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1.
Toxicol Appl Pharmacol ; 426: 115638, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34242569

RESUMO

Gonadal development begins in the intrauterine phase and females from most species are born with an established oocyte reserve. Exposure to drugs during gestation can compromise the offspring health, also affecting the gametes quality. Nicotine, the main component of cigarettes, is an oxidant agent capable of altering the fertility in men and women. As female gametes are susceptible to oxidative stress, this drug can damage the oolemma and affect oocyte maturation, induce errors during chromosomal segregation and DNA fragmentation. Oocyte mitochondria are particularly susceptible to injuries, contributing to the oocyte quality loss and embryonic development disruption. Thus, considering the high number of women who smoke during pregnancy, while significant events are occurring in the embryo for future fertility of offspring, we seek to verify the quality of the oocytes from adult rats exposed to nicotine during intrauterine phase and breastfeeding. Pregnant Wistar rats received nicotine by osmotic mini-pumps and the female progenies were evaluated in adulthood for oocyte quality (viability, lipid peroxidation, generation of reactive oxygen species and mitochondrial integrity) and reproductive capacity. Embryos (3dpc) and fetuses (20dpc) generated by these rats were also evaluated. The results showed that the dose of 2 mg/kg/day of nicotine through placenta and breast milk does not affect the number of oocytes and the fertility capacity of adult rats. However, it causes some morphological alterations in oocytes, mitochondrial changes, embryonic fragmentation and disruption of fetal development. The malformations in fetuses generated from these gametes can also indicate the occurrence of epigenetic modifications.


Assuntos
Nicotina/toxicidade , Oócitos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Reprodução/efeitos dos fármacos , Animais , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Lactação , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Troca Materno-Fetal , Mitocôndrias/efeitos dos fármacos , Oócitos/metabolismo , Gravidez , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
2.
Anticancer Res ; 41(8): 3833-3842, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281843

RESUMO

BACKGROUND/AIM: Lung cancer is the leading cause of cancer death worldwide. Cigarette smoke is the most important risk factor for cancer development. Growing evidence indicates that prolonged nicotine exposure is a potential factor associated with tumorigenesis. Here, the effect of prolonged nicotine exposure on A549 cells was investigated, using label-free quantitative proteomics. MATERIALS AND METHODS: Selection of an invasive subpopulation from the A549 cell line was performed to reveal the differential expression of proteins in relation to prolonged nicotine exposure, using Boyden chamber assays in combination with a proteomics approach. RESULTS: One hundred proteins from the NicoA549-L5 subline showed significant change in expression compared to those from the A549-L5 subline and their A549 parental cell line. Heat shock protein, protein disulfide isomerase A3, profilin-1 and legumain were expressed at higher levels in A549 cells after prolonged nicotine exposure. CONCLUSION: These aberrant proteins might serve as novel cancer biomarkers for cigarette smokers.


Assuntos
Nicotina/toxicidade , Proteínas/metabolismo , Proteômica/métodos , Células A549 , Biomarcadores Tumorais/metabolismo , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Cisteína Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Humanos , Nicotina/administração & dosagem , Profilinas/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
3.
Toxicology ; 459: 152847, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34245815

RESUMO

Previous findings have confirmed that prenatal nicotine exposure (PNE) leads to retarded cartilage development in the fetal growth plate. It is characterized by insufficient matrix synthesis and decreased expression of matrix phenotype genes aggrecan (ACAN) and Col2A1 in the fetal growth plate chondrocytes; however, the specific molecular mechanism is yet unclear. This study intends to clarify the specific molecular mechanism of fetal osteochondral retardation caused by PNE through animal and cellular experiments. The present study demonstrated that in male offspring of the PNE group (the pregnant rats were subcutaneously administered nicotine 1.0 mg/kg twice per day (2.0 mg/kg.d) at GD11-20), the cartilage matrix of the fetal growth plate was lightly stained, the collagen was reduced, and expression of the matrix phenotype genes, ACAN and Col2A1, was significantly decreased. It was further found that PNE decreased histone acetylation (H3K9/H3K14) levels in the ACAN and Col2A1 promoter regions. Moreover, the expression of Snail and HDAC1/2 was increased in the PNE group. in vitro, the nicotine treatment at different concentrations elevated the expression of Snail/HDAC1/2 while decreasing the H3K9/H3K14 levels in the ACAN and Col2A1 promoter regions. Snail-siRNA transfection partially abolished the nicotine-induced increase in HDAC1/2 expression and decreased the histone acetylation levels in the ACAN and Col2A1 promoter regions. Trichostatin A (TSA) treatment partially reversed the nicotine-induced changes in downstream parameters. In summary, PNE-induced decreased cartilage matrix synthesis in the fetal growth plate of male offspring is effectuated by Snail/HDAC1/2-mediated decreased H3K9/H3K14 levels in the ACAN and Col2A1 promoter regions.


Assuntos
Retardo do Crescimento Fetal/induzido quimicamente , Histona Desacetilase 1/efeitos dos fármacos , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/efeitos dos fármacos , Histona Desacetilase 2/metabolismo , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Fatores de Transcrição da Família Snail/efeitos dos fármacos , Fatores de Transcrição da Família Snail/metabolismo , Agrecanas/metabolismo , Animais , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Colágeno/metabolismo , Colágeno Tipo II/metabolismo , Feminino , Lâmina de Crescimento/efeitos dos fármacos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Transfecção
4.
FASEB J ; 35(7): e21702, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34153130

RESUMO

Perinatal smoke/nicotine exposure alters lung development and causes asthma in exposed offspring, transmitted transgenerationally. The mechanism underlying the transgenerational inheritance of perinatal smoke/nicotine-induced asthma remains unknown, but germline epigenetic modulations may play a role. Using a well-established rat model of perinatal nicotine-induced asthma, we determined the DNA methylation pattern of spermatozoa of F1 rats exposed perinatally to nicotine in F0 gestation. To identify differentially methylated regions (DMRs), reduced representation bisulfite sequencing was performed on spermatozoa of F1 litters. The top regulated gene body and promoter DMRs were tested for lung gene expression levels, and key proteins involved in lung development and repair were determined. The overall CpG methylation in F1 sperms across gene bodies, promoters, 5'-UTRs, exons, introns, and 3'-UTRs was not affected by nicotine exposure. However, the methylation levels were different between the different genomic regions. Eighty one CpG sites, 16 gene bodies, and 3 promoter regions were differentially methylated. Gene enrichment analysis of DMRs revealed pathways involved in oxidative stress, nicotine response, alveolar and brain development, and cellular signaling. Among the DMRs, Dio1 and Nmu were the most hypermethylated and hypomethylated genes, respectively. Gene expression analysis showed that the mRNA expression and DNA methylation were incongruous. Key proteins involved in lung development and repair were significantly different (FDR < 0.05) between the nicotine and placebo-treated groups. Our data show that DNA methylation is remodeled in offspring spermatozoa upon perinatal nicotine exposure. These epigenetic alterations may play a role in transgenerational inheritance of perinatal smoke/nicotine induced asthma.


Assuntos
Metilação de DNA , Epigênese Genética , Pulmão/patologia , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Espermatozoides/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley , Espermatozoides/patologia
5.
Toxicol Lett ; 349: 84-91, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34153408

RESUMO

AIM: Smoking has been considered as a risk factor of chronic pancreatitis (CP), but the potential mechanism is still unknown. The major pathological feature of CP is pancreatic fibrosis, whose major functional cells are pancreatic stellate cells (PSCs). Nicotine is the major component of cigarette smoke, our recent study suggested that nicotine has the potential to facilitate pancreatic fibrosis in CP. This study was aimed to analyze the function and mechanism of nicotine on PSCs and pancreatic fibrosis in rats. MATERIALS AND METHODS: In vivo, a rat CP model was induced by intraperitoneal injection of 20 % L-arginine hydrochloride (200 mg/100 g) at 1 h intervals twice per week, nicotine was injected subcutaneously at a dose of 1 mg/kg body weight per day. After four weeks, the pancreatic tissue was collected for H&E, Masson and immunohistochemical staining. In vitro, primary rPSCs were isolated from rats and treated with nicotine (0.1 µM and 1 µM). The proliferation、apoptosis、α-SMA expression、extracellular matrix (ECM) metabolism and α7nAChR-mediated JAK2/STAT3 signaling pathway of rPSCs were detected by CCK-8 assay、flow cytometry、real-time Q-PCR and western blotting analysis. The α7nAChR antagonist α-bungarotoxin (α-BTX) was used to perform inhibition experiments. KEY FINDINGS: Nicotine increased pancreatic damage, collagen deposition and activation of PSCs in the CP rat model. In rPSCs, the proliferation, α-SMA expression and ECM formation were significantly promoted by nicotine in a dose-dependent manner. Meanwhile, the apoptosis of rPSCs was significantly reduced after nicotine treatment. Moreover, nicotine also activated the α7nAChR-mediated JAK2/STAT3 signaling pathway in rPSCs. These effects of nicotine on rPSCs were blocked by α-BTX. SIGNIFICANCE: Our finding in this research suggests that nicotine facilitates pancreatic fibrosis by promoting activation of pancreatic stellate cells via α7nAChR-mediated JAK2/STAT3 signaling pathway in rats, partly revealing the mechanism of smoking on chronic pancreatitis.


Assuntos
Janus Quinase 2/metabolismo , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Células Estreladas do Pâncreas/efeitos dos fármacos , Pancreatite Crônica/induzido quimicamente , Fator de Transcrição STAT3/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose , Masculino , Células Estreladas do Pâncreas/enzimologia , Células Estreladas do Pâncreas/patologia , Pancreatite Crônica/enzimologia , Pancreatite Crônica/patologia , Ratos Wistar , Transdução de Sinais , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
6.
Toxicol Lett ; 349: 155-164, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34171359

RESUMO

Cytochrome P450 1A1 (CYP1A1) is a member of a subfamily of enzymes involved in the metabolism of both endogenous and exogenous substrates and the chemical activation of xenobiotics to carcinogenic derivatives. Here, the effects of nicotine, a major psychoactive compound present in cigarette smoke, on CYP1A1 expression and human hepatocellular carcinoma (HepG2) cell proliferation were investigated. Nicotine stimulated CYP1A1 expression via the transcription factors, activator protein 1, nuclear factor-kappa B, and the aryl hydrocarbon receptor (AhR) signaling pathway. Pharmacological inhibition and mutagenesis studies indicated that p38 mitogen-activated protein kinase, as well as RelA (or p65), mediated the upregulation of CYP1A1 of nicotine in HepG2 cells. The antioxidant compound, N-acetyl-cysteine, abrogated nicotine-activated production of reactive oxygen species and inhibited CYP1A1 expression by nicotine. Furthermore, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was inhibited by diphenyleneiodonium (an NADPH oxidase inhibitor). Thus, these results demonstrated that AhR played an important role in nicotine-induced CYP1A1 expression. Additionally, liver hepatocellular carcinoma HepG2 cells treated with nicotine exhibited markedly enhanced proliferation via CYP1A1 expression and Akt activation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/enzimologia , Citocromo P-450 CYP1A1/biossíntese , Neoplasias Hepáticas/enzimologia , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP1A1/genética , Indução Enzimática , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais , Fator de Transcrição AP-1/genética , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Artigo em Inglês | MEDLINE | ID: mdl-34065326

RESUMO

Smoking increases the risk of negative pregnancy and perinatal outcomes and may have negative effects on a child's short and long-term health [...].


Assuntos
Nicotina , Efeitos Tardios da Exposição Pré-Natal , Criança , Feminino , Humanos , Nicotina/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fumar/efeitos adversos , Fumar Tabaco
8.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065933

RESUMO

Neonicotinoid insecticides are nicotine-derived molecules which exert acute neurotoxic effects over the insect central nervous system by activating nicotinic acetylcholine receptors (nAChRs). However, these receptors are also present in the mammalian central and peripheral nervous system, where the effects of neonicotinoids are faintly known. In mammals, cholinergic synapses are crucial for the control of vascular tone, blood pressure and skeletal muscle contraction. We therefore hypothesized that neonicotinoids could affect cholinergic networks in mammals and sought to highlight functional consequences of acute intoxication in rats with sub-lethal concentrations of the highly used acetamiprid (ACE) and clothianidin (CLO). In this view, we characterized their electrophysiological effects on rat α3ß4 nAChRs, knowing that it is predominantly expressed in ganglia of the vegetative nervous system and the adrenal medulla, which initiates catecholamine secretion. Both molecules exhibited a weak agonist effect on α3ß4 receptors. Accordingly, their influence on epinephrine secretion from rat adrenal glands was also weak at 100 µM, but it was stronger at 500 µM. Challenging ACE or CLO together with nicotine (NIC) ended up with paradoxical effects on secretion. In addition, we measured the rat arterial blood pressure (ABP) in vivo by arterial catheterization. As expected, NIC induced a significant increase in ABP. ACE and CLO did not affect the ABP in the same conditions. However, simultaneous exposure of rats to both NIC and ACE/CLO promoted an increase of ABP and induced a biphasic response. Modeling the interaction of ACE or CLO on α3ß4 nAChR is consistent with a binding site located in the agonist pocket of the receptor. We present a transversal experimental approach of mammal intoxication with neonicotinoids at different scales, including in vitro, ex vivo, in vivo and in silico. It paves the way of the acute and chronic toxicity for this class of insecticides on mammalian organisms.


Assuntos
Epinefrina/metabolismo , Inseticidas/toxicidade , Neonicotinoides/toxicidade , Nicotina/toxicidade , Receptores Nicotínicos/metabolismo , Medula Suprarrenal/efeitos dos fármacos , Medula Suprarrenal/metabolismo , Animais , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Agonismo Parcial de Drogas , Gânglios/efeitos dos fármacos , Gânglios/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Guanidinas/toxicidade , Masculino , Ratos , Tiazóis/toxicidade , Testes de Toxicidade Subaguda
9.
Sci Total Environ ; 772: 145475, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-33770885

RESUMO

Electronic cigarettes (E-cigarette) are an alternative for traditional cigarette smokers to quit smoking. Based on the current understanding, electronic cigarettes have rapidly become popular among existing smokers and former non-smokers. However, increasing research at different levels reveals that e-cigarettes are unsafe. This review provides an overview of the toxicology of e-cigarettes based on existing in vivo and in vitro studies and compares their toxicity with that of traditional cigarettes. Moreover, we describe the associated toxicity components in e-cigarettes, as well as the potential mechanism by which e-cigarettes exert toxic effects. As is known to all, the nicotine in traditional cigarettes and e-cigarettes has certain toxicity. Besides, a few studies have shown that propylene glycol and vegetable glycerin mixture and flavoring agents in e-cigarettes also are the key components causing adverse effects in animals or cells. There is insufficient scientific evidence on the toxicity of e-cigarettes due to the lack of standardized research methods, prompting the need to conduct a comprehensive toxicity assessment of e-cigarette toxicity to elucidate the safety issues of e-cigarettes. Eventually, a basis for decision-making on whether people use e-cigarettes will be obtained.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Produtos do Tabaco , Animais , Glicerol , Nicotina/toxicidade , Fumar
10.
Ecotoxicol Environ Saf ; 214: 112057, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33662786

RESUMO

Cigarette smoking has been considered as an independent risk factor for colorectal cancer (CRC) initiation and progression. In this study, we found that cigarette smoking was significantly associated with poor CRC differentiation (P = 0.040). Since studies have indicated that poorly differentiated tumors are more aggressive and metastasize earlier, leading to poorer prognosis; and cancer stem cells (CSCs) are largely responsible for tumor differentiation state, here we observed that the exposure of nicotine-derived 4-(methylnitrosamino)- 1-(3-pyridyl)- 1-butanone (NNK) promoted cell sphere formation and the expression of the stem cell markers, CD44, OCT4, C-MYC and NANOG in HCT8 and DLD-1 cells. Further colony formation assay, CCK-8 assay and tumor-bearing experiment showed that NNK exposure significantly increased the proliferative and growth ability of CRC cells. In mechanism, we found that NNK-activated ERK1/2 played an important role in enrichment of CRC stem cells and the up-regulation of DUSP4, a major negative regulator of ERK1/2. Moreover, DUSP4 up-regulation was essential for maintaining NNK-activated ERK1/2 in an appropriate level, which was an required event for NNK-induced stemness enrichment of CRC cells. Taken together, our findings provided a possible mechanistic insight into cigarette smoking-induced CRC progression.


Assuntos
Nicotina/toxicidade , Nitrosaminas/toxicidade , Carcinógenos , Linhagem Celular Tumoral , Neoplasias Colorretais , Fosfatases de Especificidade Dupla/metabolismo , Células Epiteliais/efeitos dos fármacos , Retroalimentação , Humanos , Receptores de Hialuronatos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno , Fosfatases da Proteína Quinase Ativada por Mitógeno , Células-Tronco Neoplásicas/metabolismo
11.
Oncogene ; 40(11): 1974-1987, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33603170

RESUMO

Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.


Assuntos
Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Janus Quinase 2/genética , Fatores de Transcrição SOXB1/genética , Fator de Transcrição STAT3/genética , Receptor Nicotínico de Acetilcolina alfa7/genética , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Dextrometorfano/farmacologia , Reposicionamento de Medicamentos , Sistemas Eletrônicos de Liberação de Nicotina , Carcinoma de Células Escamosas do Esôfago/induzido quimicamente , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Masculino , Metformina/farmacologia , Camundongos , Nicotina/toxicidade
12.
Toxicol Lett ; 343: 44-55, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33640489

RESUMO

Paternal nicotine exposure can alter phenotypes in future generations. The aim of this study is to explore whether paternal nicotine exposure affects the hepatic repair to chronic injury which leads to hepatic fibrosis in offspring. Our results demonstrate that nicotine down regulates mmu-miR-15b expression via the hyper-methylation on its CpG island shore region in the spermatozoa. This epigenetic modification imprinted in the liver of the offspring. The decreased mmu-miR-15b promotes the expression of Wnt4 and activates the Wnt pathway in the offspring mice liver. The activation of the Wnt pathway improves the activation and proliferation of hepatic stellate cells (HSCs) leading to liver fibrosis. Moreover, the Wnt pathway promotes the activation of the TGF-ß pathway and the two pathways cooperate to promote the transcription of extracellular matrix (ECM) genes. In conclusion, this study found that nicotine promotes hepatic fibrosis in the offspring via the activation of Wnt pathway by imprinting the hyper-methylation of mmu-miR-15b.


Assuntos
Cirrose Hepática/induzido quimicamente , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Exposição Paterna , Animais , Regulação para Baixo , Epigênese Genética , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Wnt4/genética , Proteína Wnt4/metabolismo
13.
Endocrine ; 72(1): 104-115, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33420949

RESUMO

PURPOSE: Maternal nicotine exposure negatively impacts offspring's health and metabolism, leading to obesity and insulin resistance. Here we investigated the pancreatic islet function, glycemic homeostasis, and insulin signaling in adult rat offspring that were nicotine-exposed during breastfeeding. METHODS: For this, lactating Wistar rat dams were divided into two groups: Nicotine (implanted with osmotic minipumps containing 6 mg/Kg, NIC) and Control (saline, CON). Solutions were released from postnatal (PN) day 2-16. At PN110 and PN170, 10 offspring per litter/sex/group were submitted to the oral glucose tolerance test (OGTT). PN180 offspring were killed and glycemia, insulinemia, adiponectinemia, pancreas morphology as well as pancreatic islet protein expression (related to insulin secretion) and skeletal muscle (related to insulin action) were evaluated. Males and females were compared to their respective controls. RESULTS: Adult NIC offspring of both sexes showed glucose intolerance in the OGTT. Despite normoglycemia, NIC males showed hyperinsulinemia while females, although normoinsulinemic, had hyperglycemia. Both sexes showed increased IRI, reduced adiponectin/visceral fat mass ratio and higher ectopic deposition of lipids in the pancreatic tissue adipocytes. In pancreatic islets, NIC males showed lower PDX-1 expression while females had higher PDX-1 and GLUT2 expressions plus lower α2 adrenergic receptor. In the muscle, NIC offspring of both sexes showed reduction of GLUT4 expression; NIC males also had lower insulin receptor and pAKT expressions. CONCLUSIONS: Thus, glycemic homeostasis and peripheral insulin signaling in adult offspring of both sexes are affected by nicotine exposure through the milk, increasing the risk for type 2 diabetes development.


Assuntos
Diabetes Mellitus Tipo 2 , Nicotina , Animais , Feminino , Insulina , Lactação , Masculino , Nicotina/toxicidade , Pâncreas , Ratos , Ratos Wistar
14.
Appetite ; 160: 105115, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33453337

RESUMO

Tobacco smoke during gestation is associated with increased consumption of palatable foods by the offspring in humans and rats. Postpartum relapse is observed in lactating women who quit smoking during pregnancy, putting their children at risk of adverse health outcomes caused by secondhand smoke. Nicotine is transferred through milk and alters the dopaminergic reward system of adult male rats, reducing dopamine action in the nucleus accumbens (NAc) and hypothalamic arcuate nucleus. Here, we evaluated the long-term effects of nicotine-only exposure during lactation on eating behavior, anxiety, locomotion, dopaminergic system, hypothalamic leptin signaling and nicotinic receptor in the adult female rat progeny. Two days after birth (PN2), Wistar rat dams were separated into control and nicotine (Nic) groups for implantation of osmotic minipumps that released respectively saline or 6 mg/kg nicotine. Lactating dams were kept with 6 pups. After weaning (PN21; nicotine withdrawal), only the female offspring were studied. Euthanasia occurred at PN180. Nic females showed hyperphagia, preference for a high-sucrose diet, increased anxiety-like behavior, lower tyrosine hydroxylase (TH), lower dopamine transporter and higher dopamine receptor (Drd2) in NAc; lower Drd1 in prefrontal cortex and lower TH in dorsal striatum (DS). These animals showed changes that can explain their hyperphagia, such as: lower leptin signaling pathway (Leprb, pJAK2, pSTAT3) and Chrna7 expression in hypothalamus. Neonatal nicotine exposure affects the brain reward system of the female progeny differently from males, mainly decreasing dopamine production in NAc and DS. Therefore, Nic females are more susceptible to develop food addiction and obesity.


Assuntos
Dopamina , Lactação , Animais , Comportamento Alimentar , Feminino , Masculino , Nicotina/toxicidade , Ratos , Ratos Wistar
15.
Environ Sci Pollut Res Int ; 28(18): 23287-23300, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33443739

RESUMO

Nicotine is an active pharmacological ingredient in cigarette smoke, which may negatively influence the male reproductive system and fertility. This study aims to investigate the effect of fractionated low-dose radiation (fractionated-LDR) and/or ellagic acid (EA) on nicotine-induced hormonal changes and testicular toxicity in rats. Nicotine was administrated orally (1 mg/kg) for 30 days, afterward, rats were treated with LDR (2 × 0.25 Gy/1-week interval), EA (10 mg/kg, 14 consecutive days p.o.), or a combination of both fractionated-LDR and EA. Rats were sacrificed 24 h after the last dose of treatment, then testes were dissected for histopathology examination, along with some biochemical parameters in serum and testicular tissue were evaluated. Nicotine-induced oxidative stress was evidenced by an increase in testicular thiobarbituric acid reactive substances (TBARS) and a decrease in reduced glutathione (GSH) content. Additionally, the activities of testicular androgenic enzymes were decreased, and the activity of serum lactate dehydrogenase (LDH) was significantly increased. The hormonal changes were verified by a noticeable reduction in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone serum levels. Histological evaluation revealed that the testicular seminiferous tubules structure was distorted. On the contrary, fractionated-LDR plus EA attenuated the negative changes caused by nicotine observed through biochemical and histological findings. Accordingly, the exposure to fractionated-LDR combined with EA may be a promising candidate for treating hormonal changes and testicular toxicity caused by nicotine.


Assuntos
Ácido Elágico , Testículo , Animais , Ácido Elágico/metabolismo , Raios gama , Masculino , Nicotina/toxicidade , Estresse Oxidativo , Ratos , Testículo/metabolismo , Testosterona/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-33435295

RESUMO

Smoking is a well-recognized risk factor for oral mucosal and periodontal diseases. Nicotine is an important component of cigarette smoke. This study aims to investigate the impact of nicotine on the viability and inflammatory mediator production of an oral epithelial cell line in the presence of various inflammatory stimuli. Oral epithelial HSC-2 cells were challenged with nicotine (10-8-10-2 M) for 24 h in the presence or absence of Porphyromonas gingivalis lipopolysaccharide (LPS, 1 µg/mL) or tumor necrosis factor (TNF)-α (10-7 M) for 24 h. The cell proliferation/viability was determined by MTT assay. Gene expression of interleukin (IL)-8, intercellular adhesion molecule (ICAM)-1, and ß-defensin was assayed by qPCR. The production of IL-8 protein and cell surface expression of ICAM-1 was assessed by ELISA and flow cytometry, respectively. Proliferation/viability of HSC-2 cells was unaffected by nicotine at concentrations up to 10-3 M and inhibited at 10-2 M. Nicotine had no significant effect on the basal expression of IL-8, ICAM-1, and ß-defensin. At the same time, it significantly diminished P. gingivalis LPS or the TNF-α-induced expression levels of these factors. Within the limitations of this study, the first evidence was provided in vitro that nicotine probably exerts a suppressive effect on the production of inflammatory mediators and antimicrobial peptides in human oral epithelial cells.


Assuntos
Nicotina , Porphyromonas gingivalis , Células Cultivadas , Células Epiteliais , Humanos , Mediadores da Inflamação , Lipopolissacarídeos/toxicidade , Nicotina/toxicidade , Fator de Necrose Tumoral alfa/genética
17.
Acta Neurol Scand ; 143(2): 121-130, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32866996

RESUMO

Electronic cigarettes are a popular, easily purchased, alternative source of nicotine that is considered safer than conventional tobacco. However, Intentional or accidental exposure to e-liquid substances, mainly nicotine, can lead to serious, potentially fatal toxicity. Emergency and critical care physicians should keep in mind acute intoxication of this poison with a biphasic toxic syndrome. We highlight its potentially fatal outcome and suggest monitoring the adverse effects of nicotine according to a multimodal protocol integrating somatosensory evoked potentials, electroencephalography and neuroimaging data with anamnestic report and toxicological and laboratory data.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Síndromes Neurotóxicas/diagnóstico , Nicotina/toxicidade , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Humanos , Síndromes Neurotóxicas/epidemiologia , Síndromes Neurotóxicas/etiologia , Nicotina/envenenamento , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/etiologia
18.
Am J Physiol Heart Circ Physiol ; 320(1): H133-H143, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33216635

RESUMO

The usage of flavored electronic nicotine delivery systems (ENDS) is popular, specifically in the teen and young adult age-groups. The possible cardiac toxicity of the flavoring aspect of ENDS is largely unknown. Vaping, a form of electronic nicotine delivery, uses "e-liquid" to generate "e-vapor," an aerosolized mixture of nicotine and/or flavors. We report our investigation into the cardiotoxic effects of flavored e-liquids. E-vapors containing flavoring aldehydes such as vanillin and cinnamaldehyde, as indicated by mass spectrometry, were more toxic in HL-1 cardiomyocytes than fruit-flavored e-vapor. Exposure of human induced pluripotent stem cell-derived cardiomyocytes to cinnamaldehyde or vanillin-flavored e-vapor affected the beating frequency and prolonged the field potential duration of these cells more than fruit-flavored e-vapor. In addition, vanillin aldehyde-flavored e-vapor reduced the human ether-à-go-go-related gene (hERG)-encoded potassium current in transfected human embryonic kidney cells. In mice, inhalation exposure to vanillin aldehyde-flavored e-vapor for 10 wk caused increased sympathetic predominance in heart rate variability measurements. In vivo inducible ventricular tachycardia was significantly longer, and in optical mapping, the magnitude of ventricular action potential duration alternans was significantly larger in the vanillin aldehyde-flavored e-vapor-exposed mice than in controls. We conclude that the widely popular flavored ENDS are not harm free, and they have a potential for cardiac harm. More studies are needed to further assess their cardiac safety profile and long-term health effects.NEW & NOTEWORTHY The use of electronic nicotine delivery systems (ENDS) is not harm free. It is not known whether ENDS negatively affect cardiac electrophysiological function. Our study in cell lines and in mice shows that ENDS can compromise cardiac electrophysiology, leading to action potential instability and inducible ventricular arrhythmias. Further investigations are necessary to assess the long-term cardiac safety profile of ENDS products in humans and to better understand how individual components of ENDS affect cardiac toxicity.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Aromatizantes/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Taquicardia Ventricular/induzido quimicamente , Vaping/efeitos adversos , Potenciais de Ação/efeitos dos fármacos , Administração por Inalação , Animais , Cardiotoxicidade , Canal de Potássio ERG1/metabolismo , Feminino , Aromatizantes/administração & dosagem , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo
19.
Exp Mol Pathol ; 118: 104573, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33212125

RESUMO

Epidemiological studies have shown an increased risk of cardiovascular diseases in children born to mothers who smoked during pregnancy. The cardiovascular risk in the offspring associated with in utero nicotine exposure is further exaggerated by maternal obesity. The consumption of electronic cigarettes (e-cigarettes) is alarmingly increasing among adolescents and young adults without the knowledge of their harmful health effects. There has also been a substantial increase in e-cigarette use by women of reproductive age. This study investigates the detrimental effects of gestational exposure of e-cigarette and a high-fat diet (HFD) on neonatal hearts. Time-mated pregnant mice were fed a HFD and exposed to saline or e-cigarette aerosol with 2.4% nicotine from embryonic day 4 (E4) to E20. We demonstrated that in utero exposure of e-cigarettes and HFD from E4 to E20 triggers cardiomyocyte (CM) apoptosis in the offspring at postnatal day1 (PND1), PND3, and PND14. Induction of CM apoptosis following gestational exposure of e-cigarettes and HFD was associated with inactivation of AMP-activated protein kinase (AMPK), increased cardiac oxidative stress coupled with perturbation of cardiac BAX/BCL-2 ratio and activation of caspase 3 at PND 14. Electron microscopy further revealed that left ventricles of pups at PND14 after e-cigarette exposure exhibited apoptotic nuclei, convoluted nuclear membranes, myofibrillar derangement, and enlarged mitochondria occasionally showing signs of crystolysis, indicative of cardiomyopathy and cardiac dysfunction. Our results show profound adverse effects of prenatal exposure of e-cigarette plus HFD in neonatal hearts that may lead to long-term adverse cardiac consequences in the adult.


Assuntos
Apoptose , Dieta Hiperlipídica/efeitos adversos , Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Miócitos Cardíacos/patologia , Nicotina/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Masculino , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Nicotina/análise , Estresse Oxidativo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo
20.
Atherosclerosis ; 317: 1-9, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33321327

RESUMO

BACKGROUND AND AIMS: During the development of atherosclerosis, nicotine activates macrophage inflammation. However, whether nicotine induces macrophage pyroptosis and the underlying mechanisms remain unclear. This study aimed to investigate the role of histone deacetylase 6 (HDAC6) in nicotine-induced macrophage pyroptosis. METHODS: For the in vivo study, nicotine was administered to 8-week-old ApoE-/- mice fed a high-fat diet (HFD) for 12 weeks. TUNEL/CD68 and Caspase-1/CD68 staining was used to assess macrophage pyroptosis in plaque. For the in vitro study, Western blotting, lactic dehydrogenase activity (LDH), coimmunoprecipitation, chromatin immunoprecipitation and immunofluorescence were used to evaluate pyroptosis and related signaling pathway in RAW264.7 cells. RESULTS: A high-fat diet and nicotine upregulated macrophage pyroptosis in atherosclerotic lesions. Nicotine promoted pyroptosis in RAW264.7 cells, as evidenced by increased expression of cleaved Caspase1, NLRP3, IL-1ß, IL-18, and elevated LDH release. Inhibition of HDAC6 suppressed nicotine-induced pyroptosis, which is partly mediated by p65 acetylation and NLRP3 transcription. Silencing p65 or NLRP3 resulted in decreased pyroptosis in RAW264.7 cells. CONCLUSIONS: Nicotine induces macrophage pyroptosis in atherosclerosis through HDAC6/NF-κB/NLRP3 signaling pathway.


Assuntos
Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Animais , Desacetilase 6 de Histona , Inflamassomos , Macrófagos , Camundongos , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Nicotina/toxicidade , Espécies Reativas de Oxigênio
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