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1.
Chemosphere ; 251: 126340, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32135373

RESUMO

Bisphenol A (BPA) exposure during early life may increase risk of childhood obesity, however, prospective evidence of birth cohort is limited and inconclusive. We aimed to explore the associations of maternal and childhood BPA exposure with child adiposity measures, including body mass index, waist circumference and skinfold thickness and waist to height ratio of children at 7 years. 430 mother-child pairs were examined from a population-based prospective cohort in a rural area of East China. BPA concentrations of spot urine samples were quantified in mothers and their children aged 3 and 7 years. Maternal urinary BPA concentration was significantly positively associated with waist circumference in children aged 7 years (ß = 0.508 cm, 95% CI: 0.067, 0.950). These significant associations were not modified by child sex, but they were only observed among girls in sex-stratified analyses. Risk of central obesity related to prenatal BPA exposure was significantly higher in the second and the third tertile than those in the first tertile (odds ratio, OR = 2.510, 95% CI = 1.146, 5.499; OR = 2.584, 95% CI = 1.186, 5.631, respectively; p for trend = 0.022). The present findings suggested that prenatal exposure to BPA may enhance waist circumference of children and thereby increase risk of central obesity in school-age girls.

2.
Int J Hyg Environ Health ; 224: 113427, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31978725

RESUMO

BACKGROUND: Early life exposure to triclosan, an emerging endocrine disrupting chemical, may adversely impact childhood neurodevelopment, but limited epidemiologic studies have examined the associations. OBJECTIVE: We evaluated the associations between prenatal and postnatal triclosan exposure and child neurodevelopment at 3 years. METHODS: The study included 377 mother-child pairs who participated in Sheyang Mini Birth Cohort Study (SMBCS), a longitudinal birth cohort in China. Triclosan concentrations in maternal and 3-year-old child urine samples were quantified using gas chromatography-tandem mass spectrometry (GC-MS/MS). Gesell Developmental Schedules (GDS) were used to assess child neurodevelopment at 3 years of age. Multivariate linear regression models were applied to estimate associations of prenatal and postnatal urinary triclosan concentrations with children's developmental quotients (DQs). RESULTS: Detection frequencies of triclosan in maternal and childhood urine samples were 100% and 99.5%, respectively. The median values of prenatal and postnatal urinary triclosan levels were 0.65 and 0.44 µg/L, respectively. One ln-unit increase of maternal urinary triclosan concentration was associated with increase of DQ scores in motor area of children (regression coefficient, ß = 0.28, 95% confidence interval, CI: 0.03, 0.54; p = 0.03). In sex-stratified analyses, maternal urinary triclosan levels were significantly related to increases in DQ scores in motor area among boys (ß = 0.25, 95%CI: 0.01, 0.50; p = 0.04), while postnatal urinary triclosan concentrations were inversely associated with DQ scores in social area in boys (ß = -0.37, 95%CI: -0.72, -0.03; p = 0.03). CONCLUSIONS: The findings suggested that prenatal triclosan exposure predicted increases in motor scores, while postnatal triclosan exposure was related to reductions in social scores of 3-year-old children. These associations were only observed in boys. The biological mechanisms linking triclosan exposure to neurodevelopment await further studies.

3.
Toxicol Mech Methods ; 30(3): 219-227, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31805805

RESUMO

Flurochloridone (FLC) is a widely used herbicide in developing countries. Although the testes are a target organ for FLC in rats, the adverse effects of FLC on testes have not been fully elucidated. To clarify them, we performed RNA-seq analysis using the testes of FLC-treated rats from our previous subchronic toxicity tests. Unilateral testes of three male rats from solvent control groupand three FLC-treated groups (3 mg/kg, 31.25 mg/kg and 125 mg/kg) were used for RNA extraction. A poly A selection protocol coupled with an Illumina TruSeq RNA-Seq library protocol was used to construct RNA-Seq libraries. Principal component analysis (PCA), differentially expressed gene (DEG) analysis, and hierarchical clustering analysis (HCA) were conducted using R. Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to understand the biological characteristics of the DEGs using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The results indicated that many up-regulated DEGs were enriched in pathways associated with testicular injury, such as mitogen-activated protein kinase (MAPK) signaling, lysosome and focal adhesion. Many down-regulated DEGs were enriched in pathways associated with testicular reproduction function, such as sexual reproduction, spermatogenesis and germ cell development. Moreover, we confirmed the oral no-observed-adverse-effect level (NOAEL) of 3 mg/kg in subchronic toxicity test, because the overall testicular gene expression in 3 mg/kg FLC-treated group was similar to that of the solvent control group. In 31.25 mg/kg and 125 mg/kg groups, DEGs revealed that testicular injury was related to oxidative stress.

4.
Biol Trace Elem Res ; 193(1): 89-99, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30977088

RESUMO

To examine sex-specific associations of neonatal and childhood exposure to eight trace elements with cognitive abilities of school-age children. The association between exposure and effects was assessed among 296 school-age children from a population-based birth cohort study, who had manganese (Mn), cadmium (Cd), and lead (Pb) exposure measured in cord blood and chromium (Cr), manganese, cobalt (Co), copper (Cu), arsenic (As), selenium (Se), cadmium, and lead exposure quantified in spot urine. Cognitive abilities were assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models were performed to analyze associations of intelligence quotient (IQ) with trace element concentrations in cord blood and urinary trace element levels. General linear models were used to evaluate association between exposure fluctuation and children's IQ. Urinary Cd concentrations were negatively associated with full-scale IQ (ß = - 3.469, 95% confidence interval (CI) - 6.291, - 0.647; p = 0.016) and performance IQ (ß = - 4.012, 95% CI - 7.088, - 0.936; p = 0.011) in girls; however, neonatal Cd exposure expressed as Cd concentrations in cord blood was in inverse associations with verbal IQ (ß = - 2.590, 95% CI - 4.570, - 0.609; p = 0.010) only in boys. Positive association between urinary Mn concentrations and performance IQ (ß = 1.305, 95% CI 0.035, 2.575; p = 0.044) of children was observed, especially in girls. In addition, inverse association of urinary Cu concentrations with verbal IQ (ß = - 2.200, 95% CI - 4.360, - 0.039; p = 0.046) was only found in boys. Childhood Cd exposure may adversely affect cognitive abilities, while Mn exposure may beneficially modify cognitive abilities of school-age children, particularly in girls.

5.
Reprod Biol Endocrinol ; 17(1): 64, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387587

RESUMO

BACKGROUND: Fluorochloridone (FLC) is a widely used herbicide, and its target organs are testes and epididymides. The Globally Harmonized System of Classification and Labelling of Chemicals classified FLC as Level 2-possibly cause fertility or fetal damage (no relevant data support). The maximum residue levels of FLC in processed crops have been reviewed in the latest European Food Safety Authority (EFSA) report in 2018. However, the toxic effect of FLC on fertility and early embryonic development is limited, and the health risk assessment of FLC needs further consideration. This study investigated the potential effects of FLC on fertility and early embryonic development in rats. METHODS: One hundred rats of each sex were divided into four groups including three FLC-treated groups at doses of 2 mg/kg, 5 mg/kg and 15 mg/kg, and a vehicle control group (0.5% (w/v) sodium carboxymethyl cellulose). Male and female rats were dosed for 9 and 2 consecutive weeks, intragastrically, prior to cohabitation and lasted throughout the mating period for males and continued until Gestation Day 7 (GD7) for females. Parameters such as weights and coefficients of reproductive organs, epididymal sperm number and motility, indexes of copulation, fecundity and fertility indexes, mating period, estrous cycle, corporalutea number, implantations, live, dead and resorbed fetuses, preimplantation loss rate, and postimplantation loss rate were observed in this study. RESULTS: Obvious toxicity of male reproductive system was found at the dose of 15 mg/kg including decreases in testicular and epididymal weight, also in sperm motility rate. Whereas the increase in sperm abnormality rate was observed. However, no significant effects of FLC were found on lutea count, implantations count, fetuses count and weight, live fetuses count (rate), dead fetuses count (rate), resorbed fetuses count (rate), placentas weight, fetuses gender, preimplantation loss (rate) and postimplantation loss (rate). Furthermore, FLC had no adverse effects on fertility and early embryonic development in rats. CONCLUSION: The no-observable-adverse-effect level (NOAEL) of FLC on fertility and early embryonic development in rats was considered to be 5 mg/kg/day.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Genitália Masculina/efeitos dos fármacos , Herbicidas/toxicidade , Pirrolidinonas/toxicidade , Animais , Feminino , Masculino , Tamanho do Órgão , Ratos , Motilidade Espermática/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/patologia
6.
J Appl Toxicol ; 39(11): 1557-1567, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31368586

RESUMO

The developing brain is uniquely vulnerable to toxic chemical exposures. Studies indicate that neural stem cell (NSC) self-renewal is susceptible to oxidative stress caused by xenobiotics. However, the impact of antioxidants on NSC self-renewal and the potential mechanisms remain elusive. In this study, primary murine neural progenitor cells (mNPCs) from the subventricular zone were used as a research model. In addition, paraquat (PQ) was used to elicit oxidative stress and N-acetylcysteine (NAC) was used as a powerful antioxidant. mNPCs were treated with 80 µm PQ for 24 hours with or without 4 hours of NAC pretreatment. Our results showed that PQ treatment increased intracellular reactive oxygen species production, decreased cell viability and DNA synthesis, and promoted cell apoptosis. Meanwhile, pretreatment with NAC alleviated PQ-induced cytotoxicity in mNPCs. To elucidate the mechanisms further, we found that NAC pretreatment prevented PQ-induced reactive oxygen species production, mitochondrial fragmentation and autophagy in mNPCs. NAC-pretreated cells showed increased anti-apoptotic protein Bcl-2 and decreased pro-apoptotic protein Bax expression. Similarly, NAC pretreatment increased p-mTOR and decreased LC3B-II protein expression. Moreover, NAC decreased mitophagy related mRNA Pink1 and Parkin expression. Taken together, our results suggested that the antioxidant NAC treatment significantly attenuated PQ-induced mNPC self-renewal disruption through decreasing autophagy and salvaging mitochondrial morphology. These findings revealed a potential mechanism for neurological treatment relating to antioxidant and suggested potentially relevant implications for PQ-related neurodegenerative disorders. Thus, our study also provided insight into therapeutic strategies for the neurotoxic effects of oxidative stress-associated toxicants.

7.
Environ Res ; 177: 108590, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31352300

RESUMO

BACKGROUND: Carbamate pesticides exposure have been linked with adverse health effects during developmental period. Based on 377 mother-child pairs from Sheyang Mini Birth Cohort Study, the present study aimed to assess carbofuranphenol exposure of three-year-old children and explore the associations between prenatal or postnatal carbofuranphenol exposures and neurodevelopmental indicators. METHODS: Urinary carbofuranphenol concentrations were measured by gas chromatography-tandem mass spectrometry. Neural developmental quotient (DQ) of children was evaluated using Gesell Developmental Schedules. Generalized linear models were used to examine the associations between carbofuranphenol concentrations and neurodevelopment. RESULTS: Geometric mean, geometric standard deviation, median, inter quartile range of postnatal urinary carbofuranphenol concentrations were 0.653 µg/L, 9.345 µg/L, 0.413 µg/L, 0.150-1.675 µg/L, respectively. Postnatal carbofuranphenol level showed negatively significant trend in language DQ [beta (ß) = -0.121; 95% confidence interval (95% CI): 0.212, -0.031; p value (p) = 0.008] and total average DQ (ß = -0.059, 95% CI: 0.115, -0.003; p = 0.035). Prenatal carbofuranphenol level showed negative correlations with children's adaptive DQ (ß = -0.755; 95% CI: 1.257, -0.254; p = 0.003), social DQ (ß = -0.341; 95% CI: 0.656, -0.027; p = 0.032) and total average DQ (ß = -0.349; 95% CI: 0.693, -0.005; p = 0.047). CONCLUSION: The results of the present study supposed children in agricultural region of China are widely exposed to carbamate pesticides, and both prenatal and postnatal exposure to carbamate pesticides may lead to neurodevelopmental effect.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31212664

RESUMO

Paraquat (PQ) is a toxic non-selective herbicide. To date, the effect of PQ on memory immune response is still unknown. We investigated the impact of PQ on memory immune response. Adult C57BL/6 mice were subcutaneously injected with 2 mg/kg PQ, 20 mg/kg PQ or vehicle control every three days for two weeks. A single injection of keyhole limpet hemocyanin (KLH) at day four after the initial PQ treatment was used to induce a primary immune response; a second KLH challenge was performed at three months post the first KLH immunization to induce a secondary immune response. In steady state, treatment with 20 mg/kg PQ reduced the level of serum total IgG, but not that of IgM; treatment with 20 mg/kg PQ decreased the number of effector and memory lymphocytes, but not naïve or inactivated lymphocytes. During the primary immune response to KLH, treatment with 20 mg/kg PQ did not influence the proliferation of lymphocytes or expression of co-stimulatory molecules. Instead, treatment with 20 mg/kg PQ increased the apoptosis of lymphocytes at late stage, but not early stage of the primary immune response. During the secondary immune response to KLH, treatment with 20 mg/kg PQ reduced the serum anti-KLH IgG and KLH-responsive CD4 T cells and B cells. Moreover, effector or activated lymphocytes were more sensitive to PQ-induced apoptosis in vitro. Treatment with 2 mg/kg PQ did not impact memory immune response to KLH. Thus, treatment with 20 mg/kg PQ increased apoptosis of late stage effector cells to yield less memory cells and thereafter impair memory immune response, providing a novel understanding of the immunotoxicity of PQ.


Assuntos
Adjuvantes Imunológicos/farmacologia , Apoptose/fisiologia , Hemocianinas/farmacologia , Herbicidas/farmacologia , Memória Imunológica/efeitos dos fármacos , Paraquat/farmacologia , Imunidade Adaptativa , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL
9.
Environ Pollut ; 251: 538-546, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108286

RESUMO

Chlorpyrifos (CPF), an organophosphate insecticide, has been linked to adverse neurodevelopmental effects in animal studies. However, little is known about long-term neurotoxicity of early-life CPF exposure in humans. We aimed to evaluate the associations of both prenatal and early childhood CPF exposure with neurodevelopment of children. In this observational study based on Sheyang Mini Birth Cohort, pregnant women were recruited from an agricultural region between June 2009 and January 2010, and their children were followed up from birth to age three. Urinary 3,5,6-Trichloro-2-pyridinol (TCPy), a specific metabolite of CPF, was quantified using large-volume-injection gas chromatography-tandem mass spectrometry. Developmental quotients (DQs) of children in motor, adaptive, language, and social areas were assessed by trained pediatricians. Data from 377 mother-child pairs were used in the current study. Associations between CPF exposure and neurodevelopmental indicators were estimated using generalized linear models with adjustment for potential confounders. The median concentrations of TCPy in maternal and children's urine were 5.39 µg/L and 5.34 µg/L, respectively. No statistically significant association was found between maternal urinary TCPy concentrations and children neurodevelopment. While for postnatal exposure, we found lower motor area DQ score 0.61 [95% confidence interval (CI): -1.13, -0.09; p = 0.02] and social area DQ score 0.55 (95% CI: -1.07, -0.03; p = 0.04) per one-unit increase in the ln-transformed childhood urinary TCPy concentrations. Further stratification by sex indicated that the inverse associations were only observed in boys, but not in girls. Our findings suggest that adverse neurodevelopmental effects were associated with early childhood CPF exposure, but not prenatal exposure. Additional longitudinal studies are needed to replicate these results and to further understand the toxicological mechanisms of CPF.


Assuntos
Comportamento Infantil/efeitos dos fármacos , Clorpirifos/toxicidade , Exposição Ambiental/efeitos adversos , Inseticidas/toxicidade , Sistema Nervoso/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Criança , Pré-Escolar , China , Clorpirifos/urina , Feminino , Humanos , Inseticidas/urina , Estudos Longitudinais , Masculino , Sistema Nervoso/embriologia , Sistema Nervoso/crescimento & desenvolvimento , Gravidez , Efeitos Tardios da Exposição Pré-Natal/urina , Estudos Prospectivos , Piridonas/urina , Fatores Sexuais , Inquéritos e Questionários
10.
Chemosphere ; 228: 204-211, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029966

RESUMO

BACKGROUND: Chlorophenols (CPs), suspected as endocrine disrupting chemicals, exposure during early life may contribute to body size. However, limited human data with inconsistent findings have examined the developmental effects of CPs exposure. OBJECTIVE: To explore associations between prenatal and postnatal CPs exposure and anthropometric parameters in children aged 3 years. METHODS: A subset of 377 mother-child pairs with urinary five CP concentrations were enrolled from a prospective birth cohort. Generalized linear models were conducted to evaluate associations of CPs exposure with children's anthropometric measures. RESULTS: Maternal urinary 2,4,6-trichlorophenol (2,4,6-TCP) concentrations were significantly negatively associated with weight z scores [regression coefficient (ß) = -0.51, 95% confidence interval (CI): -0.96, -0.05; p = 0.01], weight for height z scores (ß = -0.54, 95% CI: -1.02, -0.06; p = 0.01) and body mass index (BMI) z scores (ß = -0.53, 95% CI: -1.03, -0.03; p = 0.01) of children aged 3 years, after adjustment for potential confounders and postnatal CPs exposure. In the sex-stratified analyses, these inverse associations remained among boys, while in girls, positive associations of prenatal 2,4,6-TCP exposure with weight for height z scores and BMI z scores were observed. Postnatal exposure to 2,5-diclorophenol (2,5-DCP) was positively associated with weight z scores (ß = 0.26, 95% CI: 0.02, 0.50; p = 0.04), after controlling for possible confounders and maternal CPs exposure during pregnancy. Considering potential sex-specific effects, these associations were only observed in girls. CONCLUSIONS: Our findings indicate that prenatal 2,4,6-TCP exposure and postnatal 2,5-DCP exposure may have adverse and sex-specific effects on children's physical development.


Assuntos
Pesos e Medidas Corporais , Desenvolvimento Infantil/efeitos dos fármacos , Clorofenóis/farmacologia , Exposição Ambiental/efeitos adversos , Exposição Materna/efeitos adversos , Adulto , Pré-Escolar , Clorofenóis/efeitos adversos , Clorofenóis/urina , Disruptores Endócrinos/efeitos adversos , Feminino , Humanos , Masculino , Gravidez , Estudos Prospectivos
11.
Artigo em Inglês | MEDLINE | ID: mdl-30769872

RESUMO

A ninety-day toxicity and toxicokinetics of flurochloridone (FLC) were studied in male Wistar rats with oral administration at doses of 3 mg/kg and 10 mg/kg respectively, following the previous study. Apparent toxicity to reproductive system of male rats was still observed at the dose of 10 mg/kg, trace amounts of FLC were still detected 24 hours after administration, testicular weight, epididymal weight and serum testosterone were significantly reduced and sperm abnormalities in epididymis were significantly increased. No abnormalities were found in 3 mg/kg group, it indicated that no-observed-adverse-effect level (NOAEL) of FLC in male rats was 3 mg/kg/day, far below the dose of 20 mg/kg/day reported by European Food Safety Authority (EFSA). Therefore, more attention should be paid to this herbicide.


Assuntos
Relação Dose-Resposta a Droga , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Pirrolidinonas/toxicidade , Testículo/efeitos dos fármacos , Administração Oral , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Testes de Toxicidade Subcrônica
12.
Food Chem Toxicol ; 121: 311-325, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30171970

RESUMO

Paraquat (PQ) is an agricultural chemical used worldwide. As a potential neurotoxicant, PQ adversely affects neurogenesis and inhibits proliferation of neural progenitor cells (NPCs). However, the molecular mechanistic insights of PQ exposure on NPCs remains to be determined. Herein, we determine the extent to which Wnt/ß-catenin signaling involved in the inhibition effect of PQ on mouse NPCs from subventricular zone (SVZ). NPCs were treated with different concentrations of PQ (40, 80, and 120 µM). PQ exposure provoked oxidative stress and apoptosis and PQ inhibited cell viability and proliferation in a concentration-dependent manner. Significantly, PQ exposure altered the expression/protein levels of the Wnt pathway genes in NPCs. In addition, PQ reduced cellular ß-catenin, p-GSK-3ß, and cyclin-D1 and increased the radio of Bax/Bcl2. Further, Wnt pathway activation by treatment with LiCl and Wnt1 attenuated PQ-induced inhibition of mNPCs proliferation. Antioxidant (NAC) treatment alleviated the inhibition of PQ-induced Wnt signaling pathway. Overall, our results suggest significant inhibitory effects of PQ on NPCs proliferation via the Wnt/ß-catenin signaling pathway. Interestingly, our results implied that activation of Wnt/ß-catenin signaling pathway attenuated PQ-induced autophagic cell death. Our results therefore bring our understanding of the molecular mechanisms of PQ-induced neurotoxicity.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Herbicidas/toxicidade , Células-Tronco Neurais/efeitos dos fármacos , Paraquat/toxicidade , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ventrículos Laterais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/fisiologia , Estresse Oxidativo , beta Catenina/genética , beta Catenina/metabolismo
13.
Toxicol Lett ; 295: 277-287, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29981920

RESUMO

There are reports of fluorochloridone (FLC)-induced male reproductive toxicity, but the underlying toxicological mechanisms remain unknown. In this study, we looked at how FLC exposure affected the integrity of the blood-testis barrier (BTB) and the Sertoli cell barrier and studied the molecular mechanisms. Male rats received gavage administration of FLC (30 mg/kg/d) for 14 consecutive days with sample collection at the 7th and 14th day; and primary cultured Sertoli cells were treated with 0-10 µM FLC in vitro for 24 h. Our in vivo findings revealed that FLC exposure caused time-dependent testicular injuries, sperm quality decrease as well as adverse changes in BTB integrity, F-actin organization, and expressions of claudin-11 and Arp3. In Sertoli cells isolated from FLC-treated rat testis, Sertoli cell barrier tightness was increased. In Sertoli cells in vitro exposed to FLC, abnormal changes in the barrier permeability were also observed, and the protein expressions of occludin, claudin-11, ZO-1, connexin-43, and Arp3 were significantly decreased in a dose- and time-dependent manner. Furthermore, the FLC-induced adverse changes in Sertoli cell barrier and F-actin were partly alleviated by the induction of Arp3 overexpression. In conclusion, our findings revealed that FLC perturbed BTB/Sertoli cell barrier function through Arp3-mediated F-actin disorganization.


Assuntos
Citoesqueleto de Actina/efeitos dos fármacos , Proteína 3 Relacionada a Actina/metabolismo , Actinas/metabolismo , Poluentes Ocupacionais do Ar/toxicidade , Barreira Hematotesticular/efeitos dos fármacos , Pirrolidinonas/toxicidade , Reprodução/efeitos dos fármacos , Células de Sertoli/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/patologia , Proteína 3 Relacionada a Actina/genética , Animais , Barreira Hematotesticular/metabolismo , Barreira Hematotesticular/patologia , Células Cultivadas , Relação Dose-Resposta a Droga , Masculino , Permeabilidade , Ratos Sprague-Dawley , Medição de Risco , Células de Sertoli/metabolismo , Células de Sertoli/patologia , Transdução de Sinais/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia , Fatores de Tempo
14.
Mol Metab ; 14: 121-129, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884546

RESUMO

OBJECTIVE: Recent studies have suggested a critical role for toll-like receptor 4 (TLR4) in the development of alcoholic liver disease. As TLR4 is widely expressed throughout the body, it is unclear which TLR4-expressing cell types contribute to alcohol-induced liver damage. METHODS: We selectively ablated TLR4 in hepatocytes and myeloid cells. Male mice were fed a liquid diet containing either 5% alcohol or pair-fed a control diet for 4 weeks to examine chronic alcohol intake-induced liver damage and inflammation. In addition, mice were administered a single oral gavage of alcohol to investigate acute alcohol drinking-associated liver injury. RESULTS: We found that selective hepatocyte TLR4 deletion protected mice from chronic alcohol-induced liver injury and fatty liver. This result was in part due to decreased expression of endogenous lipogenic genes and enhanced expression of genes involved in fatty acid oxidation. In addition, mice lacking hepatocyte TLR4 exhibited reduced mRNA expression of inflammatory genes in white adipose tissue. Furthermore, in an acute alcohol binge model, hepatocyte TLR4 deficient mice had significantly decreased plasma alanine transaminase (ALT) levels and attenuated hepatic triglyceride content compared to their alcohol-gavaged control mice. In contrast, deleting TLR4 in myeloid cells did not affect the development of chronic-alcohol induced fatty liver, despite the finding that mice lacking myeloid cell TLR4 had significantly reduced circulating ALT concentrations. CONCLUSIONS: These findings suggest that hepatocyte TLR4 plays an important role in regulating alcohol-induced liver damage and fatty liver disease.


Assuntos
Fígado Gorduroso Alcoólico/genética , Hepatócitos/metabolismo , Receptor 4 Toll-Like/genética , Adipócitos/metabolismo , Alanina Transaminase/sangue , Animais , Fígado Gorduroso Alcoólico/metabolismo , Deleção de Genes , Masculino , Camundongos , Células Mieloides/metabolismo , Receptor 4 Toll-Like/metabolismo , Triglicerídeos/metabolismo
15.
Sci Total Environ ; 625: 1667-1672, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29102186

RESUMO

Exposure to carbamates has been linked with adverse health effects on developmental period. This study aimed to monitor exposure to carbofuranphenol of pregnant women from Sheyang Birth Cohort and investigate associations between prenatal exposure to carbofuranphenol and birth outcomes. During June 2009 to January 2010, 1100 pregnant women living in Sheyang County participated in our study and donated urine sample. Urinary carbofuranphenol concentration was measured by gas chromatography-tandem mass spectrometry. Associations between urinary carbofuranphenol levels and infant birth outcomes were assessed by generalized linear models. Urinary carbofuranphenol concentrations varied from 0.01 to 395.40µg/L (0.01-303.93µg/g for creatinine adjusted), the geometric mean, median and inter quartile range are 0.81µg/L (1.28µg/g cr), 0.80µg/L (1.23µg/g cr) and 0.27-2.20µg/L (0.47-3.11µg/g cr), respectively. No statistically significant association between maternal urinary carbofuranphenol levels and birth outcomes was found in total infants and female infants. In male neonates, carbofuranphenol level was significantly associated with head circumference (b=-0.226; 95% confidence interval: -0.411, -0.041; P=0.01) and ponderal index (b=0.043, 95% CI: 0.004, 0.083; P=0.03). These findings suggested that the pregnant women were generally exposed to carbofuranphenol and prenatal exposure to carbofuranphenol might have adverse effects on fetal development.


Assuntos
Carbofurano/urina , Exposição Materna/efeitos adversos , Fenóis/urina , Adulto , Peso ao Nascer , China , Estudos de Coortes , Feminino , Desenvolvimento Fetal , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Recém-Nascido , Modelos Lineares , Masculino , Gravidez
16.
Toxicol In Vitro ; 47: 228-237, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29248592

RESUMO

Fluorochloridone (FLC) is a widely used pyrrolidone selective herbicide and reported to induce testis injuries in male rats, but the underlying mechanism is largely unknown. In the present study, primary-cultured Sertoli cells were exposed to FLC at the concentration of 0-10.00µM to study the mechanism of FLC-induced apoptosis. The roles of ROS, intracellular calcium, endoplasmic reticulum (ER), and ERK1/2 were looked at with ROS scavenger N-acetyl-cysteine (NAC), intracellular calcium chelator BAPTA-AM, ER calcium depleting agent thapsigargin (TG), and ERK1/2 inhibitor U0126, respectively. FLC induced dose-dependent apoptosis increase as well as the elevation in levels of ROS, intracellular calcium, and ERK1/2 activation. FLC treatment led to constantly increasing apoptotic rates and ERK1/2 activation over time, while inversed-V shaped change tendencies of ROS and intracellular calcium levels were observed. FLC-induced ROS generation disrupted the intracellular calcium homeostasis by attacking the ER, and the elevated intracellular calcium levels resulted in ERK1/2 over-phosphorylation and consequently promoted Sertoli cell apoptosis. Taken together, ROS and intracellular calcium-mediated ERK1/2 activation led to FLC-induced Sertoli cell apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Herbicidas/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pirrolidinonas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Células de Sertoli/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Quelantes de Cálcio/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/metabolismo , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hormese , Masculino , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Células de Sertoli/citologia
17.
Environ Toxicol Pharmacol ; 53: 184-190, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28651161

RESUMO

Connexin 43 (Cx43) is believed to play a role in the mechanisms of toxicity of many chemical species, include cadmium (Cd). In this study, human renal proximal tubule (HK-2) cells were exposed to Cd (1µM, 10 days). Of the 584 protein residues detected using a Phospho Explorer antibody microarray (PEX100), more than half changed their levels of phosphorylation after chronic Cd exposure. Cx43 siRNA attenuated Cd-induced apoptosis and inhibited proliferation, while also attenuating changes in the levels of phosphorylation of many protein residues. According to DAVID Bioinformatics Resources analysis and KEGG PATHWAY database, AKT signal pathway may be the important one. Focusing on the AKT pathway confirmed that Cx43 mediated increased levels of p-PTENSer380/Ser382/Thr383 and decreased levels of p-AKTThr308, p-AKTTyr326, p-ASK1Ser83, and p-p27Thr187, thereby possibly contributing to the Cd-induced apoptosis and inhibited proliferation. These results suggested that AKT pathway was the dominant pathway involved in Cx43-mediated chronic Cd toxicity.


Assuntos
Cádmio/toxicidade , Conexina 43/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Conexina 43/genética , Junções Comunicantes/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , RNA Interferente Pequeno/genética
18.
Am J Cancer Res ; 7(5): 1151-1163, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28560063

RESUMO

BACKGROUND & AIMS: Different immune cells in tumor microenvironment shape tumor progression. CCL20 over-expression was reported as one of the "stemness" trait in TP53 mutated hepatocellular carcinoma (HCC). We aimed to understand the effect of CCL20 on HCC progression. METHODS: In two HCC cohort patients (n=95, n=85 respectively), serum CCL20 concentration was quantified by using ELISA. Expressions of CCL20 and CCR6 in 41 paired HCC tumor and adjacent non-tumor tissues were determined by quantitative Real-Time PCR, confirmed by immunohistochemistry (CCL20) or by flow cytometry analysis (CCR6). Chemotaxis of splenocytes or purified CD19+ B cells to tumor cell-derived CCL20, and angiogenesis of different CD19+ B subtypes responding to tumor cell-derived CCL20 were measured in vitro. H22 murine hepatoma cells were inoculated into immunocompetent or immunodeficient SCID mice, tumor growth and metastasis were monitored after the mice were treated with anti-CCL20 neutralizing antibody or depleted B cells by anti-CD20. RESULTS: Elevation of pretherapy serum CCL20 in HCC patients and increase of CCR6 expression in HCC tissues were closely associated with tumor metastasis and disease poor prognosis. In HCC tissues, CCL20 expression was positively correlated with CCR6 (R2 =0.3134, P=0.0002), and CCR6 was exclusively identified in tumor infiltrated immune cells. CD19+CD5+ B lymphocytes expressed higher CCR6, responded to tumor cell-derived CCL20 and enhanced angiogenesis in vitro. Neutralizing CCL20 activity in immunocompetent mice, not in SCID mice, attenuated tumor incidence, restrained tumor growth and distal metastasis. Tumor angiogenesis was significantly inhibited after CCL20 activity was blockade. In addition, inhibiting B lymphocyte infiltration into tumor mileum also attenuated tumor growth. CONCLUSIONS: Tumor cell-derived CCL20 interacts with CCR6 highly expressed CD19+CD5+ B cells, to promote HCC progression, which might be via enhancing angiogenesis.

19.
Toxicol In Vitro ; 44: 196-205, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28619522

RESUMO

Paraquat (PQ), one of the most widely used fast-acting and non-selective herbicides in the world is believed to act as a neurotoxicant, which increases the risk of developing Parkinson's disease (PD) by selectively impairing dopaminergic neurons. However, the mechanism of PQ on neural progenitor cells remains unclear. As regulator of mRNA expression, miRNA play a crucial role in neurotoxicity. Based on our previous study, we chose 10µM PQ, which induced ROS production and inhibited proliferation but not reduced the cell viability. In this study, we present an integrative analysis of PQ-induced whole transcriptome changes and its regulatory miRNA networks in human neural progenitor cells (hNPCs). Integrated analysis of PQ-induced miRNA-mRNA alteration reveals differential expression of 3972 mRNAs and 52 miRNAs. Based on the GO analysis and pathway analysis of the intersection genes, we found 48 significantly altered GO terms and 22 significant pathways, among which, Wnt signaling being the top-ranked pathway. We verified that the expression of 9 miRNAs and 11 mRNAs related to the Wnt signaling pathway were altered in a dose-dependent manner by qPCR. These results indicate that PQ changes mRNAs and miRNAs expression in hNPCs, leading to the alteration of several neurodevelopment related key biological processes and crucial pathways, especially Wnt signaling pathway. Moreover, it suggests that PQ could downregulate Wnt signaling pathway via miRNA to induce developmental neurotoxicity.


Assuntos
Herbicidas/toxicidade , Células-Tronco Neurais/efeitos dos fármacos , Paraquat/toxicidade , Células Cultivadas , Ontologia Genética , Humanos , MicroRNAs/metabolismo , Células-Tronco Neurais/metabolismo , RNA Mensageiro/metabolismo , Transcriptoma/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
20.
J Appl Toxicol ; 37(8): 933-942, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28176351

RESUMO

Connexins (Cxs), the subunits of gap junction channels, are involved in many physiological processes. Aberrant control of Cxs and gap junction intercellular communication may contribute to many diseases, including the promotion of cancer. Cd exposure is associated with increased risk of human prostate cancer and benign prostatic hyperplasia. The roles of Cxs in the effects of Cd on the prostate have, however, not been reported previously. In this study, the human prostate epithelial cell line RWPE-1 was exposed to Cd. A low dose of Cd stimulated cell proliferation along with a lower degree of gap junction intercellular communication and an elevated level of the protein Cx43. Cd exposure increased the levels of intracellular Ca2+ and phosphorylated Cx43 at the Ser368 site. Knockdown of Cx43 using siRNA blocked Cd-induced proliferation and interfered with the Cd-induced changes in the protein levels of cyclin D1, cyclin B1, p27Kip1 (p27) and p21Waf1/Cip1 (p21). The increase in Cx43 expression induced by Cd was presumably mediated by the androgen receptor, because it was abolished upon treatment with the androgen receptor antagonist, flutamide. Thus, a low dose of Cd promotes cell proliferation in RWPE-1, possibly mediated by Cx43 expression through an effect on cell cycle-associated proteins. Cx43 might be a target for prostatic diseases associated with Cd exposure. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Cádmio/toxicidade , Proliferação de Células/efeitos dos fármacos , Conexina 43/metabolismo , Poluentes Ambientais/toxicidade , Células Epiteliais/efeitos dos fármacos , Próstata/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Técnicas de Cultura de Células , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Conexina 43/genética , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Masculino , Próstata/metabolismo , Próstata/patologia
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