Low molecular weight plasma antioxidants in healthy individuals and head and neck squamous cell carcinoma patients

Cand. Scient. Amrit Kaur Sakhi har i sin doktorgrad sett på en mulig sammenheng mellom nivået av antioksidanter i blod og overlevelsesprosent hos øre-nese-hals kreftpasienter. Øre-nese-hals kreft er den sjuende mest vanlige krefttype på verdens basis og selv om behandlingsmetodene er blitt bedre, har overlevelsesprosenten vært rundt 50 %. I sin avhandling Low molecular weight plasma antioxidants in healthy individuals and head and neck squamous cell carcinoma patients har Sakhi sett at øre-nese-hals kreftpasienter har lavere nivåer av antioksidanter sammenlignet med friske individer. I tillegg har pasienter med høyt nivå av karotenoider (en type antioksidanter som finnes i frukt og grønnsaker) både før og etter avsluttet strålebehandling bedre overlevelse enn de som har lave nivåer. Strålebehandling øker oksidativt stress i pasienter og de pasientene som har høyest økning i oksidativt stress under behandlingen har bedre overlevelse. Disse resultatene viser at det kan være gunstig å øke antioksidantnivået i øre-nese-hals kreftpasienter før og etter avsluttet strålebehandling. Derimot kan det være uheldig å øke pasientenes antioksidantnivå mens de får strålebehandling siden antioksidantene kan motvirke behandlingseffekten av stråling ved å dempe oksidativt stress. Vi konkluderer derfor med at optimalisering av antioksidantstatus i øre-nese-hals kreftpasienter er viktig for å forbedre deres overlevelse og bør studeres nærmere. Den siste rapporten fra World Cancer Research Fund har også vist at høyt inntak av frukt og grønt sannsynligvis minker risiko for å utvike denne krefttypen. Det er også viktig at forbedring av antioksidantstatus skjer ved å øke inntaket av frukt og grønt og ikke via antioksidanttilskudd, siden andre studier har vist ingen eller negative effekter av tilskudd. Sakhi´s arbeid har også vist at kaffe etterfulgt av frukt og bær er hovedkilder til antioksidanter i det norske kostholdet

Pulmonary phthalate exposure and asthma - is PPAR a plausible mechanistic link?

Due to their extensive use as plasticisers in numerous consumer products, phthalates have become ubiquitous environmental contaminants. An increasing number of epidemiological studies suggest that exposure to phthalates may be associated with worsening or development of airway diseases. Peroxisome Proliferation Activated Receptors (PPAR)s, identified as important targets for phthalates in early studies in rodent liver, have been suggested as a possible mechanistic link. In this review we discuss the likelihood of an involvement of PPARs in asthma development and exacerbation due to pulmonary phthalate exposure. First, we go through the literature on indoor air levels of phthalates and pulmonary phthalate kinetics. These data are then used to estimate the pulmonary phthalate levels due to inhalation exposure. Secondly, the literature on phthalate-induced activation or modulation of PPARs is summarized. Based on these data, we discuss whether pulmonary phthalate exposure is likely to cause PPAR activation, and if this is a plausible mechanism for adverse effects of phthalates in the lung. It is concluded that the pulmonary concentrations of some phthalates may be sufficient to cause a direct activation of PPARs. Since PPARs mainly mediate anti-inflammatory effects in the lungs, a direct activation is not a likely molecular mechanism for adverse effects of phthalates. However, possible modulatory effects of phthalates on PPARs deserve further investigation, including partial antagonist effects and/or cross talk with other signalling pathways. Moreover other mechanisms, including interactions between phthalates and other receptors, could also contribute to possible adverse pulmonary effects of phthalates

European interlaboratory comparison investigations (ICI) and external quality assurance schemes (EQUAS) for the analysis of bisphenol A, S and F in human urine: Results from the HBM4EU project

The Human Biomonitoring for Europe initiative (HBM4EU) aims to study the exposure of citizens to chemicals and potentially associated health effects. One objective of this project has been to build a network of laboratories able to answer to the requirements of European human biomonitoring studies. Within the HBM4EU quality assurance and quality control scheme (QA/QC), a number of interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) were organized to ensure data consistency, comparability and reliability. Bisphenols are among the prioritized substance groups in HBM4EU, including bisphenol A (BPA), bisphenol S (BPS) and bisphenol F (BPF) in human urine. In four rounds of ICI/EQUAS, two target concentration levels were considered, related to around P25 and P95 of the typical exposure distribution observed in the European general population. Special attention was paid to the conjugated phase II metabolites known to be most dominant in samples of environmentally exposed individuals, through the analysis of both native samples and samples fortified with glucuronide forms. For the low level, the average percentage of satisfactory results across the four rounds was 83% for BPA, 71% for BPS and 62% for BPF. For the high level, the percentages of satisfactory results increased to 93% for BPA, 89% for BPS and 86% for BPF. 24 out of 32 participating laboratories (75%) were approved for the analyses of BPA in the HBM4EU project according to the defined criterion of Z-scores for both low and high concentration levels in at least two ICI/EQUAS rounds. For BPS and BPF, the number of qualified laboratories was 18 out of 27 (67%) and 13 out of 28 (46%), respectively. These results demonstrate a strong analytical capability for BPA and BPS in Europe, while improvements may be needed for BPF.We gratefully acknowledge funding by the European Union's Horizon 2020 research and innovation programme under the grant agreement No. 733032 HBM4EU. The authors would like to thank the HBM4EU Secretariat at the German Environment Agency for administrative support. The authors acknowledge all the participating and expert laboratories (Table A1, SM) that made the HBM4EU QA/QC programme possible as well as the Management and Advisory Boards of HBM4EU.S

Pre-radiotherapy plasma carotenoids and markers of oxidative stress are associated with survival in head and neck squamous cell carcinoma patients: a prospective study

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to compare plasma levels of antioxidants and oxidative stress biomarkers in head and neck squamous cell carcinoma (HNSCC) patients with healthy controls. Furthermore, the effect of radiotherapy on these biomarkers and their association with survival in HNSCC patients were investigated.</p> <p>Methods</p> <p>Seventy-eight HNSCC patients and 100 healthy controls were included in this study. Follow-up samples at the end of radiotherapy were obtained in 60 patients. Fifteen antioxidant biomarkers (6 carotenoids, 4 tocopherols, ascorbic acid, total antioxidant capacity, glutathione redox potential, total glutathione and total cysteine) and four oxidative stress biomarkers (total hydroperoxides, γ-glutamyl transpeptidase, 8-isoprostagladin F_2αand ratio of oxidized/total ascorbic acid) were measured in plasma samples. Analysis of Covariance was used to compare biomarkers between patients and healthy controls. Kaplan-Meier plots and Cox' proportional hazards models were used to study survival among patients.</p> <p>Results</p> <p>Dietary antioxidants (carotenoids, tocopherols and ascorbic acid), ferric reducing antioxidant power (FRAP) and modified FRAP were lower in HNSCC patients compared to controls and dietary antioxidants decreased during radiotherapy. Total hydroperoxides (d-ROMs), a marker for oxidative stress, were higher in HNSCC patients compared to controls and increased during radiotherapy. Among the biomarkers analyzed, high levels of plasma carotenoids before radiotherapy are associated with a prolonged progression-free survival (hazard rate ratio: 0.42, 95% CI: 0.20-0.91, p = 0.03). Additionally, high relative increase in plasma levels of d-ROMs (hazard rate ratio: 0.31, 95% CI: 0.13-0.76, p = 0.01) and high relative decrease in FRAP (hazard rate ratio: 0.42, 95% CI: 0.17-0.998, p = 0.05) during radiotherapy are also positively associated with survival.</p> <p>Conclusions</p> <p>Biomarkers of antioxidants and oxidative stress are unfavourable in HNSCC patients compared to healthy controls, and radiotherapy affects many of these biomarkers. Increasing levels of antioxidant biomarkers before radiotherapy and increasing oxidative stress during radiotherapy may improve survival indicating that different factors/mechanisms may be important for survival before and during radiotherapy in HNSCC patients. Thus, the therapeutic potential of optimizing antioxidant status and oxidative stress should be explored further in these patients.</p

Proficiency and Interlaboratory Variability in the Determination of Phthalate and DINCH Biomarkers in Human Urine: Results from the HBM4EU Project

A quality assurance/quality control program was implemented in the framework of the EU project HBM4EU to assess and improve the comparability of biomarker analysis and to build a network of competent laboratories. Four rounds of proficiency tests were organized for 15 phthalate and two DINCH urinary biomarkers (0.2-138 ng/mL) over a period of 18 months, with the involvement of 28 laboratories. A substantial improvement in performance was observed after the first round in particular, and by the end of the program, an average satisfactory performance rate of 90% was achieved. The interlaboratory reproducibility as derived from the participants' results varied for the various biomarkers and rounds, with an average of 24% for the biomarkers of eight single-isomer phthalates (e.g., DnBP and DEHP) and 43% for the more challenging biomarkers of the mixed-isomer phthalates (DiNP, DiDP) and DINCH. When the reproducibility was based only on the laboratories that consistently achieved a satisfactory performance, this improved to 17% and 26%, respectively, clearly demonstrating the success of the QA/QC efforts. The program thus aided in building capacity and the establishment of a network of competent laboratories able to generate comparable and accurate HBM data for phthalate and DINCH biomarkers in 14 EU countries. In addition, global comparability was ensured by including external expert laboratories.This study was part of the HBM4EU project receiving funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 733032. Co-funding was received from the Dutch Ministry of Agriculture, Nature and Food Quality (project KB 37-002-014-001/002).S

Organophosphorus Pesticide Exposure at 17 Weeks’ Gestation and Odds of Offspring Attention-Deficit/Hyperactivity Disorder Diagnosis in the Norwegian Mother, Father, and Child Cohort Study

Prenatal organophosphorus pesticides (OPs) are ubiquitous and have been linked to adverse neurodevelopmental outcomes. However, few studies have examined prenatal OPs in relation to diagnosed attention-deficit/hyperactivity disorder (ADHD), with only two studies exploring this relationship in a population primarily exposed through diet. In this study, we used a nested case-control study to evaluate prenatal OP exposure and ADHD diagnosis in the Norwegian Mother, Father, and Child Cohort Study (MoBa). For births that occurred between 2003 and 2008, ADHD diagnoses were obtained from linkage of MoBa participants with the Norwegian Patient Registry (N = 297), and a reference population was randomly selected from the eligible population (N = 552). Maternal urine samples were collected at 17 weeks’ gestation and molar sums of diethyl phosphates (ΣDEP) and dimethyl phosphates metabolites (ΣDMP) were calculated. Multivariable adjusted logistic regression models were used to estimate the association between prenatal OP metabolite exposure and child ADHD diagnosis. Additionally, multiplicative effect measure modification (EMM) by child sex was assessed. In most cases, mothers in the second and third tertiles of ΣDMP and ΣDEP exposure had slightly lower odds of having a child with ADHD, although confidence intervals were wide and included the null. EMM by child sex was not observed for either ΣDMP or ΣDEP. In summary, we did not find evidence that OPs at 17 weeks’ gestation increased the odds of ADHD in this nested case-control study of ADHD in MoBa, a population primarily experiencing dietary exposure

In utero exposure to bisphenols and asthma, wheeze, and lung function in school-age children: a prospective meta-analysis of 8 European birth cohorts

[EN] BACKGROUND: In utero exposure to bisphenols, widely used in consumer products, may alter lung development and increase the risk of respiratory morbidity in the offspring. However, evidence is scarce and mostly focused on bisphenol A (BPA) only. OBJECTIVE: To examine the associations of in utero exposure to BPA, bisphenol F (BPF), and bisphenol S (BPS) with asthma, wheeze, and lung function in school-age children, and whether these associations differ by sex. METHODS: We included 3,007 mother-child pairs from eight European birth cohorts. Bisphenol concentrations were determined in maternal urine samples collected during pregnancy (1999-2010). Between 7 and 11years of age, current asthma and wheeze were assessed from questionnaires and lung function by spirometry. Wheezing patterns were constructed from questionnaires from early to mid-childhood. We performed adjusted random-effects meta-analysis on individual participant data. RESULTS: Exposure to BPA was prevalent with 90% of maternal samples containing concentrations above detection limits. BPF and BPS were found in 27% and 49% of samples. In utero exposure to BPA was associated with higher odds of current asthma (OR=1.13, 95% CI=1.01, 1.27) and wheeze (OR=1.14, 95% CI=1.01, 1.30) (p-interaction sex=0.01) among girls, but not with wheezing patterns nor lung function neither in overall nor among boys. We observed inconsistent associations of BPF and BPS with the respiratory outcomes assessed in overall and sex-stratified analyses. CONCLUSION: This study suggests that in utero BPA exposure may be associated with higher odds of asthma and wheeze among school-age girls.The research leading to these results has received funding from Instituto de Salud Carlos III and European Union’s FEDER funds (CP16/00128 – the ENDOLUNG project, and PI17/01194 – the INMA-Ado-Respi Project), the European Community’s Seventh Framework Programme (FP7/2007–206) under grant agreement no 308,333 - the HELIX project –, and from the EC’s Horizon 2020 research and innovation programme under grant agreement No 874,583 – the ATHLETE project. Generation R: This study was funded by The Erasmus MC, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. The project received funding from the European Union's Horizon 2020 research and innovation programme (LIFECYCLE, grant agreement No 733206, 2016; EUCAN-Connect grant agreement No 824989; ATHLETE, grant agreement No 874583). Dr. Vincent Jaddoe received a grant from the European Research Council (ERC-2014-CoG-648916). This study was supported by grant R01-ES022972 and R01-ES029779 from the National Institutes of Health, USA. The researchers are independent from the funders. The study sponsors had no role in the study design, data analysis, interpretation of data, or writing of this report. INMA Gipuzkoa: This study was funded by grants from Instituto de Salud Carlos III (FIS-PI13/02187 and FIS-PI18/01142 incl. FEDER funds), CIBERESP, Department of Health of the Basque Government (2015111065), and the Provincial Government of Gipuzkoa (DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). INMA Sabadell: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; PI12/01890 incl. FEDER funds; CP13/00054 incl. FEDER funds), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR (2009 SGR 501, 2014 SGR 822), Fundació La marató de TV3 (090430), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), Agence Nationale de Securite Sanitaire de l’Alimentation de l’Environnement et du Travail (1262C0010), European Commission (261357, 308333, 603,794 and 634453). Alicia Abellan holds a LifeCycle fellowship, funded from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 733206. Maribel Casas holds a Miguel Servet fellowship (CP16/00128) funded by Instituto de Salud Carlos III and co-funded by European Social Fund “Investing in your future“. We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (2018–000806-S), and support from the Generalitat de Catalunya through the CERCA Program. INMA Valencia: INMA Valencia was funded by Grants from UE (FP7-ENV-2011 cod 282,957 and HEALTH.2010.2.4.5–1), Spain: ISCIII (G03/176; FIS-FEDER: PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663, and PI19/1338; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051), Alicia Koplowitz Foundation, and Generalitat Valenciana: FISABIO (UGP 15–230, UGP-15–244, UGP-15–249, and AICO/2020/285). BiB: This report is independent research funded by the National Institute for Health Research Yorkshire and Humber ARC (NIHR200166) and BiB receives core infrastructure funding from the Wellcome Trust (WT101597MA). The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. EDEN: The EDEN study was supported by Foundation for medical research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A), and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programmes (FP7/2007–2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients (AFD)), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l’Education Nationale a complementary health insurance (MGEN), French national agency for food security, French-speaking association for the study of diabetes and metabolism (ALFEDIAM). MoBa: The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. RHEA: The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211,250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226,285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308,333 HELIX, H2020 LIFECYCLE, grant agreement No 733206, H2020 ATHLETE, grant agreement No 874583), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011–2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–15). Additional funding from NIEHS supported Dr Chatzi (R01ES030691, R01ES029944, R01ES030364, R21ES029681, R21ES028903, and P30ES007048)

Prenatal Exposure to Organophosphorus Pesticides and Preschool ADHD in the Norwegian Mother, Father and Child Cohort Study

Prenatal organophosphorus pesticide (OPP) exposure has been associated with child attention-deficit/hyperactivity disorder (ADHD) in agricultural communities and those that are exposed to residentially applied insecticides. To examine this association in populations that are exposed primarily through diet, we estimate the associations between prenatal OPP exposure and preschool ADHD in the Norwegian Mother, Father and Child Cohort Study (MoBa), and describe modification by paraoxonase 1 (PON1) gene variants. We used participants from the MoBa Preschool ADHD Sub-study (n = 259 cases) and a random sample of MoBa sub-cohort participants (n = 547) with birth years from 2004 to 2008. Prenatal urinary dialkylphosphate (DAP) metabolites (total diethylphosphate [∑DEP] and total dimethylphosphate [∑DMP]) were measured by an ultra-performance liquid chromatography-time-of-flight system and summed by molar concentration. Maternal DNA was genotyped for coding variants of PON1 (Q192R and L55M). We used a multivariable logistic regression to calculate the odds ratios (OR) and 95% confidence intervals, adjusted for maternal education, parity, income dependency, age, marital status, ADHD-like symptoms, pesticide use, produce consumption, and season. We found no associations between DAP metabolite concentrations and preschool ADHD. The adjusted ORs for exposure quartiles 2–4 relative to 1 were slightly inverse. No monotonic trends were observed, and the estimates lacked precision, likely due to the small sample size and variation in the population. We found no evidence of modification by PON1 SNP variation or child sex. Maternal urinary DAP concentrations were not associated with preschool ADHD