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1.
Artigo em Inglês | MEDLINE | ID: mdl-31378638

RESUMO

DINCH (cyclohexane-1,2-dicarboxylic acid-diisononyl ester) is a phthalate plasticizer substitute introduced into the market in 2002. It is increasingly used especially in the production of toys, food contact materials and medical devices. In this measurement campaign on 24-h urine samples of young adults (20-29 years) from the German Environmental Specimen Bank (ESB) collected in 2010, 2011, 2013, 2015 and 2017 (in total 300 samples, 60 samples/year) we analyzed three specific, oxidized DINCH metabolites (OH-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester; cx-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(carboxy-isooctyl) ester, oxo-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(oxo-isononyl) ester). We merged these data with earlier data of the ESB from the years 1999-2012 and are now able to report levels and time trends of internal DINCH exposure from 1999 to 2017. After first detections of the major oxidized DINCH metabolite OH-MINCH in 2006 (6.7%) detection rates rapidly increased to 43.3% in 2009, 80% in 2010 and 98.3% in 2011 and 2012. From the year 2013 on we could detect OH-MINCH in every urine sample analyzed. The median concentrations of OH-MINCH rapidly increased from 0.15 µg/L in 2010 to twice the concentration in 2011 (0.31 µg/L) with further increases in 2013 (0.37 µg/L), 2015 (0.59 µg/L) and 2017 (0.70 µg/L). Similar increases, albeit at lower detection rates and concentration levels, could be observed for cx-MINCH and oxo-MINCH. All metabolites strongly correlate with each other. For the ESB study population, DINCH exposures are still far below health based guidance values such as the German Human Biomonitoring Value (HBM-I; 4,500 µg/L for the sum of OH-MINCH and cx-MINCH) or the tolerable daily intake (TDI) of EFSA (1 mg/kg bw/d). The median daily DINCH intake (DI) calculated for 2017 was 0.23 µg/kg bw/d, thus 4,310-times lower than the TDI. The maximum DI calculated for one individual in 2012 (42.60 µg/kg bw/d) was a factor of more than 20 below the TDI. The ongoing increase in DINCH exposure needs to be closely monitored in the future, including populations with potentially higher exposures such as children. This close monitoring will enable timely exposure and risk reduction measures if exposures reached critical levels, or if new toxicological data lead to lower health based guidance values. DINCH belongs to the European Human Biomonitoring Initiative (HBM4EU) priority substances for which policy relevant questions still have to be answered.

2.
PLoS One ; 14(7): e0219087, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31276523

RESUMO

BACKGROUND: We compared psychomotor vigilance in female shift workers of the Bergmannsheil University Hospital in Bochum, Germany (N = 74, 94% nurses) after day and night shifts. METHODS: Participants performed a 3-minute Psychomotor Vigilance Task (PVT) test bout at the end of two consecutive day and three consecutive night shifts, respectively. Psychomotor vigilance was analyzed with respect to mean reaction time, percentage of lapses and false starts, and throughput as an overall performance score, combining reaction time and error frequencies. We also determined the reaction time coefficient of variation (RTCV) to assess relative reaction time variability after day and night shifts. Further, we examined the influence of shift type (night vs. day) by mixed linear models with associated 95% confidence intervals (CI), adjusted for age, chronotype, study day, season, and the presence of obstructive sleep apnea (OSA). RESULTS: At the end of a night shift, reaction times were increased (ß = 7.64; 95% CI 0.94; 14.35) and the number of lapses higher compared to day shifts (exp(ß) = 1.55; 95% CI 1.16-2.08). By contrast, we did not observe differences in the number of false starts between day and night shifts. Throughput was reduced after night shifts (ß = -15.52; 95% CI -27.49; -3.46). Reaction times improved across consecutive day and night shifts, whereas the frequency of lapses decreased after the third night. RTCV remained unaffected by both, night shifts and consecutive shift blocks. DISCUSSION: Our results add to the growing body of literature demonstrating that night-shift work is associated with decreased psychomotor vigilance. As the analysis of RTCV suggests, performance deficits may selectively be driven by few slow reactions at the lower end of the reaction time distribution function. Comparing intra-individual PVT-performances over three consecutive night and two consecutive day shifts, we observed performance improvements after the third night shift. Although a training effect cannot be ruled out, this finding may suggest better adaptation to the night schedule if avoiding fast-changing shift schedules.

3.
Lung ; 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31267149

RESUMO

PURPOSE: Malignant pleural mesothelioma (MPM) is a highly lethal cancer caused by exposure to asbestos. Currently, the diagnosis is a challenge, carried out by means of invasive methods of limited sensitivity. This is a case-control study to evaluate the individual and combined performance of minimally invasive biomarkers for the diagnosis of MPM. METHOD: A study of 166 incident cases of MPM and 378 population controls of Mestizo-Mexican ethnicity was conducted. Mesothelin, calretinin, and megakaryocyte potentiating factor (MPF) were quantified in plasma by ELISA. The samples were collected from 2011 to 2016. RESULTS: Based on ROC analysis and a preset specificity of 95%, the combination of the three biomarkers reached an AUC of 0.944 and a sensitivity of 82% in men. In women, an AUC of 0.937 and a sensitivity of 87% were reached. In nonconditional logistic regression models, the adjusted ORs in men were 7.92 (95% CI 3.02-20.78) for mesothelin, 20.44 (95% CI 8.90-46.94) for calretinin, and 4.37 (95% CI 1.60-11.94) for MPF. The ORs for women were 28.89 (95% CI 7.32-113.99), 17.89 (95% CI 3.93-81.49), and 2.77 (95% CI 0.47-16.21), respectively. CONCLUSIONS: To our knowledge, this is the first study evaluating a combination of mesothelin, calretinin, and MPF, and demonstrating a sex effect for calretinin. The biomarker panel showed a good performance in a Mestizo-Mexican population, with high sensitivity and specificity for the diagnosis of MPM.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31346764

RESUMO

PURPOSE: Due to a potential exposure to several definite or probable carcinogens, the IARC classified manufacturing of art glass, glass containers, and pressed ware as probably carcinogenic to humans in 1993 (Group 2A). Purpose of this study was to update the evidence from recently published scientific reports. METHODS: We searched for peer-reviewed articles published between 1993 and 2018 and combined result in terms of a meta-analysis. Overall, we considered twelve articles for a meta-analytic approach published after 1992. RESULTS: From a meta-analysis we derived a standardized incidence ratio (mSIR) and a standardized mortality ratio (mSMR) for lung cancer in men of 1.25 (95% CI 0.97-1.59) and 1.41 (95% CI 1.11-1.77), respectively. The estimated odds ratio (mOR) from five case-control studies was 1.25 (95% CI 0.90-1.73). Associated with an employment in glass factories, the estimated mSMR for larynx cancer was 2.38 (95% CI 1.23-4.16) based on two cohort studies; the mOR from four case-control studies was 1.35 (95% CI 0.73-2.52). Reports on elevated cancer risks at other sites were not consistent. CONCLUSIONS: Only few studies assessed cancer risk solely in glass workers. Gained evidence from more recent reports supports the IARC rating from 1993. Our combined results add limited evidence to a moderately elevated risk for cancer of the airways.

5.
Mol Pharmacol ; 96(2): 138-147, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31189668

RESUMO

ATP-binding cassette (ABC) transporters such as ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP) are well known for their role in rendering cancer cells resistant to chemotherapy. Additionally, recent research provided evidence that, along with other ABC transporters (ABCA1 and ABCA7), they might be cornerstones to tackle neurodegenerative diseases. Overcoming chemoresistance in cancer, understanding drug-drug interactions, and developing efficient and specific drugs that alter ABC transporter function are hindered by a lack of in vivo research models, which are fully predictive for humans. Hence, the humanization of ABC transporters in mice has become a major focus in pharmaceutical and neurodegenerative research. Here, we present a characterization of the first Abcc1 humanized mouse line. To preserve endogenous expression profiles, we chose to generate a knockin mouse model that leads to the expression of a chimeric protein that is fully human except for one amino acid. We found robust mRNA and protein expression within all major organs analyzed (brain, lung, spleen, and kidney). Furthermore, we demonstrate the functionality of the expressed human ABCC1 protein in brain and lungs using functional positron emission tomography imaging in vivo. Through the introduction of loxP sites, we additionally enabled this humanized mouse model for highly sophisticated studies involving cell type-specific transporter ablation. Based on our data, the presented mouse model appears to be a promising tool for the investigation of cell-specific ABCC1 function. It can provide a new basis for better translation of preclinical research.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31233945

RESUMO

Di(2-ethylhexyl) adipate (DEHA) is a plasticizer and phthalate substitute used in various consumer products. Relevant population exposures have to be assumed. In this study we describe the determination of three specific side chain-oxidized monoester metabolites of DEHA, mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), and mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA) in human urine as potential biomarkers of DEHA exposure. After enzymatic hydrolysis, urine samples were analyzed by online turbulent flow chromatography for matrix depletion and analyte enrichment coupled to liquid chromatography-electrospray ionization-triple quadrupole-tandem mass spectrometry (online-SPE-LC-MS/MS). For quantification stable isotope dilution was applied with limits of quantification of 0.05 µg/L for 5cx-MEPA and 5OH-MEHA, and 0.1 µg/L for 5oxo-MEHA. Method accuracies (relative recoveries) were between 92 and 109%, and relative standard deviations <5%. We investigated the applicability of the method for internal DEHA exposure assessment in six volunteers who had consumed food wrapped in commercial PVC-cling film containing DEHA and in two small pilot populations without known DEHA exposure (44 pregnant Brazilian women and 32 German adults). In the cling film experiment, we could quantify all three metabolites in all post exposure urine samples, with 5cx-MEPA being most prominent (0.30-10.2 µg/L), followed by 5OH-MEHA (0.12-4.31 µg/L) and 5oxo-MEHA (0.12-2.84 µg/L). In the Brazilian and German samples we could detect DEHA exposures in 43 and 9% of all samples, again with 5cx-MEPA as the most prominent metabolite. Based on validation and pilot biomonitoring results, the method has proven appropriate for DEHA biomonitoring and will be applied in future metabolism and population studies.

7.
Am J Ind Med ; 62(8): 663-671, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31168929

RESUMO

BACKGROUND: Fractional exhaled nitric oxide (FeNO) before and after specific inhalation challenge has been postulated as an additional tool in the diagnosis of occupational asthma (OA), but little is known about serial FeNO measurements at home and at work. The aim of the present study was to assess the contribution of serial measurements of FeNO off and at work toward the diagnosis of OA. METHODS: Forty-one subjects with suspected (n = 35) or diagnosed (n = 6) OA performed FeNO measurements once daily during a 2-week holiday and a subsequent 2-week work period. A work-related increase in FeNO by 20 ppb (parts per billion) or more was considered positive. Subjects with negative or doubtful specific inhalation challenge but a FeNO increase of 20 ppb or more were evaluated individually by an overall expert rating taking into account all available information. RESULTS: Seven of 35 subjects (20%) with suspected and three of six subjects (50%) with diagnosed OA showed a work-related FeNO increase of 20 ppb or more. Six of the seven with suspected OA were reclassified as having an OA diagnosis by the overall expert rating which also considered these FeNO changes. CONCLUSIONS: Serial FeNO measurements off and at work provide complementary information in the diagnosis in about one-fifth of cases with suspected OA, especially if specific inhalation challenges are negative or cannot be performed.

8.
Arch Toxicol ; 93(8): 2185-2195, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222524

RESUMO

Up to date, information on the validity of human biomonitoring (HBM) parameters of naphthalene exposure is poor. This study was performed to reveal the relation between occupational exposure to naphthalene and biological exposure markers. Therefore, ten lowly and highly exposed workers from the abrasives industry were selected to characterise a broad exposure range. Naphthalene in air was determined by personal air monitoring during one shift. For biological monitoring, pre- and post-shift urine samples collected on 2 days of a working week were analysed for 1,2-dihydroxynaphthalene (1,2-DHN), 1- and 2-naphthol, 1- and 2-naphthylmercapturic acid (NMA). The naphthalene concentration in air was in the range of 0.5 to 11.6 mg/m3. The biomarkers in urine showed post-shift concentration in the range of 114-51,809 µg/L for 1,2-DHN, 0.8-666 µg/L for 1-NMA, 2-2698 µg/L for 1-naphthol and 4-1135 µg/L for 2-naphthol, respectively. 2-NMA was not detected. The urinary levels increased significantly from pre- to post-shift for all analysed parameters and an accumulation over the working week was observed. Significant positive correlations were observed between 1,2-DHN, 1-NMA, 1- and 2-naphthol in post-shift urine samples and personal exposure to naphthalene in the air. 1-NMA and 1,2-DHN, 1- and 2-naphthol have been demonstrated as suitable biomarkers for naphthalene exposure monitoring. Of the determined biomarkers, 1,2-DHN is by far the metabolite with the highest concentration in the urine samples.

9.
Int J Cancer ; 145(6): 1701, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31081941
10.
Artigo em Inglês | MEDLINE | ID: mdl-31144109

RESUMO

PURPOSE: Increases of fractional exhaled nitric oxide (FeNO), sputum eosinophils, and methacholine responsiveness have been described after specific inhalation challenges (SIC) with occupational allergens, but limited information is available about their comparative performance. It was the aim of the study to assess the diagnostic accuracy of these non-invasive tests before and after SIC for the diagnosis of occupational asthma (OA). METHODS: A total of 122 subjects with work-related shortness of breath were included. The 'gold standard' was defined as airway obstruction (pulmonary responders) and/or an increase of FeNO of at least 13 ppb after SIC. The results were compared with those obtained using the pulmonary responder status alone as 'gold standard'. RESULTS: If the pulmonary responder status and/or an increase of FeNO was used as 'gold standard' for SIC, 28 out of 39 positives (72%), but also 20 out of 83 negatives (24%) showed an increase of sputum eosinophils and/or bronchial hyperresponsiveness after SIC. If the pulmonary responder status alone was used as 'gold standard', an increase of FeNO with a sensitivity of 0.57 and a specificity of 0.82 showed a higher accuracy than increases of sputum eosinophils (0.52/0.75) or bronchial hyperresponsiveness (0.43/0.87). Individual case analyses suggest that a few cases of OA may be detected by increases of sputum eosinophils or bronchial hyperresponsiveness alone, but probably false-positive tests dominate. CONCLUSION: It is recommended to use both lung function and increase of FeNO as primary effect parameters of SIC. Changes of sputum eosinophils and bronchial hyperresponsiveness after SIC have a low additional diagnostic value, but may be useful in individual cases.

11.
Toxicol Lett ; 309: 35-41, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30953687

RESUMO

The UV filter 2-ethylhexyl salicylate (EHS) is used in sunscreens and other personal care products worldwide and has been found in a variety of environmental media. We aimed to provide human toxicokinetic data on EHS as a tool for risk assessment. For that purpose, we investigated metabolism and urinary metabolite excretion after a single oral EHS dose (57.4-75.5 µg/(kg body weight)) in three male volunteers. In a suspect screening, we tentatively identified seven EHS metabolites. Three EHS specific metabolites were quantitatively investigated: 2-ethyl-5-hydroxyhexyl 2-hydroxybenzoate (5OH-EHS), 2-ethyl-5-oxohexyl 2-hydroxybenzoate (5oxo-EHS), and 5-(((2-hydroxybenzoyl)oxy)methyl)heptanoic acid (5cx-EPS). These metabolites were excreted with urinary excretion fractions of 0.28% (range: 0.13-0.54%), 0.11% (0.06-0.20%), and 0.24% (0.14-0.41%), respectively. The elimination was fast: peak urinary concentrations were found 1.6-2.6 h after dose and ≥95% of the total amounts were excreted within 24 h. Elimination kinetics were biphasic, with mean elimination half-lives of 0.8 h (first phase) and 6.6 h (second phase) for 5OH-EHS, 0.8 h and 6.3 h for 5oxo-EHS, and 1.1 h and 5.9 h for 5cx-EPS. After dermal exposure (sunscreen application), we found a considerably delayed EHS elimination. Based on urinary metabolite levels we calculated EHS exposure levels for a small pilot population.


Assuntos
Salicilatos/metabolismo , Protetores Solares/metabolismo , Administração Oral , Adulto , Biomarcadores , Eliminação Cutânea , Exposição Ambiental , Humanos , Masculino , Medição de Risco , Pele/metabolismo
12.
Int J Cancer ; 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31008534

RESUMO

Urothelial cancer (UCa) is the most predominant cancer of the urinary tract and noninvasive diagnosis using hypermethylation signatures in urinary cells is promising. Here, we assess gender differences in a newly identified set of methylation biomarkers. UCa-associated hypermethylated sites were identified in urine of a male screening cohort (n = 24) applying Infinium-450K-methylation arrays and verified in two separate mixed-gender study groups (n = 617 in total) using mass spectrometry as an independent technique. Additionally, tissue samples (n = 56) of mixed-gender UCa and urological controls (UCt) were analyzed. The hypermethylation signature of UCa in urine was specific and sensitive across all stages and grades of UCa and independent on hematuria. Individual CpG sensitivities reached up to 81.3% at 95% specificity. Albeit similar methylation differences in tissue of both genders, differences were less pronounced in urine from women, most likely due to the frequent presence of squamous epithelial cells and leukocytes. Increased repression of methylation levels was observed at leukocyte counts ≥500/µl urine which was apparent in 30% of female and 7% of male UCa cases, further confirming the significance of the relative amounts of cancerous and noncancerous cells in urine. Our study shows that gender difference is a most relevant issue when evaluating the performance of urinary biomarkers in cancer diagnostics. In case of UCa, the clinical benefits of methylation signatures to male patients may outweigh those in females due to the general composition of women's urine. Accordingly, these markers offer a diagnostic option specifically in males to decrease the number of invasive cystoscopies.

13.
Toxicol In Vitro ; 58: 215-223, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30928694

RESUMO

Biopersistent pro-inflammatory fibers are suspected human carcinogens. Cytotoxicity and transcription of pro- and anti-inflammatory mediators of different fibers were investigated in functional relationship to chemotaxis in vitro as a model for fiber-induced inflammation of the lung. We challenged NR8383 rat macrophages with multi-walled carbon nanotubes (MWCNT) and various asbestos fibers. The resulting cell supernatants were than studied using the Particle-induced Cell Migration Assay (PICMA) and cytotoxicity was determined using the LDH test. Expression of inflammatory mediators was analyzed with qPCR and verified by ELISA. Chrysotile A and the rigid, needle-shaped NM-401 caused the strongest cytotoxic effects and the largest number of migrated cells. In contrast, the MWCNT NM-400, NM-402, and NM403 were apparently non-cytotoxic but induced pronounced cell migration showing a very steep dose response. However, the strength of cell migration and cytotoxicity of the asbestos fibers were correlated. The expression profile of inflammatory mediators was comparable, although cytotoxicity of the MWCNT NM-401 and NM-403 differed strongly. Induction of the corresponding proteins was confirmed for CCL2, CCL3, CXCL1, CXCL3, IL1RA (IL1RN), CSF1, GDF15 and TNFa. Chrysotile A and NM-401 induced much stronger chemotaxis than the non-fibrous particles reported in our previous study. Cytotoxic and chemotactic effects correspond to the induction of inflammatory mediators.

14.
Biopreserv Biobank ; 17(4): 312-318, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30882231

RESUMO

Legal and ethical demands for more transparent and strict data protection measures to enhance research participant privacy have grown with an increasing number of human biobanks providing biomaterial collections long term for unspecified future research questions. The design of a data protection scheme that minimizes the risk of donor reidentification and promotes biomaterial and data use in research is a big challenge to all kinds of human biobanks. Yet, there is a lack of publications which address this basic building block of a biobank. In this study, we present the data protection concept of our project driven, stand-alone biobank, focusing on meeting two biomaterial and data management areas simultaneously: operation of primary research projects involved in sample collection and long-term provision of biomaterial for future research purposes. The concept is based on national and international laws and ethical demands. Since the presented measures are transparent and basic, they should encourage biobanks in defining their own data protection concept and be easily transferable to different legal requirements.

15.
BMC Res Notes ; 12(1): 77, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744695

RESUMO

OBJECTIVE: Malignant mesothelioma is an aggressive cancer of the serous membranes. For the detection of the tumor at early stages non- or minimally-invasive biomarkers are needed. The circulating biomarkers miR-132-3p, miR-126-3p, and miR-103a-3p were analyzed in a nested case-control study using plasma samples from 17 prediagnostic mesothelioma cases and 34 matched asbestos-exposed controls without a malignant disease. RESULTS: Using prediagnostic plasma samples collected in median 8.9 months prior the clinical diagnosis miR-132-3p, miR-126-3p, and miR-103a-3p revealed 0% sensitivity on a defined specificity of 98%. Thus, the analyzed miRNAs failed to detect the cancer in prediagnostic samples, showing that they are not feasible for the early detection of malignant mesothelioma. However, the miRNAs might still serve as possible markers for prognosis and response to therapy, but this needs to be analyzed in appropriate studies.


Assuntos
Biomarcadores Tumorais/sangue , MicroRNA Circulante/sangue , Detecção Precoce de Câncer/normas , Neoplasias Pulmonares/diagnóstico , Mesotelioma/diagnóstico , MicroRNAs/sangue , Adulto , Asbestose/sangue , Estudos de Casos e Controles , Humanos , Neoplasias Pulmonares/sangue , Masculino , Mesotelioma/sangue , Pessoa de Meia-Idade , Sintomas Prodrômicos , Sensibilidade e Especificidade
16.
Arch Toxicol ; 93(4): 921-929, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729276

RESUMO

The toxicokinetics of N-ethyl-2-pyrrolidone (NEP), an embryotoxic organic solvent, has been studied in Sprague-Dawley rats after oral exposure. NEP and its metabolites 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI) were measured in plasma of pregnant and non-pregnant rats, and fetuses after NEP administration by gavage for 14 consecutive days at 50 mg/kg/day, and in plasma of non-pregnant rats after a single NEP administration. Additionally, amniotic fluid and 24-h urine samples of the pregnant rats were analyzed for NEP metabolites. Furthermore, 24-h urine samples from a repeated dose 28-day oral toxicity study in female (non-pregnant) and male rats administered developmentally non-toxic (0, 5, and 50 mg/kg/day) or toxic (250 mg/kg/day) doses of NEP were analyzed. Median peak plasma concentrations in non-pregnant rats after a single dose and repeated doses were 551 and 611 (NEP), 182 and 158 (5-HNEP), and 63.8 and 108 µmol/L (2-HESI), respectively; whereas in pregnant rats and fetuses 653 and 619 (NEP), 80.5 and 91.7 (5-HNEP) and 77.3 and 45.7 µmol/L (2-HESI) were detected. Times to reach maximum plasma concentrations for NEP, 5-HNEP, and 2-HESI were 1, 4, and 8 h, respectively, and were comparable to N-methyl-2-pyrrolidone (NMP) and its corresponding metabolites. In pregnant rats, plasma elimination of NEP and metabolite formation/elimination was much slower compared to non-pregnant rats and efficient placental transfer of NEP was observed. Our data, overall, suggest differences in the toxicokinetics of chemicals between pregnant and non-pregnant rats which need to be addressed in risk assessment, specifically when assessing developmental toxicants such as NEP.

17.
Sci Total Environ ; 653: 1025-1033, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30759543

RESUMO

Light is the strongest zeitgeber currently known for the synchronization of the human circadian timing system. Especially shift workers are exposed to altered daily light profiles. Our objective is the characterization of differences in blue-light exposures between day and night shift taking into consideration modifying factors such as chronotype. We describe 24-hour blue-light profiles as measured with ambient light data loggers (LightWatcher) during up to three consecutive days with either day or night shifts in 100 female hospital staff including 511 observations. Linear mixed models were applied to analyze light profiles and to select time-windows for the analysis of associations between shift work, individual factors, and log mean light exposures as well as the duration of darkness per day. Blue-light profiles reflected different daily activities and were mainly influenced by work time. Except for evening (7-9 p.m.), all time windows showed large differences in blue-light exposures between day and night shifts. Night work reduced the duration of darkness per day by almost 4 h (ß^ = -3:48 hh:mm, 95% CI (-4:27; -3.09)). Late chronotypes had higher light exposures in the morning and evening compared to women with intermediate chronotype (e.g. morning ß^ = 0.50 log(mW/m2/nm), 95% CI (0.08; 0.93)). Women with children had slightly higher light exposures in the afternoon than women without children (ß^ = 0.48, 95% CI (-0.10; 1,06)). Time windows for the description of light should be chosen carefully with regard to timing of shifts. Our results are helpful for future studies to capture relevant light exposure differences and potential collinearities with individual factors. Improvement of well-being of shift workers with altered light profiles may therefore require consideration of both - light at the workplace and outside working hours.


Assuntos
Recursos Humanos em Hospital , Exposição à Radiação/análise , Jornada de Trabalho em Turnos , Adulto , Ritmo Circadiano , Feminino , Alemanha , Humanos , Modelos Lineares , Pessoa de Meia-Idade
18.
Am J Pathol ; 189(3): 619-631, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30770125

RESUMO

Histopathological differentiation between severe urocystitis with reactive urothelial atypia and carcinoma in situ (CIS) can be difficult, particularly after a treatment that deliberately induces an inflammatory reaction, such as intravesical instillation of Bacillus Calmette-Guèrin. However, precise grading in bladder cancer is critical for therapeutic decision making and thus requires reliable immunohistochemical biomarkers. Herein, an exemplary potential biomarker in bladder cancer was identified by the novel approach of Fourier transform infrared imaging for label-free tissue annotation of tissue thin sections. Identified regions of interest are collected by laser microdissection to provide homogeneous samples for liquid chromatography-tandem mass spectrometry-based proteomic analysis. This approach afforded label-free spatial classification with a high accuracy and without interobserver variability, along with the molecular resolution of the proteomic analysis. Cystitis and invasive high-grade urothelial carcinoma samples were analyzed. Three candidate biomarkers were identified and verified by immunohistochemistry in a small cohort, including low-grade urothelial carcinoma samples. The best-performing candidate AHNAK2 was further evaluated in a much larger independent verification cohort that also included CIS samples. Reactive urothelial atypia and CIS were distinguishable on the basis of the expression of this newly identified and verified immunohistochemical biomarker, with a sensitivity of 97% and a specificity of 69%. AHNAK2 can differentiate between reactive urothelial atypia in the setting of an acute or chronic cystitis and nonmuscle invasive-type CIS.

19.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1110-1111: 59-66, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30780012

RESUMO

The UV filter 2­ethylhexyl salicylate (EHS) is widely used in sunscreens and other personal care products (PCP). EHS has been detected in a variety of environmental matrices. However, data on the internal EHS exposure in humans is not available, due to the lack of exposure biomarkers and analytical methods for their determination. Here, we report a method for the determination of three oxidative EHS metabolites in human urine: 2­ethyl­5­hydroxyhexyl 2­hydroxybenzoate (5OH-EHS), 2­ethyl­5­oxohexyl 2­hydroxybenzoate (5oxo-EHS), and 5­(((2­hydroxybenzoyl)oxy)methyl)heptanoic acid (5cx-EPS). Urine samples are incubated with ß­glucuronidase and analyzed by liquid chromatography-electrospray ionization-triple quadrupole-tandem mass spectrometry, coupled with online sample clean-up and analyte enrichment using turbulent flow chromatography (online-SPE-LC-MS/MS). Quantification is performed by stable isotope dilution analysis, using deuterium-labeled standards of each of the three metabolites. The described method is precise (coefficient of variation <5% within-series and interday), accurate (mean relative recoveries between 96% and 105%), and sensitive, with limits of quantification (LOQ) of 0.01 µg/L (5cx-EPS), 0.05 µg/L (5OH-EHS), and 0.15 µg/L (5oxo-EHS). After dermal application of an EHS containing sunscreen to a human volunteer, we were able to quantify all three metabolites in urine samples collected post application, showing clear elimination kinetics. In spot urine samples from the general population (n = 35) we were able to quantify EHS biomarkers in 91% of all samples, with highest concentrations in individuals (n = 11) who stated use of PCPs containing UV filters within 5 days prior to sampling. We will apply the method for investigating human EHS metabolism and in future human biomonitoring studies for EHS exposure and risk assessment.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Salicilatos/urina , Extração em Fase Sólida/métodos , Protetores Solares/análise , Espectrometria de Massas em Tandem/métodos , Adulto , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Salicilatos/metabolismo , Sensibilidade e Especificidade , Protetores Solares/metabolismo , Adulto Jovem
20.
Cells ; 8(2)2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30699914

RESUMO

We took advantage of magnetic resonance imaging (MRI) and spectroscopy (MRS) as non-invasive methods to quantify brain iron and neurometabolites, which were analyzed along with other predictors of motor dysfunction in Parkinson's disease (PD). Tapping hits, tremor amplitude, and the scores derived from part III of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS3 scores) were determined in 35 male PD patients and 35 controls. The iron-sensitive MRI relaxation rate R2* was measured in the globus pallidus and substantia nigra. γ-aminobutyric acid (GABA)-edited and short echo-time MRS was used for the quantification of neurometabolites in the striatum and thalamus. Associations of R2*, neurometabolites, and other factors with motor function were estimated with Spearman correlations and mixed regression models to account for repeated measurements (hands, hemispheres). In PD patients, R2* and striatal GABA correlated with MDS-UPDRS3 scores if not adjusted for age. Patients with akinetic-rigid PD subtype (N = 19) presented with lower creatine and striatal glutamate and glutamine (Glx) but elevated thalamic GABA compared to controls or mixed PD subtype. In PD patients, Glx correlated with an impaired dexterity when adjusted for covariates. Elevated myo-inositol was associated with more tapping hits and lower MDS-UPDRS3 scores. Our neuroimaging study provides evidence that motor dysfunction in PD correlates with alterations in brain iron and neurometabolites.

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