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1.
Environ Pollut ; 292(Pt B): 118419, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34751155

RESUMO

Toxicological and epidemiological studies implicate exposure to dithiocarbamate (DTC) fungicides in adverse health outcomes. However, there is limited information about human exposure to these chemicals. This systematic review determined to which extent human populations worldwide, including children, pregnant women, and adults, are exposed environmentally or occupationally to DTC pesticides and how these exposures compare to the NHANES 2003-2008 population, using urinary ETU data as an outcome measure. PubMed, Embase, and SciFinder were searched using the keywords "ethylenethiourea" or CAS No.: 96-45-7, and urine or urinary. Duplicates and irrelevant studies were removed from the search results based on predetermined exclusion criteria. This screening process identified 17 relevant papers. One additional paper was found independent of this search. Data from studies were extracted using a pre-established data collection form. Ten, two, and five manuscripts reported urinary levels in environmentally exposed adults, children, and pregnant women, respectively. Median ETU levels ranged from 0.15 to 4.7 µg/g creatinine in adults (1994-2017), 0.24-0.83 µg/g creatinine in children (2011), and 2.6-5.24 ng/ml in pregnant women (2011). Eight studies reported urinary ETU levels in mostly agriculturally exposed populations, with median ETU levels ranging from 0.42 to 49.6 µg/g creatinine (1999-2011). With one exception, all studies were conducted between 1994 and 2011. ETU levels in the NHANES 2003-2008 population appeared to be generally lower than most studies identified in this review. This finding suggests that, historically, DTC fungicide exposures in the general population of high-income countries, such as the US, were low, whereas agricultural populations may have experienced higher exposure. Unfortunately, more recent exposure data are missing, especially in countries where DTC pesticides are not being phased out.


Assuntos
Etilenotioureia , Fungicidas Industriais , Adulto , Monitoramento Biológico , Biomarcadores , Criança , Etilenotioureia/análise , Feminino , Fungicidas Industriais/análise , Fungicidas Industriais/toxicidade , Humanos , Inquéritos Nutricionais , Gravidez
2.
J Exp Zool A Ecol Integr Physiol ; 335(5): 469-476, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33830665

RESUMO

Amphibian endocrine systems interact with each other during normal development. Interference with one of the endocrine systems may influence others. We studied the effect of a thyroid inhibitor (ethylenethiourea [ETU]) on metamorphosis and ovary development of three species, Sphaerotheca pashchima, Indosylvirana caesari, and Euphlyctis cyanophlyctis with different larval durations. We treated the tadpoles of these species with 50, 100, and 200 mg/L concentrations of ETU and studied their larval duration, size at metamorphosis, and ovary development. The results revealed that ETU affects metamorphosis, depending on the species and concentration. ETU delayed metamorphosis of E. cyanophlyctis tadpoles and did not affect metamorphosis in S. pashchima tadpoles. Lower concentrations of ETU stimulated metamorphosis in I. caesari tadpoles while high concentration delayed metamorphosis. In the tadpoles (E. cyanophlyctis) treated with higher concentrations of ETU, ovary development was advanced with an increased size of the diplotene oocytes. Oocyte size was smaller in the tadpoles (of I. caesari) treated with lower concentrations of ETU. These results demonstrated that the tadpoles of these species show different responses to the thyroid inhibitor, possibly due to the differences in the larval duration and sensitivity. Inhibition or acceleration of metamorphosis did not interfere in the ovary development of E. cyanophlyctis and I. caesari. These results will be useful in understanding the impact of endocrine disruptors on the interaction between thyroid and sex steroid hormones.


Assuntos
Anuros/crescimento & desenvolvimento , Etilenotioureia/toxicidade , Larva/efeitos dos fármacos , Metamorfose Biológica/efeitos dos fármacos , Ovário/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Disruptores Endócrinos/toxicidade , Etilenotioureia/administração & dosagem , Feminino , Ovário/crescimento & desenvolvimento
3.
Sci Total Environ ; 761: 143300, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33243502

RESUMO

N-nitroso compounds form from the interaction between nitrosatable precursors and nitrite under acidic conditions. A majority of N-nitroso compounds tested show evidence of carcinogenicity in animal models. Formation of N-nitroso compounds may occur from exposure to precursors in drinking water, but the extent of formation depends on a number of factors, including concentration of substrates, presence of catalysts and inhibitors, and pH. The objective of this study was to examine these factors in pesticide-associated N-nitroso (PANN) compound formation in drinking water. In preliminary screening experiments, nine nitrosatable pesticides and degradation products were individually reacted at environmentally-relevant concentrations (≤ 20 µg L--1) with sodium nitrite (NaNO2) and hydrochloric acid (HCl) in ultra-pure water. Only ethylenethiourea (ETU) showed evidence of PANN compound formation in initial experiments and was further tested for N-nitrosoethylenethiourea (N-ETU) formation in a pooled groundwater sample (comprised of five tap water samples combined into one homogenous sample) collected from an agricultural region of Prince Edward Island in Canada, where nitrate contamination is a known concern. Evidence of N-ETU formation in the groundwater sample was observed within 30 min at concentrations 7.5, 10, and 20 µg L-1. Analysis of target compounds and semi-target PANN compounds was performed using ultra-high pressure liquid chromatography coupled with high resolution orbital ion trap mass spectrometry. These preliminary experiments serve to inform about potential PANN compound formation in groundwater. The results of this study suggest that ETU is capable of forming potentially carcinogenic N-ETU in water containing nitrite/nitrate at trace concentrations under acidic conditions. Thus, these findings suggest that N-ETU formation may be a concern for individuals exposed to low concentrations of ETU in groundwater.


Assuntos
Etilenotioureia , Água Subterrânea , Animais , Canadá , Humanos , Compostos de Nitrosoureia
4.
Arch Pharm (Weinheim) ; 353(11): e2000121, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32757353

RESUMO

A series of imidazolin-2-thione derivatives was synthesized and structurally confirmed through the use of different spectroscopic techniques such as infrared, nuclear magnetic resonance, and mass spectrometry along with elemental analyses. The breast cancer cell line MCF-7 was utilized in the evaluation of the cytotoxic activity of the prepared molecules. The tested molecules 3 and 7 exhibited the best results on MCF-7 cells, with mean IC50 values of 3.26 and 4.31 µM, respectively. The results of the VEGFR-2 assay indicated that compounds 3 and 7 displayed a good inhibition of the VEGFR-2 kinase enzyme. Additionally, DNA flow cytometry of compounds 3 and 7 showed cell cycle arrest at the G0/G1 phase, cell apoptosis, and marked DNA fragmentation in MCF-7 cells. Finally, compounds 3 and 7 were proved to upregulate the activation of effector caspase-3/7, as presented by the caspase-3/7 green flow cytometry assay.


Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias da Mama/tratamento farmacológico , Etilenotioureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Desenho de Fármacos , Etilenotioureia/análogos & derivados , Feminino , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Terapia de Alvo Molecular , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
J Endocrinol ; 247(1): 53-68, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32738127

RESUMO

The intra-tissue levels of thyroid hormones (THs) regulate organ functions. Environmental factors can impair these levels by damaging the thyroid gland and/or peripheral TH metabolism. We investigated the effects of embryonic and/or long-life exposure to low-dose pesticides, ethylene thiourea (ETU), chlorpyrifos (CPF) and both combined on intra-tissue T4/T3 metabolism/signaling in zebrafish at different life stages. Hypothyroidism was evident in exposed larvae that showed reduced number of follicles and induced tshb mRNAs. Despite that, we found an increase in free T4 (fT4) and free T3 (fT3) levels/signaling that was confirmed by transcriptional regulation of TH metabolic enzymes (deiodinases) and T3-regulated mRNAs (cpt1, igfbp1a). Second-generation larvae showed that thyroid and TH signaling was affected even when not directly exposed, suggesting the role of parental exposure. In adult zebrafish, we found that sex-dependent damage of hepatic T3 level/signaling was associated with liver steatosis, which was more pronounced in females, with sex-dependent alteration of transcripts codifying the key enzymes involved in 'de novo lipogenesis' and ß-oxidation. We found impaired activation of liver T3 and PPARα/Foxo3a pathways whose deregulation was already involved in mammalian liver steatosis. The data emphasizes that the intra-tissue imbalance of the T3 level is due to thyroid endocrine disruptors (THDC) and suggests that the effect of a slight modification in T3 signaling might be amplified by its direct regulation or crosstalk with PPARα/Foxo3a pathways. Because T3 levels define the hypothyroid/hyperthyroid status of each organ, our findings might explain the pleiotropic and site-dependent effects of pesticides.


Assuntos
Larva/metabolismo , Fígado/metabolismo , Praguicidas/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Tri-Iodotironina/metabolismo , Peixe-Zebra/metabolismo , Animais , Clorpirifos/administração & dosagem , Clorpirifos/efeitos adversos , Disruptores Endócrinos , Etilenotioureia/administração & dosagem , Etilenotioureia/efeitos adversos , Feminino , Proteína Forkhead Box O3/metabolismo , Larva/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , PPAR alfa/metabolismo , Transdução de Sinais/fisiologia , Glândula Tireoide/crescimento & desenvolvimento , Glândula Tireoide/metabolismo , Tiroxina/metabolismo , Peixe-Zebra/crescimento & desenvolvimento
6.
Anal Methods ; 12(29): 3705-3712, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32729855

RESUMO

Ultra-high-performance liquid chromatography (UHPLC) coupled with a cobalt phthalocyanine screen-printed carbon electrode (CoPc-SPCE) was developed and validated for quantitative analysis of ethylenethiourea (ETU) and propylenethiourea (PTU). CoPC-SPCE provided high catalytic properties for ETU and PTU oxidation. This fabricated electrode is inexpensive, disposable, and easy to prepare by an in-house screen-printing technique. The chromatographic separation was performed in isocratic mode on a reversed phase C18 (100 mm × 4.6 mm, 3 µm) column, using a 90 : 10 (v/v) ratio of 0.05 M phosphate buffer solution (pH 4) and methanol as the mobile phase with a flow rate of 1.0 mL min-1 at an oxidation potential of +0.7 V vs. Ag/AgCl. The separation could be achieved within 3 min, and a wide linear range of 0.01-100 µg mL-1 (r2 > 0.99) was obtained for both analytes. The limits of detection (3 S/N) were found to be 0.006 and 0.009 µg mL-1 for ETU and PTU, respectively. Furthermore, this proposed method was utilized to determine ETU and PTU in fruit samples with satisfactory results, yielding excellent intra-day and inter-day relative standard deviations and recoveries. These results demonstrated that the proposed assay can be used as a new alternative way for inexpensive, rapid, selective and sensitive determination of ETU and PTU in fruit samples.


Assuntos
Etilenotioureia , Cromatografia Líquida de Alta Pressão , Frutas , Tioureia/análogos & derivados
7.
Regul Toxicol Pharmacol ; 115: 104689, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32544413

RESUMO

Pesticides represent an economical, labor-saving, and efficient tool for pest management, but their intrinsic toxic properties may endanger workers and the general population. Risk assessment is necessary, and biological monitoring represents a potentially valuable tool. Several international agencies propose biological exposure indices (BEI), especially for substances which are commonly absorbed through the skin. Biological monitoring for pesticide exposure and risk assessment seems a natural choice, but biological exposure limits (BEL) for pesticides are lacking. This study aims at establishing equivalent biological exposure limits (EBEL) for pesticides using real-life field data and the Acceptable Operator Exposure Level (AOEL) of mancozeb as the reference. This study included a group of 16 vineyard pesticide applicators from Northern Italy, a subgroup of a more extensive study of 28 applicators. Their exposure was estimated using "patch" and "hand-wash" methodologies, together with biological monitoring of free ethylene-bis-thiourea (ETU) excretion in 24-h pre- and post-exposure urine samples. Modeling was done using univariate linear regression with ETU excretion as the dependent variable and the estimated absorbed dose as the independent variable. The median skin deposition of mancozeb in our study population was 125 µg, leading to a median absorbed dose of 0.9 µg/kg. The median post-exposure ETU excretion was 3.7 µg. The modeled EBEL for mancozeb was 148 µg of free ETU or 697 µg of total ETU, accounting for around 75% of the maximum theoretical excretion based on a mass balance model. Although preliminary and based on a small population of low-exposed workers, our results demonstrate a procedure to develop strongly needed biological exposure limits for pesticides.


Assuntos
Fungicidas Industriais/normas , Maneb/normas , Exposição Ocupacional/normas , Zineb/normas , Adulto , Monitoramento Biológico , Etilenotioureia/análise , Fazendas , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Medição de Risco , Pele/metabolismo , Absorção Cutânea
8.
Biomed Pharmacother ; 127: 110117, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32244197

RESUMO

Anorectal malformations (ARMs) is one of the most common gastrointestinal anomalies. Previous research revealed that miR-92a-2-5p was upregulated in ARMs. However, the underlying roles remains unknown. The current study was to further investigate the spatiotemporal expression patterns of miR-92a-2-5p and its target gene protein kinase C alpha (PRKCA) predicted by bioinformatic method, and to explore their potential functions in anorectal malformations (ARMs). Rat models with ethylenethiourea-induced ARMs were made for subsequent experiments. Direct target relationship between miR-92a-2-5p and PRKCA was validated using a luciferase reporter assay. The spatiotemporal expression pattern of miR-92a-2-5p was evaluated using fluorescence in situ hybridization (FISH), while the expression of PRKCA was revealed by immunohistochemical staining and western blotting. IEC-6 cells were transfected with mimics/mimics NC (Negative control)/inhibitor/inhibitor NC of miR-92a-2-5p or si-PRKCA/si-PRKCA NC, respectively. Then the downstream molecules of miR-92a-2-5p, PRKCA and ß-catenin, were subsequently detected. Meanwhile, apoptosis and viability assays were measured. Dual luciferase assay confirmed the direct regulatory relationship between miR-92a-2-5p and PRKCA. FISH revealed that miR-92a-2-5p was expressed with a higher level in ARMs fetuses. Further analyses of PRKCA showed lower protein expression level in ARMs group, which was opposite to miR-92a-2-5p. In vitro experiments revealed that overexpression of miR-92a-2-5p or knockdown of PRKCA can down-regulate PRKCA, up-regulate and facilitate nuclear localization of ß-catenin, increase apoptosis and decrease proliferation of IEC-6. Taken together, these findings suggest that aberrantly high expression of miR-92a-2-5p potentially contribute to ARMs by inhibiting proliferation and enhancing apoptosis of intestinal cells via negatively regulating PRKCA/ß-catenin.


Assuntos
Malformações Anorretais/fisiopatologia , Apoptose/fisiologia , Proliferação de Células/fisiologia , MicroRNAs/fisiologia , beta Catenina/biossíntese , Animais , Malformações Anorretais/induzido quimicamente , Etilenotioureia , Feminino , MicroRNAs/biossíntese , Proteína Quinase C-alfa/biossíntese , Ratos , Regulação para Cima
9.
Int J Hyg Environ Health ; 225: 113474, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32066110

RESUMO

BACKGROUND: Growing evidence suggests that pesticide exposure may influence respiratory health, but data in young children are very limited. We examined the association of prenatal pesticide exposure with lower respiratory tract infections (LRTIs) and wheeze at one year of age in children from the Infants' Environmental Health (ISA) study in Costa Rica. METHODS: We measured seven pesticide metabolites, including ethylenethiourea (ETU, metabolite of mancozeb), in maternal urine samples collected repeatedly during pregnancy. For each woman, we averaged pesticide concentrations during each half of pregnancy (≤20 and >20 weeks of gestation) and across repeated samples collected over the course of pregnancy. We collected information about LRTIs (n = 355) and wheezing (n = 272) during the first year of life from mothers when their children were 11-19 months old. We fit multivariable logistic regression models using high (quartile 4) vs. low (quartiles 1-3) urinary pesticide concentrations as exposures and adjusted models for maternal age, education, parity, gestational age at birth, and child sex. RESULTS: Ten percent of the children had at least one LRTI and 39% had at least one episode of wheezing during their first year of life. Median (25-75th percentile) specific gravity-corrected urinary ETU concentrations during the first half, second half, and over the course of pregnancy were 3.4 (2.1-5.0), 3.3 (2.2-4.7), and 3.4 (2.4-5.0) ng/mL, respectively. We observed that high urinary ETU concentrations during the first half of pregnancy were associated with increased odds of LRTI (OR = 2.45; 95% CI: 0.96, 6.26), whereas high urinary ETU concentrations during the second half of pregnancy were associated with decreased odds of wheezing (OR = 0.50; 95% CI: 0.26, 0.96). We found that the association between high urinary ETU concentrations during the first half of pregnancy and LRTIs persisted among mother-child pairs with either high or low ETU concentrations during the second half. In contrast, the association of high urinary ETU concentrations during the second half of pregnancy with wheezing was attenuated when we simultaneously adjusted for urinary ETU concentrations during the first half. We observed null associations between other pesticide metabolites measured during pregnancy and respiratory outcomes. CONCLUSIONS: Our data indicate that exposure to mancozeb/ETU during the first half of pregnancy may be associated with respiratory outcomes in the first year of life.


Assuntos
Poluentes Ambientais/urina , Praguicidas/urina , Efeitos Tardios da Exposição Pré-Natal , Sons Respiratórios , Infecções Respiratórias/epidemiologia , Adulto , Etilenotioureia/metabolismo , Feminino , Humanos , Lactente , Saúde do Lactente , Masculino , Maneb/urina , Exposição Materna , Troca Materno-Fetal , Gravidez , Adulto Jovem , Zineb/urina
10.
Acta Histochem ; 122(1): 151466, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31787253

RESUMO

BACKGROUND: Anorectal malformations (ARMs) are common congenital malformations of the terminal digestive tract, but little is known regarding their pathogenesis. Aberrant cell proliferation/apoptosis are believed to be involved in ARMs. However, there are no studies on proliferation/apoptosis-related genes. PURPOSE: We aimed to investigate the spatiotemporal expression patterns of two proliferation/apoptosis-related genes (MYC proto-oncogene and tumor protein p53) and explore their potential functions in the hindguts of ethylene thiourea-induced ARMs rat fetuses. METHODS: MYC and p53 expression was evaluated using immunohistochemical staining, western blotting, and quantitative real-time polymerase chain reaction (RT-qPCR). Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and p53 costaining were performed to assay the colocalization of apoptotic and p53-expressing cells. RESULTS: Rat fetuses with ARMs displayed fusion failure of the urogenital septum and cloacal membrane. In the control group, MYC was persistently expressed from gestational day (GD)14 to GD16 and distributed throughout the hindgut, while p53 was weakly detected in the terminal segment of the urethra and hindgut; in the ARMs group, MYC expression was obviously reduced, while p53 was widely and highly expressed in the urethra and hindgut. Western blotting and RT-qPCR confirmed the decrease in MYC and increase in p53 expression in ARMs. TUNEL and p53 co-staining revealed considerable overlap between apoptotic and p53-expressing cells. CONCLUSION: The expression patterns of c-myc and p53 were disrupted in ARMs rat embryos, and the downregulation of c-myc and upregulation of p53 might be related to the development of ARMs at the key time points of ARMs morphogenesis.


Assuntos
Malformações Anorretais , Etilenotioureia/toxicidade , Feto , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Intestinos , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Animais , Malformações Anorretais/induzido quimicamente , Malformações Anorretais/embriologia , Malformações Anorretais/patologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Feto/embriologia , Feto/patologia , Intestinos/embriologia , Intestinos/patologia , Gravidez , Ratos , Ratos Wistar
11.
Biol Res ; 52(1): 27, 2019 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-31054579

RESUMO

BACKGROUND: To assess the expression of T-box transcription factor 4 (TBX4) during the anorectal development in normal and ethylenethiourea (ETU)-induced anorectal malformations (ARM) rat embryos. METHODS: Anorectal malformations was induced by ETU on the 10th gestational day (E10) in rat embryos. Spatio-temporal expression of TBX4 was evaluated in normal (n = 490) and ETU-induced ARM rat embryos (n = 455) from E13 to E16 by immunohistochemical staining, Western blot analysis and real-time RT-PCR. RESULTS: In the normal embryos, immunohistochemical staining revealed that TBX4 expression was detected in the epithelium of hindgut and urorectal septum (URS) on E13. TBX4-immunopositive cells were increased significantly in the epithelium of hindgut and URS, the future anal orifice part of cloacal membrane on E14. On E15, abundant stained cells were observed in the rectum, URS and dorsal cloacal membrane and the expression of positive cells reached its peak. On E16, only sporadic positive cells were distributed in the epithelium of the distal rectum. In the ARM embryos, the hindgut/rectum, URS and dorsal cloacal membrane were faint for TBX4 immunohistochemical staining. In the normal group, TBX4 protein and mRNA expression showed time-dependent changes in the hindgut/rectum from E13 to E16 on Western blot and real-time RT-PCR. On E13 and E15, the expression level of TBX4 mRNA in the ARM group was significantly lower than that in the normal group (P < 0.05). On E15, the expression level of TBX4 protein in the ARM group was significantly lower than that in the normal group (P < 0.05). CONCLUSIONS: The expression of TBX4 was downregulated in ETU-induced ARM embryos, which may play important roles in the pathogenesis of anorectal development.


Assuntos
Malformações Anorretais/genética , Etilenotioureia/farmacologia , Regulação da Expressão Gênica/genética , Proteínas com Domínio T/genética , Animais , Malformações Anorretais/induzido quimicamente , Western Blotting , Feminino , Imuno-Histoquímica , Gravidez , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Proteínas com Domínio T/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-31020935

RESUMO

BACKGROUND: With the increasing resistance and side effects caused due to antifungal agents there is an urgent need for the new potent antifungal agents with low toxicity profile. Imidazoles have been used against fungal infections since long time. Further, our previous studies demonstrated that mercaptoimidazoles possessed good antifungal potency. AIM AND OBJECTIVE: This study was aimed to study the antifungal potency of new series of 2- mercaptoimidazoles. MATERIALS AND METHODS: Eighteen new 2-mercaptoimidazoles containing substituted phenyl group were synthesized and structures of the synthesized compounds were characterized by spectral studies. The synthesized compounds were screened for their antifungal potency. Compound 2-(1-(3-hydroxyphenyl)-2- mercapto-1H-imidazol-4-yl)phenol was found to be the most potent compound among all synthesized compounds against tested fungal strains. Moreover, all the synthesized compounds were further subjected to molecular docking study for the inhibition of enzyme 14α-demethylase. RESULTS: The in-silico molecular docking study results showed that all the synthesized compounds have minimum binding energy and good affinity for the active site and may be considered as good inhibitor of 14α-demethylase. CONCLUSION: 2-mercaptoimidazoles may be used as potential lead molecules as 14α-demethylase inhibitors.


Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Etilenotioureia/análogos & derivados , Simulação de Acoplamento Molecular , Técnicas de Síntese em Fase Sólida/métodos , Inibidores de 14-alfa Desmetilase/síntese química , Inibidores de 14-alfa Desmetilase/farmacologia , Candida albicans/efeitos dos fármacos , Etilenotioureia/síntese química , Etilenotioureia/química , Etilenotioureia/farmacologia , Testes de Sensibilidade Microbiana
13.
Int J Hyg Environ Health ; 222(3): 494-502, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30685193

RESUMO

INTRODUCTION: Absorbed dose assessment from dermal exposure involves multiplying skin contamination by the dermal absorption coefficient, which is usually defined for the standard workday of 8 h. This strategy may suffer from limitations when the duration of exposure is extremely variable, such as in agricultural exposure to pesticides. OBJECTIVES: The aim of this study was to estimate the dose of mancozeb absorbed by agricultural pesticide applicators in a typical working day considering the real duration of exposure, to compare these estimates with those coming from the use of the Fixed Fractional Approach, and to assess the suitability of the dose estimates in the interpretation of biological monitoring results. METHODS: In a series of real-life field studies on 29 workers applying mancozeb in vineyards for 38 work days, three sets of data were collected: information regarding work activities for each work day, potential (on clothes) and actual skin exposure using the "patch" methodology, and excretion of ethylenethiourea (ETU) in the 24-h pre-exposure and 24-h post-exposure urine samples. The statistical analyses were done using the R Language and Environment for Statistical Computing. RESULTS: Accounting for the duration of exposure led to a substantial reduction in the absorbed dose estimates, compared to the estimates coming from the Fixed Fractional Approach. In particular, absorbed dose by the body, hands' and total absorbed dose were reduced by 50%, 81%, and 80% respectively. The body dose estimated considering both approaches still correlated better with post-exposure 24-h urine ETU levels than the hands' dose, although more than 90% of the estimated total absorbed dose comes from the hands. CONCLUSIONS: An accurate estimate of the absorbed dose, carried out considering the real duration of exposure, can result in a higher correlation with a biomarker of occupational exposure, such as urine ETU, or at least yield more accurate results. This can facilitate the interpretation of biological monitoring data in pesticide-exposed agricultural workers despite the absence of biological exposure limits. ETU should be evaluated as a potentially relevant source of exposure due to ethylenebisdithiocarbamates' (EBDCs) degradation in the formulated product or spray mixture.


Assuntos
Fazendeiros , Fungicidas Industriais , Maneb , Exposição Ocupacional/análise , Absorção Cutânea , Zineb , Etilenotioureia/metabolismo , Humanos , Masculino , Modelos Teóricos , Equipamento de Proteção Individual , Medição de Risco
14.
Environ Sci Pollut Res Int ; 26(5): 4498-4509, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29943251

RESUMO

Ethylenethiourea (ETU) is a toxic degradation product of one class of fungicide which is largely employed in the world, the ethylenebisdithiocarbamates. In this study, ETU was degraded by ozonation enhanced by UV-C light irradiation (O3/UV-C) in aqueous medium. Degradation experiments were conducted at natural pH (6.8) and neutral pH (7.0, buffered). ETU was promptly eliminated from the reactive medium during ozonation in the presence and absence of light. Within the first few minutes of reaction conducted in natural pH, the pH decreased quickly from 6.8 to 3.0. Results show that ETU mineralization occurs only in the reaction conducted in neutral pH and that it takes place in a higher rate when enhanced by UV-C irradiation. Main intermediates formed during the O3/UV-C experiments in different conditions tested were also investigated and three different degradation mechanisms were proposed considering the occurrence of direct and indirect ozone reactions. At pH 7, ethylene urea (EU) was quickly generated and degraded. Meanwhile, at natural pH, besides EU, other compounds originated from the electrophilic attack of ozone to the sulfur atom present in the contaminant molecule were also identified during reaction and EU was detected within 60 min of reaction. Results showed that ozonation enhanced by UV-C promotes a faster reaction than the same system in the absence of light, and investigation of the toxicity is recommended.


Assuntos
Etilenotioureia/química , Ozônio/química , Poluentes Químicos da Água/química , Cromatografia Líquida de Alta Pressão/métodos , Fungicidas Industriais/química , Concentração de Íons de Hidrogênio , Imidazolidinas/química , Espectrometria de Massas/métodos , Oxirredução , Raios Ultravioleta , Água/química , Purificação da Água/métodos
15.
Curr Comput Aided Drug Des ; 15(5): 409-420, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30569875

RESUMO

BACKGROUND: Imidazoles are considered as potent antimicrobial agents. In view of this 2-mercaptoimidazoles were synthesized and evaluated for antimicrobial study. METHODS: Some new 2-mercaptoimidazoles 4a-r were synthesized using substituted aniline and substituted phenacyl bromides in the presence of anhydrous sodium carbonate or potassium carbonate and potassium thiocyanate under solvent-free conditions catalyzed by eco-friendly ptoluene sulfonic acid. RESULTS: The structure of compounds was evaluated on the basis of Infrared spectroscopy (IR), 1HNMR (proton nuclear magnetic resonance) and mass spectral studies. These novel compounds were screened for in-vitro antibacterial and antifungal potency against Staphyllococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Aspergillus niger. Further, the study was rationalized by molecular modeling studies. All the compounds were subjected to molecular modeling studies for inhibition of enzyme 14α-demethylase. CONCLUSIONS: The compounds were found to be effective in inhibiting the growth of pathogens. The in-silico results depicted that, all the synthesized compounds have minimum binding energy and good affinity towards the active site and thus can be considered as good inhibitors of 14α- demethylase enzyme.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Etilenotioureia/análogos & derivados , Inibidores de 14-alfa Desmetilase/química , Inibidores de 14-alfa Desmetilase/farmacologia , Aspergillus niger/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Candida albicans/efeitos dos fármacos , Etilenotioureia/química , Etilenotioureia/farmacologia , Humanos , Simulação de Acoplamento Molecular , Micoses/tratamento farmacológico
16.
J Surg Res ; 233: 173-182, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502245

RESUMO

BACKGROUND: Postoperative incontinence and constipation still remain the major complications of anorectal malformations (ARMs), despite improvements in their treatment. One of the most important factors that affect postoperative anorectal function is malformations in the lumbosacral spinal cord. However, far too little attention has been paid to the underlying mechanism that produces these malformations. MATERIALS AND METHODS: The levels of sonic hedgehog (Shh), patched homolog 1 (Ptch1), and zinc finger-containing transcription factors 1 (Gli1) expression were investigated in the lumbosacral spinal cord in ethylenethiourea-exposed rat fetus with ARMs, and Shh, Ptch1, and Gli1 expression was confirmed with immunohistochemical staining, quantitative real-time polymerase chain reaction, and western blot analyses during lumbosacral spinal cord development both in the ARMs and normal rat embryos. RESULTS: Our results have shown that Shh, Ptch1, and Gli1 expression in the lumbosacral spinal cord of rat embryos with ARMs was decreased at both the messenger RNA and protein levels, when compared with their expression levels in normal tissues (P < 0.05). CONCLUSIONS: This study demonstrated that the expression of Shh, Ptch1, and Gli1 in lumbosacral spinal cord was remarkably reduced during late developmental stages in fetal rats with ARMs. These findings offered some important insights into the involvement of the Shh-Ptch1-Gli1 signaling pathway in the pathogenesis of lumbosacral spinal cord maldevelopment in rat fetus with ARMs, which leads to complications after procedures for ARMs.


Assuntos
Malformações Anorretais/etiologia , Proteínas Hedgehog/metabolismo , Receptor Patched-1/metabolismo , Medula Espinal/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Modelos Animais de Doenças , Embrião de Mamíferos , Etilenotioureia/toxicidade , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Região Lombossacral , Ratos , Ratos Wistar , Medula Espinal/crescimento & desenvolvimento
17.
Biol. Res ; 52: 27, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1011429

RESUMO

BACKGROUND: To assess the expression of T-box transcription factor 4 (TBX4) during the anorectal development in normal and ethylenethiourea (ETU)-induced anorectal malformations (ARM) rat embryos. METHODS: Anorectal malformations was induced by ETU on the 10th gestational day (E10) in rat embryos. Spatiotemporal expression of TBX4 was evaluated in normal (n = 490) and ETU-induced ARM rat embryos (n = 455) from E13 to E16 by immunohistochemical staining, Western blot analysis and real-time RT-PCR. RESULTS: In the normal embryos, immunohistochemical staining revealed that TBX4 expression was detected in the epithelium of hindgut and urorectal septum (URS) on E13. TBX4-immunopositive cells were increased significantly in the epithelium of hindgut and URS, the future anal orifice part of cloacal membrane on E14. On E15, abundant stained cells were observed in the rectum, URS and dorsal cloacal membrane and the expression of positive cells reached its peak. On E16, only sporadic positive cells were distributed in the epithelium of the distal rectum. In the ARM embryos, the hindgut/rectum, URS and dorsal cloacal membrane were faint for TBX4 immunohistochemical staining. In the normal group, TBX4 protein and mRNA expression showed time-dependent changes in the hindgut/rectum from E13 to E16 on Western blot and real-time RT-PCR. On E13 and E15, the expression level of TBX4 mRNA in the ARM group was significantly lower than that in the normal group (P < 0.05). On E15, the expression level of TBX4 protein in the ARM group was significantly lower than that in the normal group (P < 0.05). CONCLUSIONS: The expression of TBX4 was downregulated in ETU-induced ARM embryos, which may play important roles in the pathogenesis of anorectal development.


Assuntos
Animais , Feminino , Gravidez , Ratos , Regulação da Expressão Gênica/genética , Proteínas com Domínio T/genética , Etilenotioureia/farmacologia , Malformações Anorretais/genética , Imuno-Histoquímica , Western Blotting , Ratos Wistar , Proteínas com Domínio T/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Malformações Anorretais/induzido quimicamente
18.
Se Pu ; 36(12): 1238-1244, 2018 Dec 08.
Artigo em Chinês | MEDLINE | ID: mdl-30574702

RESUMO

A method based on precolumn derivatization along with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the determination of ethylenethiourea residues in tea. The sample was extracted using acetonitrile; the extracting solution was purified by matrix-dispersed solid phase extraction and precolumn derivatization using 9-fluorenylmethyl chloroformate (FMOC-CL). The UPLC separation was carried out on an Acquity BEH C18 column (100 mm×2.1 mm, 1.7 µm) and quantified using the isotope internal standard method. The mobile phase was 0.1% (v/v) formic acid and acetonitrile. For tea samples, the detection limit of this method was 1.3 µg/kg and the limit of quantitation was 4.2 µg/kg. The recoveries were in the range 97.7%-107.5% with relative standard deviation (RSD) of 2.1%-10.0% (n=6). The linear correlation coefficient (r) was 0.9993 over the concentration range 1.0-203.4 µg/L. This method showed high sensitivity, good reproducibility, and qualitative and quantitative accuracy, and could be suitable for the detection of ethylenethiourea residues in tea.


Assuntos
Cromatografia Líquida de Alta Pressão , Etilenotioureia/análise , Contaminação de Alimentos , Espectrometria de Massas em Tandem , Chá/química , Fluorenos , Limite de Detecção , Reprodutibilidade dos Testes , Extração em Fase Sólida
19.
Exp Mol Pathol ; 105(3): 311-321, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30268882

RESUMO

BACKGROUND: This study aimed to determine Msh homeobox 2 (MSX2) and B cell lymphoma-2 (BCL2) expression patterns during anorectal development in anorectal malformations (ARM) and normal rat embryos, with the goals of determining the role of MSX2 and BCL2 in ARM pathogenesis. METHODS: ARM was induced in rat embryos with ethylenethiourea administered to dams on gestational day 10 (GD10). Embryos were harvested by cesarean deliveries from GD14 to GD16. MSX2 and BCL2 expression was evaluated via immunohistochemical staining, immunofluorescence, western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Immunohistochemical staining of ARM embryos revealed that MSX2 was mainly expressed in the epithelium of the hindgut and urorectal septum (URS) on GD14. On GD15 and GD16, MSX2-immunolabeled cells were noted in the epithelium of the rectum, fistula and URS. However, in normal embryos, faint immunopositivity for MSX2 was demonstrated in the epithelium of the rectum and URS from GD14 to GD16. As for BCL2, in normal embryos, BCL2-immunopositive cells were extensively expressed in the epithelium of the hindgut and URS on GD14 and GD15. In ARM embryos, weak immunopositivity for BCL2 was detected in the epithelium of hindgut and URS on GD14 and GD15. Immunofluorescence revealed that MSX2 and BCL2 colocalized in the hindgut. In ARM embryos, we observed more MSX2-positive than BCL2-positive cells on GD14; the normal embryos had the opposite pattern. Analyses by western blot and qRT-PCR showed that MSX2 protein and mRNA expression was significantly increased in ARM embryos compared with the normal embryos on GD15 and GD16 (p < 0.05). However, BCL2 protein and mRNA expression was significantly decreased in ARM embryos compared with the normal embryos on GD14 (p < 0.05). The MSX2/BCL2 ratio of protein and mRNA expression level in the ARM group was the highest on GD15. CONCLUSION: These results indicate that upregulation of MSX2 and downregulation of BCL2 during cloacal development into the rectum and urethra might be related to the ARM development, and MSX2 promoted apoptosis through reduction of BCL2 expression during the development of anorectal development in ARM.


Assuntos
Malformações Anorretais/induzido quimicamente , Malformações Anorretais/metabolismo , Etilenotioureia/toxicidade , Proteínas de Homeodomínio/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Animais , Embrião de Mamíferos , Ratos , Ratos Wistar
20.
Int J Mol Med ; 42(5): 2363-2372, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30106085

RESUMO

Anorectal malformations (ARMs) are one of the most common congenital malformations of the digestive tract; however, the pathogenesis of this disease remains to be fully elucidated. MicroRNAs (miRNAs) are important in gastrointestinal development and may be involved in the pathogenesis of ARMs. The present study aimed to profile miRNAs and examine their potential functions in rats with ethylenethiourea (ETU)­induced ARMs. Pregnant Wistar rats (n=36) were divided randomly into ETU­treated and control groups. The rats in the ETU­treated group were gavage­fed 1% ETU (125 mg/kg) on gestational day 10 (GD10), whereas the control group rats received a corresponding dose of saline. Embryos were harvested by cesarean section on GD14, GD15 and GD16. Hindgut tissue was isolated from the fetuses for RNA extraction and microarray analysis, followed by bioinformatics analysis and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) validation. Overall, 38 miRNAs were differentially expressed (all upregulated) on GD14, 49 (32 upregulated and 17 downregulated) on GD15, and 42 (all upregulated) on GD16 in the ARM group compared with the normal group. The top 18 miRNAs with |log2(fold change)| >4.25 were selected for further bioinformatics analysis. Among these miRNAs, five were differentially expressed at two time-points and were involved in ARM­associated signaling pathways. The RT­qPCR analysis revealed that three miRNA (miR), miR­125b­2­3p, miR­92a­2­5p and miR­99a­5p, were significantly differentially expressed in rats with ARMs compared with the normal group. In conclusion, the results suggested that the differential expression of miR­125b­2­3p, miR­92a­2­5p and miR­99a­5p during key time-points of anorectal formation in rats may have functions in the pathogenesis of ARM.


Assuntos
Malformações Anorretais/induzido quimicamente , Malformações Anorretais/genética , Embrião de Mamíferos/metabolismo , Etilenotioureia/toxicidade , MicroRNAs/metabolismo , Análise em Microsséries/métodos , Animais , Biologia Computacional , Feminino , Gravidez , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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