Introduction
This paper discusses the central currently studied relationships and effects of various environmental toxicants and the development of neurodegenerative diseases. The literature review showed that this relationship exists, but at the moment, it has been studied pointwise; in the scientific community, there is no systematization or classification of the available knowledge for various groups of toxicants. As a result, a quantitative study of a sample of a risk group of people who have already been exposed to toxication for a specific time, for example, in the workplace, is proposed. With the help of GWAS analysis, it is proposed to analyze the potential correlation and evaluate its statistical significance using the t-test.
Background
Neurotoxicity is a property of chemicals acting on the body in a non-mechanical way to cause a violation of the structure and functions of the nervous system. The developing toxic process can be based on damage to any structural element of the nervous system by modifying plastic, energy exchanges, disruption of generation, conduction of a nerve impulse along excitable membranes, and signal transmission in synapses. Neurotoxicity can manifest direct and mediated damage to other organs and systems, the action of toxicants on the nervous system (Li et al., 2021). Neurotoxicity is inherent in most known substances. Therefore, almost any acute intoxication is accompanied to some extent by dysfunctions of the nervous system (Brecht et al., 2004). Substances for which the threshold of sensitivity of the nervous system itself or its individual histological and anatomical formations is significantly lower than other organs and systems, and the intoxication of which is based on violations of the motor, sensory functions of the nervous system, memory, thinking, emotions, behavior, are conditionally referred to as neurotoxicants, even if the mechanisms of their toxic action are not known (Li et al., 2021). For example, lead intoxication in children leads to mental retardation and impairs learning abilities. The mechanism of this phenomenon is unknown, but it is generally accepted that neurotoxicity is a property of lead. The study of the features of the action of individual neurotoxicants allows us to understand the mechanisms of the phenomenon of neurotoxicity in general.
The vulnerability of the nervous system to the damaging effects of chemicals is due to the following circumstances. Firstly, many chemicals easily penetrate the BBB and also act on nerve formations that the BBB does not protect, and long nerve processes (axons and dendrites) significantly increase the contact area of ​​the neuron with its environment, increasing the vulnerability of cells to toxic damage. Second, for the ordinary course of physiological processes in the CNS, it is necessary to maintain the electrochemical balance in the elements of the nervous system, which is ensured by numerous mechanisms that can be affected by various chemicals (Brecht et al., 2004). Thirdly, nerve cells, as a rule, cannot regenerate; therefore, their death leads to relatively permanent consequences. Finally, toxic damage sustained at an early age may manifest and intensify as the body ages, as neuronal loss and other changes in the nervous system progressively increase in the second half of life. Even minor violations of the structure and function of the nervous system can have detrimental consequences for the functioning of the body as a whole, manifested by neurological and behavioral disorders and changes in the functions of other organs and systems.
Neurotoxicants, like other xenobiotics, enter the body by inhalation through the mouth or skin. Several substances can act in several ways. The essential condition for the direct action of a neurotoxicant on the central nervous system is its ability to penetrate the blood-brain barrier. Substances that do not penetrate the BBB can cause toxic effects in the periphery, mainly in ​​synaptic contacts between nerve fibers and innervated cells of organs, autonomic and sensory ganglia (Morris et al., 2014). All neurotoxicants can be divided into five groups, the representatives of which will be evaluated in this study. The first group represents organic solvents: benzene, xylene, methanol, and others. Metals, such as zinc, and aluminum, comprise the second group. Organophosphorus compounds, carbamates, and methylmercury are included in the group of pesticides. Finally, toxic gases are released, such as carbon monoxide, hydrogen sulfide, hydrocyanic acid, and a group of substances not included in all the previous ones, namely phenol and acrylamide.
A selective effect of toxicants on individual nervous system elements is possible. So, some substances damage neurons, mainly the bodies of nerve cells, axons, synapses, and glial elements. The points of application of most of the toxicants have not been determined. The selectivity of toxic action is relative. With an increase in the dose of poisons, the damage becomes less and less selective.
The developing pathology is a consequence of the effect of toxicants on excitable membranes, the mechanisms of nerve impulse transmission in synapses, plastic or energy-hypoxia, and ischemia – metabolism in the nervous tissue. The neurotoxic process manifests itself in the form of disturbances in motor, and sensory functions, emotional status, and integrative functions of the brain, such as memory and learning. Vision, hearing, tactile and pain sensitivity, and many more are often impaired. Sensorimotor disturbances lead to muscle weakness, paresis, and paralysis (Zhang et al., 2016). Damage to the mechanisms of regulation of the functions of vital organs and systems – respiratory, cardiovascular judicial – sometimes ends with the death of the poisoned. In some cases, the main manifestations of the toxic process may be a change in the behavior of affected or experimental animals.
Acute neurotoxic processes are usually caused by disturbances in physiological or biochemical mechanisms in the nervous system and are not associated with degenerative changes in neurocellular elements. Such effects usually form after a single exposure to a relatively high toxicant dose and are reversible. As a rule, intoxication develops in this way with substances that disrupt the transmission of a nerve impulse in synapses – numerous synaptic poisons, conduction of excitation through excitable membranes, such as veratrin, tetrodotoxin, saxitoxin, ethanol, chloroform, and others, and some substances that disrupt energy metabolism in the brain, for example, hydrocyanic acid, dinitrophenol, and others.
Acute neurotoxic processes in the central nervous system are manifested either by hyperactivation of nervous structures: agitation, convulsive syndrome, or their inhibition: lethargy, deafness, loss of consciousness, or disorganization of higher nervous activity with the development of a transient psychodysleptic state: inadequate emotions, illusions, hallucinations, delirium, and many more. In acute intoxication with any central neurotoxicant, depending on the effective dose, separate signs of each of the mentioned effects can be observed (Cai et al., 2020). However, a significant predominance of excitatory, inhibitory, or psychodysleptic elements in the toxic effect allows us to conditionally classify substances, respectively, as convulsive, sedative-hypnotic, and psychodysleptic agents.
Manifestations of acute neurotoxic action on the periphery are, as a rule, a consequence of impaired conduction of nerve impulses along motor and autonomic fibers and blockade or distortion of incoming sensory information (numbness of the extremities, paresthesia, pain). Chronically proceeding neurotoxic processes are caused by long-term or, more rarely, the single action of toxicants that mainly disrupt plastic: lead, tetraethyl lead, trimethyltin, thallium, mercury, TOCP, and others, or energy, such as carbon monoxide, metabolism. Their development is often associated with the alteration of the structural elements of the nervous system: neurons, their dendrites and axons, myelin, myelin-forming cells, and endothelial cells. Central chronic neurotoxic processes are usually not specific (Cai et al., 2020). However, in case of intoxication with certain substances, the period of development of chronic effects is preceded by a specific clinic of acute brain dysfunction.
The scientific literature shows the depth and complexity of this process due to the availability of research on only pretty narrow issues. The effect of synthetic compounds on astrocyte function is considered in detail in a recent review of the literature by the authors as a specific mechanism in the pathogenesis of neurodegenerative diseases (McCann & Maguire-Zeiss, 2020). However, this process is only one of the many effects of interaction with toxicants, and the article does not differentiate by types of toxicants. Sharma et al., in turn, gave a broader classification of toxicants, dividing them into heavy metals, solvents, and pesticides. However, the impact considered was limited to Parkinson’s and Alzheimer’s diseases (2020). The latter ailment is studied most often in this context, and, as a rule, the results are statistically significant and confirm this correlation (Dunn et al., 2019, Mir et al., 2020). As a rule, the more detailed the study, the more narrowly specialized it is: a targeted study of a specific group of metals as toxicants was carried out in the context of the development of dementia (Antoniadou et al., 2020). Therefore, although environmental toxicants are often considered without differentiation into species, the diversification of their influence may be different. As a result, this study will fill this gap.
Scientific Approach
For this study, quantitative and integrated approaches will be used. First of all, according to the literature review, various environmental toxicants will be differentiated into five groups. Then, a sample of more than 100 people should be recruited to test, using the GWAS methodology, the effect of these toxicants on the development of symptoms of neurodegenerative diseases. The most challenging process is selecting suitable participants for a sample where age, gender, and other demographic variables should not significantly affect the experiment. In addition, according to the ethics of the scientific community, in this work, it is impossible to deliberately negatively influence the participants in the experiment with the help of toxicants to the potential detriment of health. Consequently, it will be necessary to select a sample among the most significant risk groups: employees of metallurgical plants and workers in construction or chemical companies.
The variables in this study will be the following. Evaluation of the diagnosis of potentially neurodegenerative diseases lies in a plane common to any group of toxins. According to studies, the accumulation of β-amyloid peptide leads to aggregation and deterioration of brain function and memory, as well as hyperphosphorylation of tau protein, which also leads to neurological disorder (Sharma et al., 2020). These factors can help identify a comprehensive analysis that includes both GWAS and a blood test. Accordingly, the level of β-amyloid protein and tau protein will become dependent variables in this study, as they most clearly and with more extraordinary evidence signal potential neurological disorders. The dependent variables are the level of toxicants in the subject’s body, which will be differentiated into five possible groups. To analyze the statistical significance of the results, a t-test will be used, which will show the presence of a correlation between these variables. The minimum significance level at which the null hypothesis can be rejected will be taken as 0.05. Finally, the null hypothesis itself will deny the existence of a statistically significant relationship between toxicants and their negative impact on the development of neurodegenerative diseases.
The experiment will take place in several stages. The first of these includes the initial check and fixation of the “before” state of the participants in the experiment, in particular, determining the concentration of β-amyloid peptide and tau protein. Then, in the second stage, the impact of toxicants on the body is assessed: their content in the human body and concentration at the workplace are analyzed. After the received data, two weeks later, similar analyzes are carried out to monitor the dynamics. At the same time, a GWAS analysis is being carried out to obtain a more detailed assessment of the impact. As a result, the data obtained are tested for statistical significance and appropriate processing for a particular time, and then conclusions are provided.
Interpretation
As a result, as a result of the study, diversified data will be obtained, which, to varying degrees, can refute or confirm the null hypothesis. Among the sample members, those most affected by the various five groups of toxicants will be classified, perhaps in a complex manner. Consideration and calculations will be carried out separately for each group, and accordingly, the presence of several representatives of various groups in the body at once will be taken into account. For each group of toxicants, a separate table of characteristics of the impact on the two indicated dependent variables, as well as on the development of potential diseases, will be compiled – this information will be obtained as a result of the GWAS analysis.
The significance of the data obtained lies in the differentiation of all possible groups of toxicants for the development of certain diseases. A clearer picture of knowledge’s classification and systematization will allow future research on the most dangerous group of effects on the human body. GWAS analysis is rarely used in studies of this kind, which, on the one hand, is explained by the duration and high cost of conducting. On the other hand, it makes it possible to obtain more accurate information regarding the development of specific diseases. As a result, people will be able to receive health education information about how to protect themselves and their health, and companies – new scientific data on the conditions of safe workplaces.
Conclusion
This work is essential from the point of view of theory since it can partly, including through empirical experiments, systematize and classify knowledge about toxicants in the context of their influence on the development of neurodegenerative diseases. In addition, the scientific community may look to GWAS as a potential tool to provide more detailed answers to complex questions. Finally, the study is also applied in nature, as it will be helpful in the fight against diseases such as Parkinson’s, Alzheimer’s at the level of knowledge of patients and interested parties, and not just professionals, doctors, or scientists.
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