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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.
Phytomedicine ; 68: 153182, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32065953

RESUMO

BACKGROUND: Gegen Qinlian decoction (GQ) is a well-known traditional Chinese medicine that has been clinically proven to be effective in treating ulcerative colitis (UC). However, its therapeutic mechanism has not been fully elucidated. Notch signaling plays an essential role in the regeneration of the intestinal epithelium. PURPOSE: This study was designed to ascertain the mechanism by which GQ participates in the recovery of the colonic mucosa by regulating Notch signaling in acute and chronic UC models. METHODS: Acute and chronic UC mice (C57BL/6) were established with 3 and 2% dextran sulfate sodium (DSS), respectively, and treated with oral administration of GQ. The expression of the Notch target gene Hes1 and the Notch-related proteins RBP-J, MAML and Math1 was analyzed by western blotting. PTEN mRNA levels were detected by qRT-PCR. Mucin production that is characteristic of goblet cells was determined by Alcian blue/periodic acid-Schiff staining and verified by examining MUC2 mRNA levels by qRT-PCR. Cell proliferation was assayed by immunohistochemistry analysis of Ki67. HT-29 and FHC cells and Toll-like receptor 4 knockout (TLR4-/-) acute UC mice were also used in this study. RESULTS: GQ restored the injured colonic mucosa in both acute and chronic UC models. We found that Notch signaling was hyperactive in acute UC mice and hypoactive in chronic UC mice. GQ downregulated Hes1, RBP-J and MAML proteins and augmented goblet cells in the acute UC models, whereas GQ upregulated Hes1, RBP-J and MAML proteins in chronic UC mice, reducing goblet cell differentiation and promoting crypt base columnar (CBC) stem cell proliferation. Hes1 mRNA was suppressed in TLR4-/- UC mice, and GQ treatment reversed this effect. In vitro, GQ reduced Hes1 protein in Notch-activated HT29 and FHC cells but increased Hes1 protein in Notch-inhibited cells. CONCLUSIONS: GQ restored the colonic epithelium by maintaining mucosal homeostasis via bidirectional regulation of Notch signaling in acute/chronic UC models.

3.
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.

4.
Clin Linguist Phon ; : 1-16, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31986915

RESUMO

Congenital amusia is a lifelong impairment in musical ability. Individuals with amusia are found to show reduced sensitivity to emotion recognition in speech prosody and silent facial expressions, implying a possible cross-modal emotion-processing deficit. However, it is not clear whether the observed deficits are primarily confined to socio-emotional contexts, where visual cues (facial expression) often co-occur with auditory cues (emotion prosody) to express intended emotions, or extend to linguistic emotion processing. In order to better understand the underlying deficiency mechanism of emotion processing in individuals with amusia, we examined whether reduced sensitivity to emotional processing extends to the recognition of emotion category and valence of written words in individuals with amusia. Twenty Cantonese speakers with amusia and 17 controls were tested in three experiments: (1) emotion prosody rating, in which participants rated how much each spoken sentence was expressed in each of the four emotions on 7-point rating scales; (2) written word emotion recognition, in which participants recognized the emotion of written emotion words; and (3) written word valence judgment, in which participants judged the valence of written words. Results showed that participants with amusia preformed significantly less accurately than controls in emotion prosody recognition; in contrast, the two groups showed no significant difference in accuracy rates in both written word tasks (emotion recognition and valence judgment). The results indicate that the impairment of individuals with amusia in emotion processing may not generalize to linguistic emotion processing in written words, implying that the emotion deficit is likely to be restricted to socio-emotional contexts in individuals with amusia.

5.
Int Immunopharmacol ; 80: 106137, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31931366

RESUMO

Demethyleneberberine (DMB) is a natural product which has been reported to possess mitochondria-targeting anti-oxidative and anti-inflammatory effect. However, the pharmacological action and molecular mechanism of DMB on autoimmune hepatitis (AIH) have not been explored. In this study, AIH was induced by intravenously injecting Con A (20 mg/kg) in mice for 8 h, and DMB protected against Con A-induced AIH, evidenced by obvious reduction of hepatic enzymes in serum and histological lesion. DMB significantly inhibited the infiltration of CD4+ T cell and Kupffer cell as well as the expression of inflammatory cytokines, such as TNF-α, IL-6, IL-1ß and IFN-γ by ELISA and qPCR analysis. Western blotting analysis illustrated that DMB remarkably inhibited Con A-induced phosphorylation of IKK, IκB, NF-κB p65, ERK, JNK, p38 MAPK and STAT3 induced by Con A. Moreover, DMB also effectively suppressed hepatic oxidative stress with reduction of MDA and elevation of GSH. Taken together, our findings indicated that DMB could prevent Con A-induced AIH by regulating NF-κB and MAPK signaling, suggesting that DMB can serve as a promising candidate for therapy of AIH.

6.
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.

7.
Water Res ; 170: 115280, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759237

RESUMO

In this study, an ammonium nitrogen (NH4+-N) adsorption and regeneration (AAR) was constructed by a zeolite-packed column and NaClO-NaCl regeneration unit, and coupled with an anoxic/aerobic (AO) system to achieve efficient removal of carbon, nitrogen and phosphorus under short hydraulic retention time (HRT) and sludge retention time (SRT). Compared to conventional anaerobic/anoxic/aerobic (AAO) process, the proposed AO-AAR process achieved more efficient and stable nitrogen removal with greatly shorter HRT (5.6 h) and SRT (8 d) at 10.4 °C, with NH4+-N and total nitrogen in the effluent below 1.5 and 8.0 mg/L, respectively. The AO-AAR also obtained efficient phosphorus removal (<0.5 mg/L) by dosing aluminum in aerobic tank. High load and short SRT deteriorated sludge settleability and dewaterability, but enhanced methane production by improving sludge biodegradability. Dosing aluminum made the AO operating module more stable with improved settleability and dewaterability, and further enhanced methane production. Short HRT and SRT also resulted in the thriving of filamentous bacteria (Thiothrix) and heterotrophic nitrifiers (Acinetobacter, Pseudomonas and Rhodobacter) in the AO module, which helped in enhancing denitrification potential and nitrification efficiency under low temperature. Long-term operation showed that exchange capacity and physicochemical properties of zeolite were unchanged under NaClO-NaCl regeneration by introducing the tail gas from aerobic tank into the used regenerant to remove Ca2+ and Mg2+ exchanged from effluent of the AO module. Techno-economic analysis showed that the AO-AAR process is attractive and sustainable for municipal wastewater treatment by significantly improving nitrogen removal, greatly reducing land occupancy, enhancing methane production and achieving efficient reduction of carbon dioxide emission.


Assuntos
Poluentes Ambientais , Águas Residuárias , Adsorção , Amônia , Reatores Biológicos , Nitrogênio , Esgotos , Eliminação de Resíduos Líquidos
8.
J Food Sci ; 85(1): 77-85, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31816098

RESUMO

This study aimed to explore the effect exerted by oxidative stress on apoptosis-inducing factors (AIF)-mediated apoptosis and bovine muscle tenderness during postmortem aging. We investigated the reactive oxygen species (ROS) content, mitochondrial membrane permeability, AIF expression level, nucleus apoptosis, shear force, myofibril fragmentation index, pH, and energy level. According to the results, a rise in ROS content was accompanied by the rise in mitochondrial membrane permeability from 6 to 72 hr. In the meantime, the AIF expression in mitochondria was downregulated significantly within 72 hr. However, samples treated with N-acetylcysteine had significantly lower ROS content (6 to 72 hr) and mitochondrial membrane permeability (12 to 72 hr) than the control group. Moreover, during postmortem aging, the variations in AIF levels in mitochondria were closely associated with meat tenderization and nucleus apoptosis. These findings demonstrated that oxidative stress induced by ROS significantly promoted AIF release from mitochondria by enhancing the mitochondrial membrane permeability, and the released AIF mediated nucleus apoptosis that further enhanced bovine muscle tenderness. Besides, results suggest that in the early stage, the environmental factors (ATP content and pH) significantly decreased (0 to 72 hr), whereas ROS-induced oxidative stress had no significant effect on environmental factors. These observations further suggested that during postmortem aging, the decrease of pH and ATP consumption are required by AIF release. We conclude that ROS-induced oxidative stress and internal environment are vital for meat tenderization through the regulation of AIF-mediated apoptosis pathway. PRACTICAL APPLICATION: ROS-induced oxidative stress contributes to bovine muscle tenderization by promoting cell apoptosis. It is likely to lay a theoretical foundation for developing innovative tenderization techniques by altering the internal oxidation environment of postmortem muscles.

9.
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.

10.
Environ Health Perspect ; 127(12): 127006, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31850806

RESUMO

BACKGROUND: As a ubiquitous environmental pollutant, methylmercury (MeHg) induces toxic effects in the nervous system, one of its main targets. However, the exact mechanisms of its neurotoxicity have not been fully elucidated. Hypoxia-inducible factor-1α (HIF-1α), a transcription factor, plays a crucial role in adaptive and cytoprotective responses in cells and is involved in cell survival, proliferation, apoptosis, inflammation, angiogenesis, glucose metabolism, erythropoiesis, and other physiological activities. OBJECTIVES: The aim of this study was to explore the role of HIF-1α in response to acute MeHg exposure in rat brain and primary cultured astrocytes to improve understanding of the mechanisms of MeHg-induced neurotoxicity and the development of effective neuroprotective strategies. METHODS: Primary rat astrocytes were treated with MeHg (0-10µM) for 0.5h. Cell proliferation and cytotoxicity were assessed with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl diphenyltetrazolium bromide (MTT) assay and a lactate dehydrogenase (LDH) release assay, respectively. Reactive oxygen species (ROS) levels were analyzed to assess the level of oxidative stress using 2',7'-dichlorofluorescin diacetate (DCFH-DA) fluorescence. HIF-1α, and its downstream proteins, glucose transporter 1 (GLUT-1), erythropoietin (EPO), and vascular endothelial growth factor A (VEGF-A) were analyzed by means of Western blotting. Real-time PCR was used to detect the expression of HIF-1α mRNA. Pretreatment with protein synthesis inhibitor (CHX), proteasome inhibitor (MG132), or proline hydroxylase inhibitor (DHB) were applied to explore the possible mechanisms of HIF-1α inhibition by MeHg. To investigate the role of HIF-1α in MeHg-induced neurotoxicity, cobalt chloride (CoCl2), 2-methoxyestradiol (2-MeOE2), small interfering RNA (siRNA) transfection and adenovirus overexpression were used. Pretreatment with N-acetyl-L-cysteine (NAC) and vitamin E (Trolox) were used to investigate the putative role of oxidative stress in MeHg-induced alterations in HIF-1α levels. The expression of HIF-1α and related downstream proteins was detected in adult rat brain exposed to MeHg (0-10mg/kg) for 0.5h in vivo. RESULTS: MeHg caused lower cell proliferation and higher cytotoxicity in primary rat astrocytes in a time- and concentration-dependent manner. In comparison with the control cells, exposure to 10µM MeHg for 0.5h significantly inhibited the expression of astrocytic HIF-1α, and the downstream genes GLUT-1, EPO, and VEGF-A (p<0.05), in the absence of a significant decrease in HIF-1α mRNA levels. When protein synthesis was inhibited by CHX, MeHg promoted the degradation rate of HIF-1α. MG132 and DHB significantly blocked the MeHg-induced decrease in HIF-1α expression (p<0.05). Overexpression of HIF-1α significantly attenuated the decline in MeHg-induced cell proliferation, whereas the inhibition of HIF-1α significantly increased the decline in cell proliferation (p<0.05). NAC and Trolox, two established antioxidants, reversed the MeHg-induced decline in HIF-1α protein levels and the decrease in cell proliferation (p<0.05). MeHg suppressed the expression of HIF-1α and related downstream target proteins in adult rat brain. DISCUSSION: MeHg induced a significant reduction in HIF-1α protein by activating proline hydroxylase (PHD) and the ubiquitin proteasome system (UPS) in primary rat astrocytes. Additionally, ROS scavenging by antioxidants played a neuroprotective role via increasing HIF-1α expression in response to MeHg toxicity. Moreover, we established that up-regulation of HIF-1α might serve to mitigate the acute toxicity of MeHg in astrocytes, affording a novel therapeutic target for future exploration. https://doi.org/10.1289/EHP5139.


Assuntos
Poluentes Ambientais/toxicidade , Compostos de Metilmercúrio/toxicidade , Testes de Toxicidade Aguda , Animais , Astrócitos , Encéfalo , Proliferação de Células , Sobrevivência Celular , Regulação da Expressão Gênica , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , RNA Mensageiro/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Ativação Transcricional , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular
11.
Mucosal Immunol ; 12(6): 1304-1315, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31534167

RESUMO

Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have a greater risk for developing colorectal cancer. STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of epithelial STAT6 in colitis development. Here, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumorigenesis. This could be due to the enhancing-effect of STAT6 on gut permeability and microbiota translocation via interruption of epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Furthermore, neutralization of IL-13, which was primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent way, inhibited epithelial STAT6 activation and improved gut permeability and DSS-induced colitis. Importantly, pharmacological inhibition of STAT6 reduces murine intestinal tumor formation, and tumoral p-STAT6 levels positively correlated to the clinical stage and poor prognosis of human colorectal cancer. Thus, our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity and colitis development, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.

12.
Nano Lett ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31545613

RESUMO

All-solid-state lithium batteries (ASLBs) are promising for the next generation energy storage system with critical safety. Among various candidates, thiophosphate-based electrolytes have shown great promise because of their high ionic conductivity. However, the narrow operation voltage and poor compatibility with high voltage cathode materials impede their application in the development of high energy ASLBs. In this work, we studied the failure mechanism of Li6PS5Cl at high voltage through in situ Raman spectra and investigated the stability with high-voltage LiNi1/3Mn1/3Co1/3O2 (NMC) cathode. With a facile wet chemical approach, we coated a thin layer of amorphous Li0.35La0.5Sr0.05TiO3 (LLSTO) with 15-20 nm at the interface between NMC and Li6PS5Cl. We studied different coating parameters and optimized the coating thickness of the interface layers. Meanwhile, we studied the effect of NMC dimension to the ASLBs performance. We further conducted the first-principles thermodynamic calculations to understand the electrochemical stability between Li6PS5Cl and carbon, NMC, LLSTO, NMC/LLSTO. Attributed to the high stability of Li6PS5Cl with NMC/LLSTO and outstanding ionic conductivity of the LLSTO and Li6PS5Cl, at room temperature, the ASLBs exhibit outstanding capacity of 107 mAh g-1 and keep stable for 850 cycles with a high capacity retention of 91.5% at C/3 and voltage window 2.5-4.0 V (vs Li-In).

13.
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
14.
Toxicology ; 425: 152248, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31330227

RESUMO

Methylmercury (MeHg) is a ubiquitous environmental toxicant that leads to long-lasting neurological deficits in animals and humans. Curcumin, a polyphenol obtained from the rhizome of turmeric, has well-known antioxidant functions. Here, we evaluated curcumin's efficacy in mitigating MeHg-induced cytotoxicity and further investigated the underlying mechanism of this neuroprotection in primary rat astrocytes. Pretreatment with curcumin (2, 5, 10 and 20 µM for 3, 6, 12 or 24 h) protected against MeHg-induced (5 µM for 6 h) cell death in a time and dose-dependent manner. Curcumin (2, 5, 10 or 20 µM) pretreatment for 12 h significantly ameliorated the MeHg-induced astrocyte injury and oxidative stress, as evidenced by morphological alterations, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, and glutathione (GSH) and catalase (CAT) levels. Moreover, curcumin pretreatment increased Nrf2 nuclear translocation and downstream enzyme expression, heme oxygenase-1 (HO-1) and NADPH quinone reductase-1 (NQO1). Knockdown of Nrf2 with siRNA attenuated the protective effect of curcumin against MeHg-induced cell death. However, both the pan-protein kinase C (PKC) inhibitor, Ro 31-8220, and the selective PKCδ inhibitor, rottlerin, failed to suppress the curcumin-activated Nrf2/Antioxidant Response Element(ARE) pathway and attenuate the protection exerted by curcumin. Taken together, these findings confirm that curcumin protects against MeHg-induced neurotoxicity by activating the Nrf2/ARE pathway and this protection is independent of PKCδ activation. More studies are needed to understand the mechanisms of curcumin cytoprotection.

15.
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.

16.
J Chromatogr A ; 1602: 64-73, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31182308

RESUMO

Flame retardants have evoked public concerns owing to their extensive usage in consumer products and potential adverse effects on human health. In this study, a rapid and sensitive solid-phase extraction-ultra-high-performance liquid chromatography-tandem mass spectrometry (SPE-UPLC-MS/MS) method was developed to determine hexabromocyclododecane (HBCD), tetrabromobisphenol-A (TBBPA), six bromophenols (BPs), and nine organophosphate flame retardants (OPFRs) in water. Because of the differences in elution conditions and ionization modes for group 1 (HBCD, TBBPA, and the BPs) and group 2 (OPFRs), we had to run them twice under the different conditions to analyse group 1 and group 2 using UPLC-MS/MS. The method detection limits were 0.1-2.5 ng/L, linearity range was 0.1-100.0 ng/L for group 1 (HBCD, TBBPA, and the BPs). The method detection limit was 0.10 ng/L, and the linearity range was 0.25-250 ng/L for the OPFRs. First, the pH values of the water samples were adjusted to the range of 2-3. Then, the acidified water samples were extracted by hydrophilic-lipophilic-balance solid phase extraction (HLB-SPE) cartridges, which were eluted with 12 mL of acetonitrile. Finally, the recoveries of HBCD, TBBPA, and the BPs were 76.2-98.1%, and the relative standard deviations (RSDs, n = 5) were 2.0-28.5%. Regarding the OPFRs, the recoveries were 72.4-110.3%, and the RSDs were 0.6-6.9%. The stability experiment showed that the concentration differences were less than 15%, meeting the requirement for quality control samples. This proposed method was successfully applied to surface water, ground water, raw water, finished water, tap water, and bottled water samples.


Assuntos
Técnicas de Química Analítica/métodos , Cromatografia Líquida de Alta Pressão , Retardadores de Chama/isolamento & purificação , Extração em Fase Sólida , Espectrometria de Massas em Tandem , Poluentes Químicos da Água/isolamento & purificação , Retardadores de Chama/análise , Limite de Detecção , Água , Poluentes Químicos da Água/análise
17.
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
18.
Mol Pharm ; 16(7): 3133-3144, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31198046

RESUMO

The clinical translation of methotrexate (MTX) is limited because of low aqueous solubility, poor bioavailability, low uptake efficiency, and toxicity concerns. Herein, dual-acting MTX (not only targeting folate receptors but also killing cells via inhibition of intracellular folate metabolism) and hyaluronic acid (HA, targeting CD44 receptors) were selected to be covalently linked by the redox-responsive disulfide bond. The synthesized prodrug (HA-SS-MTX) as a molecular structural motif could self-assemble into simple yet multifunctional nanoparticles (HA-SS-MTX NPs) in aqueous solution. The HA-SS-MTX NPs displayed an average diameter of ∼110 nm with a uniformly spherical shape and maintained stability in different physiological media. Moreover, the HA-SS-MTX NPs could exhibit a sharp redox-dependent response for rapid structure disassembly and sequential MTX release compared to the redox-irresponsive group (HA-ADH-MTX NPs). Furthermore, the results of confocal microscopy and flow cytometry verified that the nanosystems were selectively uptaken by cancer cells via folate and CD44 receptor-mediated internalization through the dual-active targeting mechanism. In addition, HA-SS-MTX NPs could accumulate within tumor sites for a longer period. Notably, in vitro and in vivo antitumor results demonstrated that HA-SS-MTX NPs significantly promoted the death of cancer cells and enhanced the inhibition of tumor growth while reducing the toxicity as compared to MTX and HA-ADH-MTX NPs. Therefore, the smart HA-SS-MTX NPs as the simple and efficient platform have great potential in tumor-targeting drug delivery and therapy.

19.
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
20.
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
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