of different neurotransmitters. The OPs affect the central nervous system by inhibiting AChE, which catalyzes the hydrolysis of ACh into choline and acetate. Because of AChE inhibition, an excessive accumulation of ACh occurs in the synaptic cleft, causing overstimulation of nicotinic and muscarinic receptors located both in the central nervous system and at the neuromuscular junction, hence the importance of the dose, exposure time, and severity of the poisoning [6,44] (Figure 2). The overstimulation of muscarinic receptors results in a loss of integrity of the cholinergic pathways and generates neuronal death in brain regions such as the hypothalamus, thalamus, and basal anterior cerebral cortex [6]. Stimulation of muscarinic receptors causes miosis, urination, bradycardia, bronchorrhea, bronchospasm, emesis, and salivation [45].
Overactivation of the nicotinic receptor favors the influx of Ca 2+ into the cell and promotes increased levels of reactive oxygen species (ROS), oxidative stress, and apoptosis [46]. In addition, the production of ROS in the mitochondria causes the release of cytochrome C, which in turn activates caspases 3 and 9, increasing the expression of apoptotic genes [47]. At the central nervous system level, nicotinic effects cause headaches, confusion, anxiety, ataxia, and seizures [45].
OPs also inhibit the esterase target of neuropathy, present in peripheral nerves, lymphocytes, and the brain, causing tardive polyneuropathy [48]. Conditions seen in subjects with tardive polyneuropathy include depression, psychosis, and impaired processing and problem-solving abilities [49]. The overstimulation of muscarinic receptors results in a loss of integrity of the cholinergic pathways and generates neuronal death in brain regions such as the hypothalamus, thalamus, and basal anterior cerebral cortex [6]. Stimulation of muscarinic receptors causes miosis, urination, bradycardia, bronchorrhea, bronchospasm, emesis, and salivation [45].
Overactivation of the nicotinic receptor favors the influx of Ca 2+ into the cell and promotes increased levels of reactive oxygen species (ROS), oxidative stress, and apoptosis [46]. In addition, the production of ROS in the mitochondria causes the release of cytochrome C, which in turn activates caspases 3 and 9, increasing the expression of apoptotic genes [47]. At the central nervous system level, nicotinic effects cause headaches, confusion, anxiety, ataxia, and seizures [45].
OPs also inhibit the esterase target of neuropathy, present in peripheral nerves, lymphocytes, and the brain, causing tardive polyneuropathy [48]. Conditions seen in subjects with tardive polyneuropathy include depression, psychosis, and impaired processing and problem-solving abilities [49].
A recent study sought to associate OP exposure with neurological disorders such as dementia, attention deficit hyperactivity disorder, Parkinson's, cognitive development, chronic neuropsychiatric disorders, and autism. The authors presented evidence of a strong link between repeated exposure to OPs and neurodevelopmental, cognitive, and attention deficit disorders in children [46].

Discussion
Although the existing information on a possible relationship between the development of dissociative disorders and pesticide exposure is null, an association can be made between the characteristic symptoms of said disorders, particularly dementia and memory loss since there is evidence that the pesticides participate in the development of these symptoms, affecting different neurotransmitters or organs, and may represent a risk factor acting alone or in conjunction with other components such as stress, abuse, or a congenital disease related to the development of dissociative disorders.
The main alterations in different organs, organelles, and neurotransmitters due to pesticide exposure are discussed in Table 3. The mechanisms involved in these alterations are similar to the mechanisms that trigger characteristic symptoms of dissociative disorders, mainly amnesia and loss of memory.
One of the mechanisms involved is the one that induces rotenone by inhibiting the electron transport chain in the mitochondria, causing hyperphosphorylation of the Tau protein, the formation of β-amyloid peptides, and increased lipid peroxidation (causing oxidative stress). DDT also impairs the electron transport chain. [50][51][52][53].
Likewise, Souders et al. (2021) reported malformation of the nervous system, neurofibrillary tangles, neuroinflammation, and nerve fiber degeneration in neuronal cells of rats exposed to fipronil [54]. Moreover, Cam et al., (2018) have demonstrated that fipronil stimulated the production of amyloid peptides which constitute a characteristic abnormality in Alzheimer's disease [55].
Pesticides such as dieldrin, rotenone, and paraquat induce apoptosis of dopaminergic neurons, thereby altering their proper functioning in the brain and resulting in neurodegenerative conditions such as Parkinson's disease and/or Alzheimer's disease [21].
OPs are AChE inhibitors that impair the cholinergic system and interrupt axonal transport and mitochondrial function, thereby triggering neurological disorders, e.g., memory loss [44,56]. OPs are distributed to all regions of the brain, including the hippocampus, the major region involved in learning and memory regulation. Organophosphate-oxons disrupt the development of the nervous system, glial cell proliferation, differentiation, and neural function [57]. Other evidence indicates that there is a gradual loss of neuronal cells in the amygdala in acute diisopropylfluorophosphate poisoning, with behavioral changes as the major consequence [58]. Constant memory deterioration is one of the most observed behavioral changes in people intoxicated with OPs [59].
A study by Nasuti et al. (2014) showed that early exposure to permethrin led to severe hippocampal lesions such as impairment of long-term memory and disruption of synaptic morphology [61]. Continued exposure to deltamethrin, a synthetic pyrethroid, led to apoptotic cell death in the hippocampus, endoplasmic reticulum stress, and decreased proliferation of the hippocampal precursor, all of which are associated with learning deficits [62].
It has been reported that chronic administration of chlorpyrifos significantly impaired learning, memory, and motor coordination [63]. Exposure to pesticides such as parathion, hexachlorocyclohexane, and aldrin resulted in an increased risk of dementia and the subsequent onset of Alzheimer's disease [64]. Chronic exposure to OPs and organochlorines produces neurobehavioral effects [65].   Table 4 presents specific evidence of the association between pesticides and dissociative disorders.
In DA, there is an alteration in brain structures, with high levels of pesticides such as glufosinate ammonium accumulating in the brain, thereby affecting the central nervous system and producing alterations in adults [68]. Studies have shown that parathion causes alterations in cholinergic, serotonergic, and dopaminergic synaptic functions in brain regions. Changes in neurotransmitter systems alter memory-related functions and affect neural connections, thereby contributing to the formation of neurodevelopmental disorders [6,69,70].
Dissociative Identity Disorder (DID) is associated with behavioral changes, memory loss, and amnesia. Evidence for the link between these symptoms and pesticides, particularly OPs, was found in medical studies carried out on patients with prolonged pesticide exposure who manifested chronic changes in behavior such as personality al-teration, decreased memory, anxiety, depression, nervousness, and incoordination [71,72]. García (2000) carried out a descriptive follow-up study of patients with a history of acute poisoning by OPs. The main symptoms found corresponded to changes in behavior, such as irritability, difficulty with concentration, depression, memory problems, and tiredness [73].
Finally, dieldrin is a GABA A receptor antagonist that has been shown to decrease the number of functional NMDA receptors in primary cultures of mouse cortical neurons. Since these receptors are involved in associative functions in long-term memory, a decrease in their activity produces symptoms of DD [43,74].

Conclusions
Exposure to different types of pesticides could be related to neurotransmitter, organelle, and effector organ dysfunction that triggers dissociative disorders. These types of disorders are becoming more frequent in human populations, as is the massive use of different pesticides; however, this review exposes the necessity to increase the number of prospective studies that evaluate the neurotoxic potential of these substances and their relationship with dissociative disorders in humans.
The information shown in this review suggests that exposure to organochlorines, OPs, pyrethroids, etc., produces different brain disorders such as Alzheimer's disease and PD. At the same time, it opens the possibility of developing new lines of research focused on exposure to pesticides and dissociative disorders. This possibility could provide alternatives that contribute to the prevention and treatment of these disorders.
However, more research is necessary to link pesticide exposure to the pathophysiology of dissociative disorders in humans. In addition, a larger number of studies are required in subjects exposed to a single pesticide to associate its effects with the dysfunction of different neurotransmitters, organelles, and effector organs, since the analysis of the data in this review comes from studies performed mainly in animals.
Finally, the analysis of the data shows the relationship between pesticides and symptoms of dissociative disorders, not those resulting from pesticide exposure, and does not describe the molecular mechanisms involved.