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Chen T.,University of Maryland, Baltimore | Tompkins L.M.,University of Maryland, Baltimore | Li L.,University of Maryland, Baltimore | Li H.,University of Maryland, Baltimore | And 3 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

The constitutive androstane receptor (CAR) is constitutively activated in immortalized cell lines independent of xenobiotic stimuli. This feature of CAR has limited its use as a sensor for xenobiotic-induced expression of drug-metabolizing enzymes. Recent reports, however, reveal that a splicing variant of human CAR (hCAR3), which contains an insertion of five amino acids (APYLT), exhibits low basal but xenobiotic-inducible activities in cell-based reporter assays. Nonetheless, the underlying mechanisms of this functional shift are not well understood. We have now generated chimeric constructs containing various residues of the five amino acids of hCAR3 and examined their response to typical hCAR activators. Our results showed that the retention of alanine (hCAR1+A) alone is sufficient to confer the constitutively activated hCAR1 to the xenobiotic-sensitive hCAR3. It is noteworthy that hCAR1+A was significantly activated by a series of known hCAR activators, and displayed activation superior to that of hCAR3. Moreover, intracellular localization assays revealed that hCAR1+A exhibits nuclear accumulation upon 6-(4-chlorophenyl) imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime (CITCO) treatment in COS1 cells, which differs from the spontaneous nuclear distribution of hCAR1 and the nontranslocatable hCAR3. Mammalian two-hybrid and glutathione S-transferase pulldown assays further demonstrated that hCAR1+A interacts with the coactivator SRC-1 and GRIP-1 at low level before activation, while at significantly enhanced level in the presence of CITCO. Thus, the alanine residue in the insertion of hCAR3 seems in charge of the xenobiotic response of hCAR3 through direct and indirect mechanisms. Activation of hCAR1+A may represent a sensitive avenue for the identification of hCAR activators. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.


Yu W.L.,National Institute for Occupational Health and Poison Control
Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases | Year: 2011

To investigate occupational health status of female workers in pharmaceutical industries and to propose the protective measures for the occupational health. A total of 2816 female workers from 19 pharmaceutical industries in Shandong and Gansu provinces were investigated by a questionnaire. 73.1% of female workers exposed to occupational hazards, mainly to toxic chemicals. 63.2% of them suffered from dysmenorrhea; 38.5% of them have reproductive system diseases, i.e. mammary gland hyperplasia (44.1%), cervical erosion (26.5%), uterine annex inflammation (24.2%); 17.1% of them suffered from accidental work injuries; 34.7% of them complained about low back pain, and 29.7% of them perceived hearing loss. 94.9% of female workers hoped to get the occupational health and labor protection knowledge and skills. Strengthening the supervision of labor protection for female workers, including technical measures occupational hazards control and health-related knowledge, and improving the occupational health status of female workers should be conducted.


Bin P.,National Institute for Occupational Health and Poison Control
Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases | Year: 2011

To investigate the association between the polymorphisms of metabolic genes and telomere length of genomic DNA in peripheral blood of workers exposed to polycyclic aromatic hydrocarbons (PAHs). One hundred and forty five coke-oven workers exposed to PAHs and sixty eight non-exposed medical staffs were recruited in this study. Urinary 1-hydroxypyrene (1-OHP) served as the internal exposure dose of PAHs for all subjects. Relative telomere length (RTL) of genomic DNA in peripheral blood was used as telomere length and measured by real-time PCR. Polymorphisms of metabolic genes were detected by PCR-based methods. Compared with control group, the exposure group shown a decreased RTL (1.10 +/- 0.75 vs 1.43 +/- 1.06, P < 0.05). In the coke-oven workers, after adjusting the sex, age, cigarettes per day and urinary 1-OHP, RTL (1.25 +/- 0.93) of workers with CT genotype at the CYP1A1 3801 T > C was significantly longer than that (0.93 +/- 0.51) of workers with TT genotype (P < 0.05). RTL (0.90 +/- 0.58) of individuals with the Tyr/His genotype at mEH Tyr113His was significantly shorter than that (1.24 +/- 0.90) of individuals with the Tyr/Tyr genotype (P < 0.05). RTL (1.02 +/- 0.64) of individuals with the CT genotype at AHR rs10250822 was significantly shorter than that (1.36 +/- 1.14) of individuals with the CC genotype (P < 0.05). RTL (0.93 +/- 0.54) of individuals with the AT genotype at AHR rs10247158 was significantly shorter than that (1.19 +/- 0.84) of individuals with the AA genotype (P < 0.05). The results of present study suggested that PAHs exposure could induce the shorted RTL, CYP1A1, mEH, AHR polymorphisms might influence the change of telomere length of genomic DNA in peripheral blood of workers exposed to PAHs.


Guo X.,National Institute for Occupational Health and Poison Control
Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases | Year: 2012

To evaluate the therapeutic effects of epidermal growth factor (EGF) combined with plasma cryoprecipitate (CRYO) on the corneal injury induced by paraquat (PQ). According to the "Toxicological test methods of pesticides for registration" (GB 15670-1995), the conjunctival sacs of 18 health New Zealand rabbits were exposed to 100 μl 20% PQ, which were randomly divided into EGF, CRYO and EGF plus CRYO groups. The routine treatments (normal saline washing and antibiotic eyedrops) were administrated to the injured eyes of 3 groups, at the same time the left eyes of 3 groups were treated with EGF, CRYO and EGF plus CRYO, respectively. The injury of conjunctival, iris and corneal, fluorescent stranded and pathology changes of corneal were observed. The injury score was calculated and the recovery time of corneal injury was recorded. The recovery time of corneal injury in EGF and EGF plus CRYO groups were 19.50 ± 3.08 and 18.67 ± 2.73 days, respectively which were significantly lower than those (27.33 ± 2.58 and 26.83 ± 3.13 days) in corresponding routine treatment controls (P < 0.05). EGF and EGF plus CRYO could be used to treat the corneal injury induced by paraquat.


Zang D.,National Institute for Occupational Health and Poison Control
Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] | Year: 2012

To detect the cytokines levels in serums of patients with trichloroethylene-induced hypersensitivity dermatitis and explore the effect biomarkers associated with this disease. Twenty-two patients with TCE-induced hypersensitivity dermatitis, twenty-two healthy TCE-exposed workers from the same workshops with patients and twenty-two comparable unexposed controls were recruited in this study. Eight cytokines in serums from all subjects were detected using Liquid Suspended Biochip; the correlation among the eight cytokines including interleukin (IL)-1β (IL-1β), IL-5, IL-8, IL-10, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1β (MIP-1β) and the correlation between IL-5 and eosinophil count were analyzed. The medians of levels of IL-1β, IFN-γ, IL-5, IL-10, MCP-1, MIP-1β, IL-8 among patients were 0.15, 80.13, 2.95, 6.45, 83.83, 1057.90, 440.22 pg/ml, respectively, which were higher than those among the TCE-exposed workers (0.09, 16.93, 0.11, 0.07, 28.75, 241.07, 28.26 pg/ml, respectively, all P values < 0.01) and unexposed controls (0.09, 3.14, 0.11, 0.07, 25.27, 209.64, 207.34 pg/ml, respectively, all P values < 0.01). The median of level of TNF-α among the patients was 13.26 pg/ml, which was significantly higher than that among TCE-exposed workers (4.87 pg/ml, P < 0.01) but not among unexposed controls; the median of level of IL-5 among the TCE-exposed workers was 0.11 pg/ml, which was significantly higher than that among the unexposed controls (0.11 pg/ml, P < 0.01). The median of levels of IL-8 among the unexposed controls was 207.34 pg/ml, which was significantly higher than that among the TCE-exposed workers (28.26 pg/ml, P < 0.01). In case group, except for correlation of TNF-α and IFN-γ, TNF-α and IL-5, the significant positive correlations were found among any two cytokines (r(IL-1β,IFN-γ) = 0.500, r(IL-1β,TNF-α) = 0.348, r(IL-1β,MCP-1) = 0.537, r(IL-1β,MIP-1β) = 0.477, r(IL-1β,IL-8) = 0.466, r(IL-1β,IL-5) = 0.610, r(IL-1β,IL-10) = 0.626, r(IFN-γ,MCP-1) = 0.460, r(IFN-γ,MIP-1β) = 0.491, r(IFN-γ,IL-8) = 0.322, r(IFN-γ,IL-5) = 0.532, r(IFN-γ,IL-10) = 0.511, r(TNF-α,MCP-1) = 0.325, r(TNF-α,MIP-1β) = 0.283, r(TNF-α,IL-8) = 0.430, r(TNF-α,IL-10) = 0.271, r(MCP-1,MIP-1β) = 0.659, r(MCP-1,IL-8) = 0.526, r(MCP-1,IL-5) = 0.504, r(MCP-1,IL-10) = 0.614, r(MIP-1β,IL-8) = 0.601, r(MIP-1β,IL-5) = 0.451, r(MIP-1β,IL-10) = 0.579, r(IL-8,IL-5) = 0.255, r(IL-8,IL-10) = 0.403, r(IL-5,IL-10) = 0.798, all P values < 0.05). The median of level of IL-5 among the patients with high eosinophils counts was 8.92 pg/ml, which was significantly higher than that among the patients with low eosinophils counts (1.04 pg/ml, P < 0.05). The abnormal production of IL-1β, IFN-γ, TNF-α, IL-8, MCP-1, MIP-1β, IL-5 and IL-10 was related with the pathogenesis of hypersensitivity dermatitis induced by TCE. These cytokines could be used as referential indexes in the early health surveillance and clinic disease treatment.


Xiao J.W.,National Institute for Occupational Health and Poison Control
Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] | Year: 2011

To explore effects of acrylamide on synaptic plasticity of rat neuron and its mechanisms. 24 Wistar rats were divided into control and test groups randomly, 12 rats in each group. The ratio of male and female in each group was 1:1. Acrylamide (30 mg/kg) was administered to rats by intraperitoneal injection in test group and normal saline (5 g/kg) was given to rats in control group. The neurobehavioral and pathologic changes of heart, liver, spleen, lung and kidney were observed. Changes of parameters in synapse were recorded by electron microscope. As an important target of synapse, change of Synapsin I was measured by immunohistochemical method. Compared with the control group (male: 1.00 ± 0.00; female: 1.00 ± 0.00), the gait score was increased significantly in ACR treated group (male: 2.50 ± 0.55, t = -7.24, P < 0.01; female: 3.17 ± 0.41, t = -12.19, P < 0.01). No obvious pathological changes of heart, liver, spleen, lung and kidney were found in all rats. Compared with the control group (male: (0.41 ± 0.09) μm; female: (0.40 ± 0.06) μm), the length of active zone of synapse was decreased significantly in ACR treated group (male: (0.15 ± 0.05) μm, t = 6.59, P < 0.05; female: (0.14 ± 0.07) μm, t = 7.26, P < 0.05). The width and postsynaptic density of synapse in ACR treated group had no significant difference with control group. The location of Synapsin I of control group and ACR treated group was both in gray matter of spinal dorsal horn. Compared with the control group (male: 195.40 ± 12.30; female: 195.19 ± 6.71), the concentration of Synapsin I was decreased significantly in ACR treated group (male: 60.90 ± 29.19, t = 10.40, P < 0.05; female: 67.56 ± 20.23, t = 15.65, P < 0.05). Neuronal synaptic plasticity was found in damage of nervous system induced by acrylamide in rats, which might be associated with the expression of Synapsin I.


Yang H.,National Institute for Occupational Health and Poison Control | Dong H.,National Institute for Occupational Health and Poison Control | Dai Y.,National Institute for Occupational Health and Poison Control | Zheng Y.,National Institute for Occupational Health and Poison Control
Respirology | Year: 2011

Background and objective: Polymorphisms in the IL13 gene have been reported to be associated with susceptibility to asthma. However, a number of studies have shown inconsistent results. A meta-analysis was performed to investigate whether polymorphisms in the IL13 gene were associated with the risk of asthma. Methods: Searches were performed of the Medline and Chinese National Knowledge Infrastructure (CNKI) databases, covering all papers published up to 31 August 2010. A recently proposed logistic regression-based method for meta-analysis of case-control genetic association studies was used to analyse pooled data. All statistical analyses were performed using stata version 10.0 software. Results: The IL13 C-1112T and G+2044A polymorphisms were investigated in 10 and 14 studies, respectively. The summary estimates suggested that both these polymorphisms were associated with susceptibility to asthma. Carriers of the IL13 -1112T allele had a 38.9% increased risk of asthma compared with homozygotes (-1112CC) (odds ratio (OR) 1.389, 95% confidence interval (CI): 1.103-1.749). Carriers of the IL13+2044A allele had a 40.0% increased risk of asthma compared with homozygotes (+2044GG) (OR 1.400, 95% CI: 1.137-1.724). In a subgroup analysis by ethnicity, the IL13 -1112T allele was associated with an increased risk of asthma among Caucasians (OR 1.629, 95% CI: 1.255-2.113) but not among Asians, and the IL13+2044A allele was associated with an increased risk of asthma among Asians (OR 1.436, 95% CI: 1.101-1.873) but not among Caucasians. Conclusions: This meta-analysis indicated that the IL13 C-1112T and G+2044A polymorphisms predispose to asthma. Further studies, including pooling of individual data to facilitate evaluation of gene-gene and gene-environment interactions between these IL13 gene polymorphisms and asthma susceptibility, are recommended. A meta-analysis showed that both the IL13 C-1112T and G+2044A polymorphisms were associated with an increased risk of asthma. The C-1112T polymorphism was associated with an increased risk of asthma in Caucasian but not Asian populations. The G+2044A polymorphism was associated with an increased risk of asthma in Asian but not Caucasian populations. © 2011 Asian Pacific Society of Respirology.


Zhao L.,National Institute for Occupational Health and Poison Control
Wei sheng yan jiu = Journal of hygiene research | Year: 2010

Myelin protein zero (P0) is the major structural element of peripheral myelin that plays a very important role in maintaining the stability of myelin. Recently, many researches find that the structure, distribution and function of P0 have transcended people's early understanding. In this review, the basic features of structure, distribution and function of P0 and its current research advances in neurotoxicology are simply summarized.


Yu T.,National Institute for Occupational Health and Poison Control
Wei sheng yan jiu = Journal of hygiene research | Year: 2010

To explore effects of lead exposure on the concentrations of serum male sex hormone in male workers. Blood sample of 153 male workers occupationally exposed to lead and 47 male worker without exposure history were collected, of which the concentrations of testosterone (T), luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2) and inhibin B were measured by ELISA. The results showed that concentration of T in exposure group were significantly lower (P < 0.05) compared with non-exposured group. In contrast, serum inhibin B concentration were significantly increased (P < 0.05) than control group. The main influencing factors changing serum T are effect of lead and age, meanwhile positive effects of lead were also observed on serum inhibin B increased by Logistic analysis. The results suggest that the lead exposure may alter the male sexual hormone, which might injure the endocrine function and Sertoli cells.


Huang C.,National Institute for Occupational Health and Poison Control
Wei sheng yan jiu = Journal of hygiene research | Year: 2010

To establish a HPLC-MS/MS method for the simultaneous determination of 4 monohydroxy metabolites of polycyclic aromatic hydrocarbons (PAHs) in urine, including 1-naphthol, 2-naphthol, 3-phenanthrol and 1-pyrenol). After being treated by enzymatic hydrolysis, urine samples were purified by liquid-liquid extraction, evaporated under nitrogen to constant volume and examined by HPLC-MS/MS. Target compounds were quantified by internal standard calibration curve. The reproducibility and precision were improved by internal standard calibration. The recovery of four target compounds were in the range of 89.7%-103.0%. The precision of intra- and inter-batch was 1.0%-4.2% and 1.8%-5.8% respectively. The limits of quantification was 0.2 microg/L for 1-naphthol, 2-naphthol and 1-pyrenol and the limits of quantification was 0.1 microg/L for 3-phenanthrol. The sensitivity, reproducibility and recovery of HPLC-MS/MS method were good for the analysis of 1-naphthol, 2-naphthol, 3-phenanthrol and 1-pyrenol in the urine of people on occupational and nonoccupational exposure to PAHs.

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