Disulfoton
Introduction
Section titled “Introduction”Disulfoton is an organophosphate insecticide that has been widely used in agriculture to protect crops from various pests. It is known for its systemic action, meaning it is absorbed by plants and distributed throughout their tissues, making the entire plant toxic to insects. However, disulfoton is also highly toxic to humans and other non-target organisms, posing significant environmental and public health concerns.
Biological Basis
Section titled “Biological Basis”The primary biological basis of disulfoton’s toxicity lies in its mechanism as a cholinesterase inhibitor. Once absorbed into the body, disulfoton is metabolized into active compounds that irreversibly bind to and inhibit acetylcholinesterase, an enzyme crucial for the proper functioning of the nervous system. Acetylcholinesterase is responsible for breaking down acetylcholine, a neurotransmitter, at the synaptic cleft. Its inhibition leads to an excessive accumulation of acetylcholine, causing continuous stimulation of nerve cells, muscles, and glands. This overstimulation disrupts normal nerve impulse transmission, leading to a cascade of effects throughout the central and peripheral nervous systems.[1]
Clinical Relevance
Section titled “Clinical Relevance”Clinically, exposure to disulfoton can lead to a range of symptoms, from mild to severe, depending on the dose and duration of exposure. Acute poisoning symptoms typically manifest rapidly and include nausea, vomiting, abdominal cramps, diarrhea, excessive salivation, sweating, constricted pupils, muscle weakness, tremors, and dizziness. In more severe cases, individuals may experience convulsions, respiratory distress, pulmonary edema, and coma, potentially leading to death due to respiratory failure. Chronic exposure, even at lower levels, can result in persistent neurological and neuropsychological effects. Treatment for disulfoton poisoning involves decontamination, supportive care, and the administration of antidotes such as atropine and pralidoxime, which help to counteract the effects of acetylcholine overstimulation.[2]
Social Importance
Section titled “Social Importance”Disulfoton holds significant social importance primarily due to its dual role as an effective agricultural pest control agent and a potent environmental and health hazard. Its efficacy in protecting crops has contributed to food security and agricultural productivity. However, its high toxicity necessitates strict regulatory oversight to minimize exposure risks for agricultural workers, consumers, and the environment. Concerns include potential contamination of water sources, soil, and food products, as well as its impact on biodiversity, particularly non-target insects and wildlife. Public health campaigns and safety guidelines are crucial for managing its use and mitigating its adverse effects, balancing agricultural needs with environmental protection and human safety.[3]
Limitations
Section titled “Limitations”The interpretation of genetic associations for disulfoton, as with many complex traits studied through genome-wide association studies (GWAS), is subject to several methodological and contextual limitations derived from the approaches used in similar research. These limitations pertain to study design, generalizability, and the comprehensive understanding of underlying biological mechanisms.
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Many studies, particularly those with moderate cohort sizes, face inherent limitations in statistical power, which can increase the risk of both false negative findings and difficulty in detecting modest genetic associations. This lack of power often contributes to the non-replication of previously reported phenotype-genotype associations, which may stem from either false positives in initial discovery reports or insufficient power in subsequent replication attempts. Indeed, research indicates that a substantial portion of examined associations may not consistently replicate across studies, underscoring the ongoing challenge of distinguishing true genetic signals from statistical noise in the broader GWAS landscape. [4]
Furthermore, the accuracy of genotype imputation, a common practice in GWAS to infer untyped single nucleotide polymorphisms (SNPs), introduces a degree of uncertainty, with estimated error rates observed when comparing imputed genotypes to experimentally derived ones. Analytical choices, such as an exclusive focus on multivariable models, might inadvertently overlook important bivariate associations between genetic variants and specific phenotypes. The variability in effect sizes observed between discovery and replication cohorts, sometimes with larger effects reported in replication, suggests dynamic or context-dependent genetic influences that warrant further investigation, hinting at potential underestimation or context-specific effects in initial analyses.[5]
Generalizability and Phenotypic Characterization
Section titled “Generalizability and Phenotypic Characterization”A significant limitation across many genetic studies is the predominant focus on cohorts of white European ancestry, which inherently restricts the generalizability of findings for disulfoton levels to other ethnic or racial groups. Researchers frequently acknowledge that their samples are not ethnically diverse or nationally representative, leading to uncertainty regarding how identified genetic associations would apply to populations with different genetic backgrounds or environmental exposures. Additionally, some cohorts are largely composed of middle-aged to elderly individuals, which raises questions about the direct applicability of results to younger populations, potentially introducing age-related biases.[4]
The methodologies used for phenotype assessment can also introduce specific limitations. For instance, the collection of DNA at later examination points in longitudinal studies may introduce a survival bias, as only individuals who remained in the study are included, potentially skewing the genetic landscape of the surviving cohort. In biomarker analyses, the choice of a specific marker may not fully capture the complexity of the underlying biological process, especially when more direct or comprehensive measures are unavailable. Moreover, the common practice of excluding individuals on certain medications, such as lipid-lowering therapies, while useful for isolating genetic effects, means that the findings may not be directly applicable to the broader population that includes individuals using such treatments. [4]
Environmental Influences and Remaining Knowledge Gaps
Section titled “Environmental Influences and Remaining Knowledge Gaps”Genetic associations for disulfoton levels can be modulated by various environmental or lifestyle factors that may not be fully captured or accounted for in study designs. Differences in key environmental factors between study cohorts could contribute to discrepancies in replication attempts, suggesting that complex gene-environment interactions or unmeasured confounders play a significant role. Although studies often employ methods to control for population stratification and other covariates, the possibility of residual confounding from unmeasured environmental exposures or lifestyle choices remains, potentially influencing observed genetic effects.[4]
Current genome-wide association studies primarily identify statistical associations, but a fundamental challenge lies in translating these findings into a comprehensive biological understanding. The ultimate validation of identified genetic loci requires further replication in independent cohorts and, crucially, functional studies to elucidate the precise molecular mechanisms by which these genetic variants influence disulfoton levels. Without such functional insights, the etiological pathways remain largely unknown, highlighting a continuing need for larger samples and advanced analytical approaches to uncover additional sequence variants and fully explain the genetic contribution to the trait.[4]
Variants
Section titled “Variants”Genetic variations play a crucial role in shaping individual physiological responses and disease susceptibilities, including potential interactions with environmental agents like disulfoton. Variations within genes such asPDE4D, CDC14A, and FGF12 can subtly alter fundamental cellular pathways. PDE4D(Phosphodiesterase 4D) is a key enzyme involved in regulating cyclic AMP (cAMP) signaling, a ubiquitous second messenger system that influences processes ranging from inflammation and immune response to cardiovascular and neurological function. A variant likers10491442 could modify PDE4D activity, leading to altered cAMP levels and subsequently impacting these diverse cellular activities. CDC14A (Cell Division Cycle 14A) is a phosphatase critical for proper cell cycle progression, particularly during mitosis and meiosis; rs17122597 may influence cellular proliferation, DNA repair, or genomic stability, which are vital for tissue maintenance and response to cellular stress. FGF12 (Fibroblast Growth Factor 12) is involved in the development and function of the nervous system, playing a role in neuronal excitability and axonal growth. Genetic alterations such as rs72607877 could therefore affect neurological signaling and overall brain health. The broader field of genetic research, including genome-wide association studies, continues to uncover how such variations contribute to complex traits and disease risk.[6]An individual’s unique genetic profile, encompassing these variants, may influence their metabolic capacity to process xenobiotics, like the organophosphate disulfoton, and their inherent susceptibility to neurotoxicity or other adverse effects.[7]
Further impacting sensory perception, mitochondrial function, and developmental pathways are variants within USH2A, SYNJ2BP-COX16, and TSHZ2. USH2A (Usher Syndrome Type 2A) is essential for the normal development and maintenance of the inner ear and retina, thus affecting hearing and vision. A variant like rs114726772 could influence the integrity of these sensory systems, potentially altering an individual’s baseline sensory function and making them more sensitive to environmental stressors that affect these areas. The SYNJ2BP-COX16 locus includes COX16 (Cytochrome C Oxidase Assembly Factor 16), a gene vital for mitochondrial function, specifically in the assembly of cytochrome c oxidase, a critical component of the electron transport chain responsible for cellular energy production. The rs8021014 variant may therefore impact mitochondrial efficiency, which is fundamental to overall cellular health and resilience against oxidative damage. TSHZ2 (Teashirt Zinc Finger Homeobox 2) is a transcription factor involved in various developmental processes, including those of the nervous system and skeletal structures. rs6022454 could affect the precise regulation of gene expression during development or tissue maintenance. Genetic variations affecting mitochondrial function or neurological development are broadly studied for their impact on human health [8]and could modulate an individual’s vulnerability to neurotoxic compounds like disulfoton by altering cellular energy states or the integrity of neural tissues.[4]
Finally, variants in COMMD1, LINC00607, PLPPR1, and LINC02462 - EEF1A1P35 highlight roles in diverse cellular processes from nutrient homeostasis to gene regulation. COMMD1(COMM Domain Containing 1) is a gene involved in copper homeostasis, sodium transport, and the regulation of the NF-κB signaling pathway, which is central to inflammatory and stress responses. Thers7607266 variant might influence these crucial regulatory mechanisms, affecting how cells manage metal ions, fluid balance, and inflammation. LINC00607 and LINC02462 are long intergenic non-coding RNAs (lincRNAs), which are non-protein-coding RNA molecules that play significant roles in gene expression regulation. Variants such as rs72942461 and rs115347967 could impact the expression or function of these regulatory RNAs, leading to broad effects on gene networks involved in various biological processes. PLPPR1 (Phospholipid Phosphatase Related 1) is involved in lipid metabolism and cell migration, influencing cell membrane dynamics and signaling pathways that control cellular movement and communication. The rs7867688 variant could alter these lipid-mediated processes. The collective influence of such genetic variations on metabolic health and cellular regulation is a key area of research in human genetics [9]and could significantly modify an individual’s response to environmental toxins like disulfoton by affecting detoxification pathways, cellular stress responses, or overall metabolic robustness.[10]
There is no information about ‘disulfoton’ in the provided context. Therefore, a Classification, Definition, and Terminology section cannot be generated for this trait.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs10491442 | PDE4D | environmental exposure measurement DDT metabolite measurement cadmium chloride measurement 2,4,5-trichlorophenol measurement aldrin measurement |
| rs17122597 | CDC14A | environmental exposure measurement chlorpyrifos measurement cadmium chloride measurement 2,4,5-trichlorophenol measurement 4,6-dinitro-o-cresol measurement |
| rs114726772 | USH2A | environmental exposure measurement chlorpyrifos measurement DDT metabolite measurement cadmium chloride measurement 2,4,5-trichlorophenol measurement |
| rs72607877 | FGF12 | environmental exposure measurement DDT metabolite measurement cadmium chloride measurement 2,4,5-trichlorophenol measurement aldrin measurement |
| rs8021014 | SYNJ2BP-COX16, COX16 | cadmium chloride measurement chlorpyrifos measurement DDT metabolite measurement 2,4,5-trichlorophenol measurement 4,6-dinitro-o-cresol measurement |
| rs6022454 | TSHZ2 | cadmium chloride measurement chlorpyrifos measurement azinphos methyl measurement 2,4,5-trichlorophenol measurement 4,6-dinitro-o-cresol measurement |
| rs7607266 | COMMD1 | environmental exposure measurement chlorpyrifos measurement DDT metabolite measurement cadmium chloride measurement 4,6-dinitro-o-cresol measurement |
| rs72942461 | LINC00607 | environmental exposure measurement DDT metabolite measurement cadmium chloride measurement 4,6-dinitro-o-cresol measurement 2,4,5-trichlorophenol measurement |
| rs7867688 | PLPPR1 | lipid measurement cadmium chloride measurement chlorpyrifos measurement DDT metabolite measurement 2,4,5-trichlorophenol measurement |
| rs115347967 | LINC02462 - EEF1A1P35 | environmental exposure measurement DDT metabolite measurement cadmium chloride measurement 2,4,5-trichlorophenol measurement aldrin measurement |
Biological Background
Section titled “Biological Background”Genetic Foundations of Metabolic Regulation
Section titled “Genetic Foundations of Metabolic Regulation”Genetic variations play a fundamental role in shaping an individual’s metabolic profile and influencing the homeostasis of vital biomolecules. For instance, specific genetic loci, such as variations within MLXIPL, are significantly associated with plasma triglyceride levels, indicating a clear genetic influence on lipid metabolism.[11]Similarly, the regulation of serum urate concentrations is profoundly affected by genetic factors, withSLC2A9identified as a key transporter gene impacting both serum urate levels and its excretion.[12]Furthermore, the levels of serum transferrin, a crucial iron-binding protein, are substantially explained by genetic variants in genes likeTF and HFE, underscoring how genetic mechanisms dictate the balance of essential elements. [13]
Beyond individual metabolites, genome-wide association studies have elucidated the genetic underpinnings of broader metabolic traits, including plasma levels of liver enzymes, where regions like the ABO gene and the NBPF3-ALPL intergenic area demonstrate significant associations. [14]These genetic insights reveal complex regulatory networks where single nucleotide polymorphisms (SNPs) can alter gene expression patterns or protein function, thereby impacting a wide array of physiological processes and influencing an individual’s unique metabolic signature.[7]
Molecular and Cellular Dynamics of Lipid Metabolism
Section titled “Molecular and Cellular Dynamics of Lipid Metabolism”The intricate processes of lipid metabolism are governed by a network of molecular and cellular pathways, involving specific enzymes and structural components that dictate the synthesis, modification, and transport of various lipid species. The FADS1 genotype, for example, is critically associated with the efficiency of the fatty acid delta-5 desaturase reaction, an enzymatic activity essential for the production of polyunsaturated fatty acids. [7] This enzymatic action directly influences the concentrations of key phospholipids, including phosphatidylcholines, plasmalogen/plasmenogen phosphatidylcholines, and phosphatidylethanolamines, which are fundamental components of cellular membranes. [7]
Disruptions in the balanced activity of these pathways can lead to altered levels of interconnected lipids; for instance, changes in phosphatidylcholine homeostasis can modulate sphingomyelin concentrations, as sphingomyelin can be synthesized from phosphatidylcholine through the action of sphingomyelin synthase.[7]Likewise, the overall balance in glycerophospholipid metabolism affects the production of metabolites such as lyso-phosphatidylethanolamine, which is formed from different phosphatidylethanolamines via the abstraction of an arachidonic acid moiety.[7] These molecular interconnections highlight the complex cellular functions necessary for maintaining lipid health and the critical roles of specific enzymes and lipid classes.
Urate Transport and Renal Physiology
Section titled “Urate Transport and Renal Physiology”Maintaining the body’s serum urate concentration is a precisely regulated homeostatic process, primarily dependent on renal excretion, which is facilitated by specialized transport proteins. The geneSLC2A9encodes a critical urate transporter that significantly influences both circulating serum urate levels and the rate of urate excretion, thus playing a pivotal role in the pathophysiology of conditions like gout.[12]As a member of the facilitative glucose transport protein family,SLC2A9actively participates in the reabsorption and secretion of urate within the kidney, demonstrating its essential cellular function in upholding the balance of purine metabolism.[12]
Genetic variations within the SLC2A9gene can lead to altered transporter activity, resulting in either elevated urate levels (hyperuricemia) or reduced levels (hypouricemia), representing direct disruptions of normal homeostatic balance.[12] The tissue-level biology of the kidney, characterized by specialized cells expressing SLC2A9, is therefore central to systemic urate regulation, illustrating how the organ-specific effects of a single protein can have widespread consequences for overall metabolic health.[12]
Systemic Homeostasis and Disease Manifestations
Section titled “Systemic Homeostasis and Disease Manifestations”Disruptions in various homeostatic processes can lead to systemic consequences, influencing the risk and progression of complex diseases across different organ systems. Polygenic dyslipidemia, a condition characterized by abnormal concentrations of lipids in the blood, is influenced by common genetic variants at numerous loci, collectively contributing to an increased risk of coronary artery disease.[15]These lipid imbalances involve key biomolecules such as low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, whose levels are modulated by a multitude of genetic factors.[15]
Beyond lipid metabolism, other physiological traits linked to systemic health include pulmonary function measures, which are influenced by genes like HMOX1, IL10, and various matrix metalloproteinases (MMP1, MMP9), alongside serine proteinase inhibitors (SERPINA3, SERPINE2). [8] Additionally, levels of liver enzymes, hemostatic factors, and even red blood cell production (e.g., F cell production, influenced by a zinc-finger protein on chromosome 2p15) are under genetic control, collectively demonstrating the broad impact of genetic and molecular mechanisms on tissue interactions and overall physiological well-being. [14]
There is no information about ‘disulfoton’ in the provided context. Therefore, a clinical relevance section for ‘disulfoton’ cannot be generated based on the given sources.
References
Section titled “References”[1] U.S. Environmental Protection Agency. Reregistration Eligibility Decision (RED) for Disulfoton. 1999.
[2] World Health Organization. Environmental Health Criteria 63: Organophosphorus Insecticides - A General Introduction. 1986.
[3] National Pesticide Information Center. Disulfoton General Fact Sheet. 2010.
[4] Benjamin, E. J., et al. “Genome-Wide Association with Select Biomarker Traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, 2007, p. 62.
[5] Willer, C. J. et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, 2008.
[6] Hwang, S. J., et al. “A Genome-Wide Association for Kidney Function and Endocrine-Related Traits in the NHLBI’s Framingham Heart Study.” BMC Medical Genetics, vol. 8, 2007, p. 55.
[7] Gieger, C. et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet, 2008.
[8] Wilk, J. B. et al. “Framingham Heart Study genome-wide association: results for pulmonary function measures.” BMC Med Genet, 2007.
[9] Saxena, Richa, et al. “Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.”Science, vol. 316, no. 5829, 2007, pp. 1331–1336.
[10] Chambers, John C., et al. “Common genetic variation near MC4R is associated with waist circumference and insulin resistance.”Nature Genetics, vol. 40, no. 6, 2008, pp. 718–720.
[11] Kooner, J. S. et al. “Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.” Nat Genet, 2008.
[12] Vitart, V. et al. “SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.”Nat Genet, 2008.
[13] Benyamin, B., et al. “Variants in TF and HFEExplain Approximately 40% of Genetic Variation in Serum-Transferrin Levels.”American Journal of Human Genetics, vol. 83, no. 6, 2008, pp. 693-702.
[14] Yuan, X. et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” Am J Hum Genet, 2008.
[15] Kathiresan, S. et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, 2008.