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1.
Chemosphere ; 248: 125904, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32014633

RESUMO

Cadmium (Cd) pollution is widespread in paddy filed soil in China. In this study, the toxicity of Cd with regard to the female reproductive system of paddy spider Pardosa pseudoannulata was investigated by means of multi-omics analyses (transcriptome, proteome, and miRNAs). Decreased activities of detoxifying enzymes including peroxidase (POD), Glutathione S-transferases (GST), and superoxide dismutase were detected in the ovary of P. pseudoannulata. Of these, GST and POD were consistently down-regulated at the transcriptional and translational levels. Vitellogenin content and fecundity of the spider were also reduced by Cd burden. Five vitellogenin encodes genes were down-regulated while only vitellogenin-6 protein was up-regulated. But protein lipovitellin-1, the main composition of vitellin, was down-regulated. In addition, the correlation between the mitogen-activated protein kinase (MAPK) signaling pathway and Cd stress was identified. A down-regulated gene that encoding connector of kinase to AP-1 in the MAPK signaling pathway was regulated by the up-regulated miRNA (miRNA id: miRNA dan-miR- 318>der-miR-318>dgr-miR-318>dme-miR-318-3p > dmo-miR-318>dpe-miR-318>dps-miR-318>dse-miR-318>dsi-miR-318>dvi-miR-318>dwi-miR-318>dya-miR-318). In conclusion, Cd stress possesses distinct female reproductive toxicity on P. pseudoannulata through impairing antioxidant system and synthesis of vitellin.


Assuntos
Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Ovário/efeitos dos fármacos , Aranhas/efeitos dos fármacos , Animais , China , Feminino , Inativação Metabólica/genética , MicroRNAs , Aranhas/fisiologia , Superóxido Dismutase/genética , Transcriptoma
2.
Xenobiotica ; 50(1): 19-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31317802

RESUMO

The review focuses on genetic variants of human flavin-containing monooxygenase 3 (FMO3) and their impact on enzyme activity, drug metabolism and disease.The majority of FMO-mediated metabolism in adult human liver is catalyzed by FMO3. Some drugs are metabolized in human liver predominantly by FMO3, but most drug substrates of FMO3 are metabolized also by other enzymes, particularly cytochromes P-450, and the FMO3-catalyzed reaction is not the major route of metabolism.Rare variants that severely affect production or activity of FMO3 cause the disorder trimethylaminuria and impair metabolism of drug substrates of FMO3. More common variants, particularly p.[(Glu158Lys);(Glu308Gly)], can moderately affect activity of FMO3 in vitro and reduce metabolism of drug substrates in vivo, in some cases increasing drug efficacy or toxicity.Common variants of FMO3 have been associated with a number of disorders, but additional studies are needed to confirm or refute such associations.Elevated plasma concentrations of trimethylamine N-oxide, a product of an FMO3-catalyzed reaction, have been implicated in certain diseases, particularly cardiovascular disease. However, the evidence is often contradictory and additional work is required to establish whether trimethylamine N-oxide is a cause, effect or biomarker of the disease.Genetic variants of other FMOs are also briefly discussed.


Assuntos
Inativação Metabólica/genética , Oxigenases/genética , Adulto , Humanos , Erros Inatos do Metabolismo , Metilaminas/urina , Oxigenases/metabolismo , Polimorfismo Genético
3.
Xenobiotica ; 50(1): 92-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31601149

RESUMO

The carboxylesterase drug hydrolysis pathway has been used extensively to improve the oral availability of drugs under the assumption that the high capacity and low substrate specificity of hydrolytic enzymes would ensure rapid, complete, and consistent conversion of prodrugs to their active metabolite. However, a growing body of literature indicates that drug hydrolysis is usually catalyzed by one primary enzyme, either carboxylesterase-1 or carboxlylesterase-2, and that there is wide variability in enzyme activity affecting the metabolism of prodrugs to their active metabolites.This review identifies carboxylesterase substrates and describes our current understanding of the influence of genetic polymorphisms on substrate disposition and clinical effects. Several polymorphisms are described in the literature and included in the personalized medicine database PharmGKB, but there are no carboxylesterase genotypes referenced in Food and Drug Administration approved drug labeling. The limited validation of metabolic pathways for drugs undergoing hydrolysis, and the small number of studies evaluating genotype-drug interactions confirm that this is an emerging field of drug metabolism research.The dependence of prodrugs, many with low therapeutic indexes, on carboxylesterase-mediated hydrolysis indicate that genetic variation plays an important role in prodrug activation, and that carboxylesterase genotyping will become an important component of personalized medicine.


Assuntos
Hidrolases de Éster Carboxílico/genética , Medicina de Precisão , Hidrolases de Éster Carboxílico/metabolismo , Interações Medicamentosas , Genótipo , Humanos , Hidrólise , Inativação Metabólica/genética , Taxa de Depuração Metabólica , Polimorfismo Genético , Pró-Fármacos , Especificidade por Substrato
4.
Bull Entomol Res ; 110(1): 57-67, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31217039

RESUMO

Glyphodes pyloalis Walker (Lepidoptera: Pyralididae) is a common pest in sericulture and has developed resistance to different insecticides. However, the mechanisms involved in insecticide resistance of G. pyloalis are poorly understood. Here, we present the first whole-transcriptome analysis of differential expression genes in insecticide-resistant and susceptible G. pyloalis. Clustering and enrichment analysis of DEGs revealed several biological pathways and enriched Gene Ontology terms were related to detoxification or insecticide resistance. Genes involved in insecticide metabolic processes, including cytochrome P450, glutathione S-transferases and carboxylesterase, were identified in the larval midgut of G. pyloalis. Among them, CYP324A19, CYP304F17, CYP6AW1, CYP6AB10, GSTs5, and AChE-like were significantly increased after propoxur treatment, while CYP324A19, CCE001c, and AChE-like were significantly induced by phoxim, suggesting that these genes were involved in insecticide metabolism. Furthermore, the sequence variation analysis identified 21 single nucleotide polymorphisms within CYP9A20, CYP6AB47, and CYP6AW1. Our findings reveal many candidate genes related to insecticide resistance of G. pyloalis. These results provide novel insights into insecticide resistance and facilitate the development of insecticides with greater specificity to G. pyloalis.


Assuntos
Inativação Metabólica/genética , Resistência a Inseticidas/genética , Mariposas/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/genética , Feminino , Perfilação da Expressão Gênica , Genes de Insetos , Masculino , Mariposas/genética , Polimorfismo de Nucleotídeo Único , Transcriptoma
5.
Arch Insect Biochem Physiol ; 103(4): e21653, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31859418

RESUMO

Terpinen-4-ol has high fumigating activity to stored-grain pests including Tribolium confusum. To understand the detoxification of terpinen-4-ol in insects, proteomic analysis was performed to identify related proteins and pathways in response to terpinen-4-ol fumigation in T. confusum. By using isobaric tags for relative and absolute quantitation (iTRAQ)-based strategy, 4,618 proteins were obtained from T. confusum adults in the present study. Comparative proteomic analysis showed that 148 proteins were upregulated and 137 proteins were downregulated in beetles under the LC50 of terpinen-4-ol treatment for 24 hr. According to functional classifications, differentially expressed proteins (DEPs) were enriched in xenobiotic metabolism pathways. In the detoxification pathway, the levels of 25 cytochrome P450s, 5 glutathione S-transferases, and 2 uridine diphosphate (UDP)-glucuronosyltransferases were changed, most of which were upregulated in T. confusum exposed to terpinen-4-ol. The results indicated that terpinen-4-ol was potentially metabolized and detoxified by enzymes like P450s in T. confusum.


Assuntos
Fumigação , Inativação Metabólica/genética , Controle de Insetos , Proteínas de Insetos/genética , Terpenos/farmacologia , Tribolium/efeitos dos fármacos , Animais , Regulação para Baixo/genética , Proteínas de Insetos/metabolismo , Tribolium/metabolismo , Regulação para Cima/genética
6.
PLoS One ; 14(12): e0226039, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31846465

RESUMO

The fat body, a multifunctional organ analogous to the liver and fat tissue of vertebrates, plays an important role in insect life cycles. The fat body is involved in protein storage, energy metabolism, elimination of xenobiotics, and production of immunity regulator-like proteins. However, the molecular mechanism of the fat body's physiological functions in the tephritid stem gall-forming fly, Procecidochares utilis, are still unknown. In this study, we performed transcriptome analysis of the fat body of P. utilis using Illumina sequencing technology. In total, 3.71 G of clean reads were obtained and assembled into 30,559 unigenes, with an average length of 539 bp. Among those unigenes, 21,439 (70.16%) were annotated based on sequence similarity to proteins in NCBI's non-redundant protein sequence database (Nr). Sequences were also compared to NCBI's non-redundant nucleotide sequence database (Nt), a manually curated and reviewed protein sequence database (SwissProt), and KEGG and gene ontology annotations were applied to better understand the functions of these unigenes. A comparative analysis was performed to identify unigenes related to detoxification, immunity and energy metabolism. Many unigenes involved in detoxification were identified, including 50 unigenes of putative cytochrome P450s (P450s), 18 of glutathione S-transferases (GSTs), 35 of carboxylesterases (CarEs) and 26 of ATP-binding cassette (ABC) transporters. Many unigenes related to immunity were identified, including 17 putative serpin genes, five peptidoglycan recognition proteins (PGRPs) and four lysozyme genes. In addition, unigenes potentially involved in energy metabolism, including 18 lipase genes, five fatty acid synthase (FAS) genes and six elongases of very long chain fatty acid (ELOVL) genes, were identified. This transcriptome improves our genetic understanding of P. utilis and the identification of a numerous transcripts in the fat body of P. utilis offer a series of valuable molecular resources for future studies on the functions of these genes.


Assuntos
Metabolismo Energético/genética , Corpo Adiposo/metabolismo , Imunidade/genética , Inativação Metabólica/genética , Tephritidae/genética , Transcriptoma , Transportadores de Cassetes de Ligação de ATP/classificação , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Hidrolases de Éster Carboxílico/classificação , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Sistema Enzimático do Citocromo P-450/classificação , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Repetições de Microssatélites , Filogenia , Análise de Sequência de DNA
7.
Pestic Biochem Physiol ; 161: 86-94, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31685201

RESUMO

While insecticide resistance presents a challenge for those intent on controlling insect populations, these challenges have also generated a set of tools that can be used to ask fundamental biological questions about that resistance. Numerous species of insects have evolved resistance to multiple classes of insecticides. Each one of these species and their respective resistant populations represent a potential tool for understanding the molecular basis of the evolution of resistance. However, in-laboratory maintenance of resistant insect populations (and their comparative susceptible populations) suitable for asking the needed set of questions around the molecular consequences of long-term pesticide exposure requires a significant, in places prohibitive, level of resources. Drosophila melanogaster (hereafter referred to as Drosophila) is a model insect system with populations easily selected with pesticides and readily maintainable over decades. Even within Drosophila, however, few populations exist where long-term pesticide selection has occurred along with contrasting non-selected population. As such, the Drosophila 91-C and 91-R populations, which exhibit insecticide resistance to DDT (91-R), compared to a non-selection population (91-C), represent a unique resource for the study of high level DDT resistance. Moreover, with the availability of "omics" technologies over the past several decades, this paired population has emerged as a useful tool for understanding both the molecular basis of pesticide resistance and the molecular consequences of long-term pesticide exposure. In this review, we summarize the studies with these aforementioned populations over the past several decades, addressing what has been learned from these efforts.


Assuntos
DDT/farmacologia , Drosophila melanogaster/efeitos dos fármacos , Resistência a Inseticidas/genética , Animais , Drosophila melanogaster/genética , Genoma de Inseto , Inativação Metabólica/genética
8.
Ecotoxicol Environ Saf ; 185: 109735, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31586846

RESUMO

Nilaparvata lugens(Stål) is a serious pest of rice and has evolved different levels of resistance against most chemical pesticides. ß-asarone is the main bioactive insecticidal compound of Acorus calamus L. that shows strong insecticidal activity against pests. In this study, we conducted a bioassay experiment to determine the contact toxicity of ß-asarone to N. lugens nymphs. The LD30 sublethal dose was 0.106 µg per nymph, with 95% confidence limits of 0.070-0.140 µg. We applied the LD30 concentration of ß-asarone to nymphs for 24 h or 72 h and then performed a transcriptome sequence analysis by referencing the N. lugens genome to characterize the variation. The transcriptomic analysis showed that several GO terms and KEGG pathways presented significant changes. Individually, 126 differentially expressed genes (DEGs), including 72 upregulated and 54 downregulated genes, were identified at 24 h, and 1771 DEGs, including 882 upregulated and 889 downregulated genes, were identified at 72 h. From the DEGs, we identified a total of 40 detoxification-related genes, including eighteen Cytochrome P450 monooxygenase genes (P450s), three Glutathione S-transferase genes, one Carboxylesterase gene, twelve UDP-glucosyltransferases and six ATP-binding cassette genes. We selected the eighteen P450s for subsequent verification by quantitative PCR. These findings indicated that ß-asarone presented strong contact toxicity to N. lugens nymphs and induced obvious variation of detoxification-related genes that may be involved in the response to ß-asarone.


Assuntos
Anisóis/farmacologia , Hemípteros/efeitos dos fármacos , Inseticidas/farmacologia , Ninfa/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Carboxilesterase/genética , Sistema Enzimático do Citocromo P-450/genética , Perfilação da Expressão Gênica , Genoma , Glutationa Transferase/genética , Hemípteros/genética , Hemípteros/metabolismo , Inativação Metabólica/genética , Ninfa/genética , Ninfa/metabolismo , Oryza/crescimento & desenvolvimento
9.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370155

RESUMO

Despite the significant recent advances in clinical practice, gastric cancer (GC) represents a leading cause of cancer-related deaths in the world. In fact, occurrence of chemo-resistance still remains a daunting hindrance to effectiveness of the current approach to GC therapy. There is accumulating evidence that a plethora of cellular and molecular factors is implicated in drug-induced phenotypical switching of GC cells. Among them, epithelial-mesenchymal transition (EMT), autophagy, drug detoxification, DNA damage response and drug target alterations, have been reported as major determinants. Intriguingly, resistant GC phenotype may be the result of GC cell-induced tumor microenvironment (TME) remodeling, which is currently emerging as a key player in promoting drug resistance and overcoming cytotoxic effects of drugs. In this review, we discuss the possible mechanisms of drug resistance and their involvement in determining current GC therapies failure.


Assuntos
Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/genética , Neoplasias Gástricas/genética , Microambiente Tumoral/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Sobrevivência Celular/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/genética , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Helicobacter pylori/crescimento & desenvolvimento , Helicobacter pylori/patogenicidade , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/genética , Hipóxia/metabolismo , Hipóxia/patologia , Inativação Metabólica/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Microambiente Tumoral/efeitos dos fármacos
10.
Chemosphere ; 235: 734-748, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31280042

RESUMO

Jasmonic acid (JA) is an important phytohormone associated in defense responses against stress. Crop plants experience heavy metal toxicity and needs to be explored to enhance the crop production. Lead (Pb) is one of the dangerous heavy metal that pollutes soil and water bodies and is released from various sources like discharge from batteries, automobile exhaust, and paints. The present study was designed to evaluate the role of JA (100 nM) on photosynthetic pigments, secondary metabolites, organic acids, and metal ligation compounds in tomato seedlings under different concentrations of Pb (0.25, 0.50, and 0.75 mM). It was observed that Pb treatment declined pigment content, relative water content, and heavy metal tolerance index. Expression of chlorophyllase was also enhanced in Pb-treated seedlings. Seeds primed with JA lowered the expression of chlorophyllase under Pb stress. JA application enhanced the contents of secondary metabolites (total phenols, polyphenols, flavonoids, and anthocyanin) which were confirmed with enhanced expression of chalcone synthase and phenylalanine ammonia lyase in Pb-exposed seedlings. Treatment of JA further elevated the levels of organic acids and metal chelating compounds under Pb toxicity. JA up-regulated the expression of succinate dehydrogenase and fumarate hydratase in Pb-exposed seedlings. Results revealed that seeds primed with JA reduced Pb toxicity by elevating, the levels of photosynthetic pigments, secondary metabolites, osmolytes, metal ligation compounds, organic acids, and polyamine accumulation in tomato seedlings.


Assuntos
Ciclopentanos/química , Chumbo/química , Lycopersicon esculentum/fisiologia , Oxilipinas/química , Poluentes do Solo/química , Ciclopentanos/metabolismo , Expressão Gênica , Inativação Metabólica/genética , Chumbo/metabolismo , Chumbo/toxicidade , Lycopersicon esculentum/genética , Lycopersicon esculentum/metabolismo , Oxilipinas/metabolismo , Fenóis/metabolismo , Fotossíntese , Reguladores de Crescimento de Planta/metabolismo , Polifenóis/metabolismo , Plântula/metabolismo , Sementes/metabolismo , Poluentes do Solo/toxicidade
11.
Environ Sci Pollut Res Int ; 26(26): 26553-26562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31292876

RESUMO

Our study evaluated 163 individuals, being 74 soybean farmers, occupationally exposed to pesticides, and 89 individuals from Goias municipalities, Central Brazil, with similar conditions to the exposed group, comprising the control group. Of the 74 soybean farmers, 43 exposed directly to pesticides and 31 exposed indirectly. The exposed group consisted of individuals aged 19 to 63 years, 21 women and 53 men, and the control group had ages ranging from 18 to 64 years, being 36 women and 53 men. 18.9% of the exposed group were poisoned by pesticides, and the most common symptoms were headache and gastrointestinal problems. The genotype frequencies of the rs2031920 (T>C) polymorphism in the CYP2E1 gene present significant differences between the exposed and control groups (p = 0.02), showing that 24.3% of the exposed group were heterozygotes against 6.7% in the control group. For the OGG1 gene, two SNPs, rs1052133 (G>C) and rs293795 (T>C), were evaluated and the genotype frequencies were not statistically different between the exposed and control groups. The DNA damage was distinct (p < 0.05) in the three analyzed comet parameters (tail length, Olive tail moment, %DNA) between groups. However, there was no influence of age and alcohol consumption between the groups associated with the polymorphisms in the CYP2E1 and OGG1 genes and DNA damage. We also did not find altered hematological and biochemical parameters in the exposed group. Thus, this pioneering study at Goias State carried out an overview of the health of soybean farmers. We evaluated classic laboratory exams, associated with exposure markers (comet assay) and susceptibility markers (genetic polymorphisms), emphasizing the need to expand the Brazilian health assessment protocol. We found, in soybean farmers, increased DNA damage and a higher number of heterozygotes in CYP2E1 gene, compared with the control group, despite the lack of association with age, educational level, smoking, drinking habits, and genetic polymorphisms.


Assuntos
Citocromo P-450 CYP2E1/genética , Dano ao DNA , DNA Glicosilases/genética , Reparo do DNA , Fazendeiros , Polimorfismo Genético , Adolescente , Adulto , Idoso , Poluentes Ocupacionais do Ar/análise , Poluentes Ocupacionais do Ar/toxicidade , Biomarcadores/sangue , Brasil , Ensaio Cometa , Feminino , Humanos , Inativação Metabólica/genética , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/análise , Praguicidas/análise , Praguicidas/toxicidade , Soja/crescimento & desenvolvimento , Adulto Jovem
12.
Ecotoxicol Environ Saf ; 182: 109389, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31272027

RESUMO

Simvastatin (SV), as an hypocholesterolaemic drug, has been detected in various aquatic environment. However, limited information is available on the effects of SV on freshwater invertebrates. In the present study, we investigated the toxic effects of SV on Daphnia. magna (D. magna) through measuring the physiological changes (e.g., survival, growth rate, and reproduction) in a 21-d chronic toxicity test We also determined the expression of seven detoxification and reproduction-related genes (i.e. HR96, P-gp, CYP360A8, GST, CYP314, EcR and Vtg) and several enzymes (i.e. APND, ERND, GST and CAT) in a acute test (24 h). Results showed that high concentration (e.g. 50 µg L-1) of SV for short time exposure (e.g. 24 h) significantly induced the expression of HR96 and P-gp (e.g. up to 2.5 folds)and enzymes (e.g. increasing 4.0 folds for ERND and GST activity) in D. magna.. The long-term chronic exposure (21 days) may cause the changes of life history parameters such as decreasing total egg production number per individual and intrinsic growth rates etc. SV may act as a potential endocrine disruptor to D. magna and the reproduction parameters were more sensitive endpoints than the survival and growth for evaluating SV exposure.


Assuntos
Daphnia , Disruptores Endócrinos/toxicidade , Sinvastatina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Daphnia/efeitos dos fármacos , Daphnia/enzimologia , Daphnia/genética , Inativação Metabólica/efeitos dos fármacos , Inativação Metabólica/genética , Reprodução/efeitos dos fármacos , Reprodução/genética , Testes de Toxicidade Crônica
13.
PLoS One ; 14(6): e0218343, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31206537

RESUMO

Many insect species display daily variation of sensitivity to insecticides when they are exposed to the same concentration at different times during the day. To date, this has not been investigated in bed bugs. To address this, we explored circadian rhythms in insecticide susceptibility, xenobiotic metabolizing (XM) gene expressions, and metabolic detoxification in the common bed bug, Cimex lectularius. An insecticide susceptible Monheim strain of C. lectularius was most tolerant of deltamethrin during the late photophase at ZT9 (i.e. nine hours after light is present in the light-dark cycle (LD) cycle) and similarly repeated at CT9 (i.e. nine hours into the subjective day in constant darkness (DD)) suggesting endogenous circadian involvement in susceptibility to deltamethrin. No diel rhythm was observed against imidacloprid insecticide despite significant daily susceptibility in both LD and DD conditions. Rhythmic expressions of metabolic detoxification genes, GSTs1 and CYP397A1 displayed similar expression patterns with total GST and P450 enzyme activities in LD and DD conditions, respectively. The oscillation of mRNA levels of GSTs1 and CYP397A1 was found consistent with peak phases of deltamethrin susceptibility in C. lectularius. This study demonstrates that circadian patterns of metabolic detoxification gene expression occur within C. lectularius. As a consequence, insecticide efficacy can vary dramatically throughout a 24 hour period.


Assuntos
Percevejos-de-Cama/fisiologia , Ritmo Circadiano , Enzimas/metabolismo , Expressão Gênica , Inseticidas/farmacologia , Animais , Percevejos-de-Cama/efeitos dos fármacos , Percevejos-de-Cama/metabolismo , Inativação Metabólica/genética , Resistência a Inseticidas , Nitrilos/farmacologia , Fotoperíodo , Piretrinas/farmacologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-31154023

RESUMO

Rare earth elements (REEs) are increasingly used in electronics industry and other areas of our economy and questions were raised about their impacts to the environment. The purpose of this study was to examine the lethal and sublethal toxicity of REEs in juvenile rainbow (Oncorhynchus mykiss) trout. The fish were exposed to increasing concentrations (0.064, 0.32, 1.6, 8 and 40 mg/L) of the following 7 REEs for 96 h at 15 °C: cerium (CeCl3), erbium (ErCl3), gadolinium (GdCl3), lanthanum (LaCl3), neodymium (NdCl3), samarium (SmCl3) and yttrium (YCl3). The mortality were determined and in the surviving fish, 10 target gene transcripts were measured in the liver to track changes in oxidative stress, DNA repair, tissue growth/proliferation, protein chaperoning, xenobiotic biotransformation and ammonia metabolism. The data revealed that Y, Sm, Er and Gd formed a distinct group based on toxicity (mortality) and gene expression changes. Electronegativity was significantly correlated (r = -0.8, p < 0.01) with the lethal concentration (LC50). Gene expression changes occurred at concentration circa 120 times lower than the LC50 and the following transcripts in protein chaperoning (heat shock proteins), DNA repair (growth arrest DNA Damage) and CYP1A1 gene expression involved in the metabolism of coplanar aromatic hydrocarbons were involved. In conclusion, the study revealed that the more electronegative REEs were the most toxic to trout juveniles and produced sublethal effects at concentrations 2 orders of magnitude lower than the lethal concentrations. The toxicity of REEs depends on the elements were toxicity involves specific pathways at the gene expression level.


Assuntos
Expressão Gênica/efeitos dos fármacos , Metais Terras Raras/toxicidade , Oncorhynchus mykiss/genética , Amônia/metabolismo , Animais , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Ecotoxicologia , Inativação Metabólica/efeitos dos fármacos , Inativação Metabólica/genética , Mortalidade , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Poluentes Químicos da Água/toxicidade , Xenobióticos/farmacocinética
15.
Artigo em Inglês | MEDLINE | ID: mdl-31254664

RESUMO

Spider mites are destructive arthropod pests on many crops and they have developed resistance to nearly all acaricides. In recent years, along with the application of high throughput sequencing, the molecular mechanisms of mite resistance had made a series of progress. But, the response in molecular level of mite exposure to acaricides, as well as the original mechanism of resistance development was still unclear. To disclose the deeply mechanisms, we used RNA sequencing to analyze the responses of mite exposure to a sublethal concentration (LC30) treatment of the three different action mode acaricides (Abamectin, Fenpropathrin, and Tebufenpyrad). A high number of differentially expressed genes may well be involved in detoxification and regulatory, with extensive overlap in differentially expressed genes between the three insecticide treatments. Two cytochrome P450 genes were co-up-regulated and one glutathione S-transferase genes were co-down-regulated in all the treatments, while carboxylesterase genes only had a response to abamectin. This interesting phenomenon revealed that P450 enzymes play an important role in the early stage of mite exposure to acaricide. Moreover, a P8 nuclear receptor gene was in response to stress caused by exposure to acaricides and RNA interference (RNAi) experiment indicated P8 nuclear receptor regulates the P450 enzyme activity and susceptibility of mites to acaricide. The differential response information of gene expression based on a large-scale sequence would provide some useful clues for studying the molecular mechanisms of mite resistance formation and development.


Assuntos
Acaricidas/toxicidade , Sistema Enzimático do Citocromo P-450/genética , Resistência a Medicamentos/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Tetranychidae/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Acaricidas/metabolismo , Animais , Proteínas de Artrópodes/metabolismo , Inativação Metabólica/genética , Ivermectina/análogos & derivados , Ivermectina/metabolismo , Ivermectina/toxicidade , Proteínas Nucleares/metabolismo , Pirazóis/metabolismo , Pirazóis/toxicidade , Piretrinas/metabolismo , Piretrinas/toxicidade , Receptores Citoplasmáticos e Nucleares/genética , Tetranychidae/genética
16.
Genes (Basel) ; 10(5)2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31137904

RESUMO

Xenobiotic-metabolizing enzymes (XME) mediate the body's response to potentially harmful compounds of exogenous/endogenous origin to which individuals are exposed during their lifetime. Aging adversely affects such responses, making the elderly more susceptible to toxics. Of note, XME genetic variability was found to impact the ability to cope with xenobiotics and, consequently, disease predisposition. We hypothesized that the variability of these genes influencing the interaction with the exposome could affect the individual chance of becoming long-lived. We tested this hypothesis by screening a cohort of 1112 individuals aged 20-108 years for 35 variants in 23 XME genes. Four variants in different genes (CYP2B6/rs3745274-G/T, CYP3A5/rs776746-G/A, COMT/rs4680-G/A and ABCC2/rs2273697-G/A) differently impacted the longevity phenotype. In particular, the highest impact was observed in the age group 65-89 years, known to have the highest incidence of age-related diseases. In fact, genetic variability of these genes we found to account for 7.7% of the chance to survive beyond the age of 89 years. Results presented herein confirm that XME genes, by mediating the dynamic and the complex gene-environment interactions, can affect the possibility to reach advanced ages, pointing to them as novel genes for future studies on genetic determinants for age-related traits.


Assuntos
Envelhecimento/genética , Inativação Metabólica/genética , Longevidade/genética , Xenobióticos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/patologia , Catecol O-Metiltransferase/genética , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP3A/genética , Feminino , Humanos , Itália/epidemiologia , Masculino , Metabolômica , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
17.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083458

RESUMO

To appraise how evolutionary processes, such as gene duplication and loss, influence an organism's xenobiotic sensitivity is a critical question in toxicology. Of particular importance are gene families involved in the mediation of detoxification responses, such as members of the nuclear receptor subfamily 1 group I (NR1I), the pregnane X receptor (PXR), and the constitutive androstane receptor (CAR). While documented in multiple vertebrate genomes, PXR and CAR display an intriguing gene distribution. PXR is absent in birds and reptiles, while CAR shows a tetrapod-specific occurrence. More elusive is the presence of PXR and CAR gene orthologs in early branching and ecologically-important Chondrichthyes (chimaeras, sharks and rays). Therefore, we investigated various genome projects and use them to provide the first identification and functional characterization of a Chondrichthyan PXR from the chimaera elephant shark (Callorhinchus milii, Holocephali). Additionally, we substantiate the targeted PXR gene loss in Elasmobranchii (sharks and rays). Compared to other vertebrate groups, the chimaera PXR ortholog displays a diverse expression pattern (skin and gills) and a unique activation profile by classical xenobiotic ligands. Our findings provide insights into the molecular landscape of detoxification mechanisms and suggest lineage-specific adaptations in response to xenobiotics in gnathostome evolution.


Assuntos
Elasmobrânquios/classificação , Elasmobrânquios/genética , Evolução Molecular , Redes Reguladoras de Genes , Filogenia , Receptor de Pregnano X/genética , Animais , Células COS , Genes Reporter , Inativação Metabólica/genética , Luciferases/metabolismo , Receptor de Pregnano X/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Sintenia/genética , Ativação Transcricional/genética
18.
Artigo em Inglês | MEDLINE | ID: mdl-31048018

RESUMO

Enrofloxacin (ENR) is the most commonly used antibiotic in crustacean farming in China. Diet supplementation with lactic acid (LA) may, however, affect the efficacy and safety of ENR-based drugs. The aims of this study were to investigate the effects of LA on drug residues and elimination of oral ENR in Chinese mitten crab (Eriocheir sinensis) and to determine ENR and gene expression levels of drug-metabolizing enzymes in the hepatopancreas. To this end, ENR was orally administered to the crabs at a dose of 10.0 mg kg-1 body weight on the eighth day after feeding diets supplemented with 0.3%LA. The results showed that ENR levels in the hepatopancreas were significantly different at 1 and 12 h between the ENR and ENR + 0.3% LA groups (P < 0.05). Lactic acid did not significantly affect the expression of CYP2A (phase I). However, the expressions of CYP3 (phase I) and GST (phase II) were significantly up-regulated by LA during the elimination process of ENR (6-24 h). At Tmax (1 h), the expression of phosphoenolpyruvate carboxykinase (PEPCK) was induced and expression of succinate dehydrogenase (SDH) was inhibited by LA. Both of these enzymes were significantly inhibited during the elimination process of ENR. The results suggest that LA contributes to the elimination of ENR, and thus, enhances hepatopancreas biotransformation and anti-injury capacity in E. sinensis.


Assuntos
Braquiúros/efeitos dos fármacos , Enrofloxacina/farmacocinética , Inativação Metabólica/efeitos dos fármacos , Ácido Láctico/farmacologia , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Aquicultura , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Braquiúros/enzimologia , Família 3 do Citocromo P450/genética , Família 3 do Citocromo P450/metabolismo , Suplementos Nutricionais , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Enrofloxacina/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatopâncreas/efeitos dos fármacos , Hepatopâncreas/metabolismo , Inativação Metabólica/genética , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo
19.
Cell Mol Life Sci ; 76(20): 4131-4144, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31053883

RESUMO

ABCB6 belongs to the family of ATP-binding cassette (ABC) transporters, which transport various molecules across extra- and intra-cellular membranes, bearing significant impact on human disease and pharmacology. Although mutations in the ABCB6 gene have been linked to a variety of pathophysiological conditions ranging from transfusion incompatibility to pigmentation defects, its precise cellular localization and function is not understood. In particular, the intracellular localization of ABCB6 has been a matter of debate, with conflicting reports suggesting mitochondrial or endolysosomal expression. ABCB6 shows significant sequence identity to HMT-1 (heavy metal tolerance factor 1) proteins, whose evolutionarily conserved role is to confer tolerance to heavy metals through the intracellular sequestration of metal complexes. Here, we show that the cadmium-sensitive phenotype of Schizosaccharomyces pombe and Caenorhabditis elegans strains defective for HMT-1 is rescued by the human ABCB6 protein. Overexpression of ABCB6 conferred tolerance to cadmium and As(III) (As2O3), but not to As(V) (Na2HAsO4), Sb(V), Hg(II), or Zn(II). Inactivating mutations of ABCB6 abolished vacuolar sequestration of cadmium, effectively suppressing the cadmium tolerance phenotype. Modulation of ABCB6 expression levels in human glioblastoma cells resulted in a concomitant change in cadmium sensitivity. Our findings reveal ABCB6 as a functional homologue of the HMT-1 proteins, linking endolysosomal ABCB6 to the highly conserved mechanism of intracellular cadmium detoxification.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Cádmio/toxicidade , Proteínas de Caenorhabditis elegans/genética , Inativação Metabólica/genética , Poluentes Químicos da Água/toxicidade , Transportadores de Cassetes de Ligação de ATP/deficiência , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antimônio/toxicidade , Arseniatos/toxicidade , Trióxido de Arsênio/toxicidade , Cádmio/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Linhagem Celular Tumoral , Sequência Conservada , Expressão Gênica , Teste de Complementação Genética , Células HeLa , Humanos , Mercúrio/toxicidade , Mutação , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Schizosaccharomyces/efeitos dos fármacos , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo , Poluentes Químicos da Água/metabolismo , Zinco/toxicidade
20.
Curr Opin Insect Sci ; 31: 131-138, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31109666

RESUMO

We use the genomes of 160 insect species to test the hypothesis that the size of detoxifying enzyme families is greater in species using more chemically diverse food resources. Phylogenetically appropriate contrasts in subsamples of the data generally support the hypothesis. We find relatively high numbers of cytochrome P450, glutathione S-transferase and carboxyl/choline esterase genes in omnivores and herbivores feeding on chemically complex tissues and relatively low numbers of these genes in specialists on relatively simple diets, including plant sap, nectar and pollen, and blood. Among Lepidoptera feeding on green plant tissue and Condylognatha feeding on sap we also find more of these genes in highly polyphagous species, many of which are major agricultural pests. These genomic signatures of food resource use are consistent with the hypothesis that some taxa are preadapted for insecticide resistance evolution.


Assuntos
Inativação Metabólica/genética , Insetos/enzimologia , Animais , Sistema Enzimático do Citocromo P-450/genética , Esterases/genética , Preferências Alimentares , Glutationa Transferase/genética , Insetos/genética , Resistência a Inseticidas/genética , Fenótipo
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