RESUMEN
We carried out a meta-analytical review of possible DNA damage resulting from occupational exposure to pesticides in farmers in the scientific literature. After the search, screening, and eligibility criteria steps, we included 42 studies to analyze random effect calculation. DNA damage in farmers occupationally exposed to pesticides represents an effect of SMD 4.63 [CI 95% 3.94-5.32; p <0.001]. We observed a high heterogeneity rate between the studies and an asymmetry of the bias analysis results. We performed a meta-regression on the parameters. The Olive Tail Moment (OTM) was the most effective comet assay parameter in the evaluated studies. The Damage Index (DI) was more conservative and highlighted the variability between studies caused by distinct methodologies that showed more significant effects and greater deviations. An analysis of confounding factors demonstrated a slight DNA damage in smokers who were occupationally exposed to pesticides compared to nonsmokers, indicating genotoxicity but smaller than the pesticide effect. The present study shows the greater risk that occupationally exposed rural workers have of developing related diseases due to pesticides' genotoxic effect.
Asunto(s)
Exposición Profesional , Plaguicidas , Ensayo Cometa , Daño del ADN , Agricultores , Humanos , Exposición Profesional/análisis , Plaguicidas/efectos adversosRESUMEN
We evaluated farmworkers exposed to pesticides and individuals with no history of occupational exposure to pesticides. It was performed the comet assay to evaluate DNA damage. The immunophenotyping of TCD4+ lymphocyte subpopulations in peripheral blood was performed by flow cytometry. The single nucleotide polymorphisms (SNPs) in PON1, XRCC1, IL6, IL6R, TNF-α, and MIR137 genes were evaluated by real-time PCR. The exposed group was composed mostly by males (69.44%), with direct exposure to pesticides (56%) and with an average age range of 46 ± 13.89 years, being that 58.3% of farmworkers directly exposed to pesticides and reported the full use of personal protective equipment (PPE). DNA damage was greater in the exposed group (p < 0.05), reinforced by the use of PPE to denote a lower degree of DNA damage (p = 0.002). In this context, in the exposed group, we demonstrated that the use of PPE, age, gender and intoxication events were the variables that most contributed to increase DNA damage (p < 0.0001). Besides, the exposed group showed a significant increase in the subpopulations of T lymphocytes CD3+CD4+ (p < 0.05) and CD3+CD4+CD25+ (p < 0.0001) and a significant decrease in CD3+CD4+CD25-FOXP3+ (p < 0.05). SNPs in the TNF-α (rs361525) gene presented a difference in the genotype distribution between the groups (p = 0.002). The genotype distribution of TNF-α (rs361525) was also positively correlated with the DNA damage of the exposed group (r = 0.19; p = 0.01), demonstrating a higher risk of DNA damage in the farmworkers presenting the A mutated allele. Our findings demonstrate that pesticides can exert various deleterious effects on human health by damaging the DNA as well as by influencing the immune system in the case of both direct or indirect exposure and these issues are associated to age, gender, intoxication and the nonuse of PPE.
Asunto(s)
MicroARNs , Exposición Profesional , Plaguicidas , Adulto , Arildialquilfosfatasa/genética , Biomarcadores , Brasil , Ensayo Cometa , Daño del ADN , Agricultores , Humanos , Masculino , Persona de Mediana Edad , Exposición Profesional/análisis , Plaguicidas/toxicidad , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
Parkinson's disease (PD) is a neurodegenerative, chronic, and progressive disease, common in the elderly. The catechol-O-methyltransferase (COMT) is a monomeric enzyme involved in dopamine (DA) degradation, the neurotransmitter in deficit in patients with PD. The reference treatment of PD consists of levodopa (L-dopa) administration, which is the precursor of DA. The inhibition of COMT is an adjuvant treatment in PD since it keeps DA levels constant. The goal of this study was to identify drug candidates capable of inhibiting COMT for the treatment of PD and identify important fragments of these molecules. Initially, we analyzed the flexibility of COMT and defined its main conformations in solution regarding the absence (system I) and presence of the S-adenosyl-L-methionine (SAM) cofactor (system II) through molecular dynamics (MD) simulations. Two regions in these structures were selected for molecular docking, firstly the entire cavity where the cofactor and substrates are bound and secondly the specific biding region of the enzyme substrates. Based on the conformations of the MD, the virtual screening (VS) was performed against FDA Approved and Zinc Natural Products databases aiming at the selection of the best compounds. Subsequently, the absorption, distribution, metabolization, excretion, and toxicity (ADMET) properties, as well as drug-score and drug-likeness indexes of the most promising compounds were analyzed. After a detailed analysis of the compounds selected by structure-based VS, it was possible to highlight the fragments most frequently involved in their stability: 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 9H-Benz(c)indole(3,2,1-ij)(1,5)naphthyridin-9-one and (10R,13S)-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17dodecahydrocyclopenta[a]phenanthren-3-one. The identification of these potential fragments is essential for the prospection of more specific inhibitors against COMT using the technique of Fragment-based lead discovery (FBLD). Besides, this study allowed us to identify the potential COMT inhibitors through a complete understanding of molecular-level interactions based on the flexibility of this protein.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Catecol O-Metiltransferasa , Enfermedad de Parkinson , Anciano , Inhibidores de Catecol O-Metiltransferasa , Inhibidores Enzimáticos , Humanos , Levodopa , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
In Brazil, the increased use of pesticides has caused several consequences such as mortality of non-target species, contamination of aquatic environments, and changes in biodiversity. Regarding humans, such products could increase the cases of poisoning, the number of different types of cancer, and also neurodegenerative and autoimmune diseases, especially in workers who occupationally handle pesticides. Therefore, this study aimed to evaluate the number of agricultural poisonings from 2007 to 2017 and if there is a correlation between harvested areas, and to analyze the possible factors that contribute to poisonings. Our results demonstrated an increase in poisonings by 8% and a correlation with the growth of the harvested area. We emphasize that other factors are also determinant for the increase of poisonings such as the absence or inappropriate use of personal protective equipment (PPE), the toxicity of mixtures, the mishandling, and the lack of information on how to use and spray such products. Among the circumstances about poisoning, we presented suicide attempts and accidental causes. We found that the area planted and harvested is also associated with the amount of poisoning; however, several other behavioral factors are also determinant for the growth of agricultural poisoning in Brazil.