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Funding Information: We acknowledge all the participants and researchers of the 23 biobanks that have contributed to the GBMI. Biobank-specific acknowledgments are included in the Data S3 . We thank H. Huang, A.R. Martin, B.M. Neale, Y. Okada, K. Tsuo, J.C. Ulirsch, Y. Wang, and all the members of Finucane and Daly labs for their helpful feedback. M.K. was supported by a Nakajima Foundation Fellowship and the Masason Foundation . H.K.F. was funded by NIH grant DP5 OD024582 . Publisher Copyright: © 2022 The Author(s) Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWASs). Fine-mapping of meta-analysis studies is typically performed as in a single-cohort study. Here, we first demonstrate that heterogeneity (e.g., of sample size, phenotyping, imputation) hurts calibration of meta-analysis fine-mapping. We propose a summary statistics-based quality-control (QC) method, suspicious loci analysis of meta-analysis summary statistics (SLALOM), that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics. We validate SLALOM in simulations and the GWAS Catalog. Applying SLALOM to 14 meta-analyses from the Global Biobank Meta-analysis Initiative (GBMI), we find that 67% of loci show suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci are significantly depleted for having nonsynonymous variants as lead variant (2.7×; Fisher's exact p = 7.3 × 10−4). We find limited evidence of fine-mapping improvement in the GBMI meta-analyses compared with individual biobanks. We urge extreme caution when interpreting fine-mapping results from meta-analysis of heterogeneous cohorts.

Background: During the COVID-19 outbreak, Qatar Biobank (QBB) adapted its services to collect, process, and store high-quality data and specimens. This transformation period brought opportunities, risks, and challenges. Methods: QBB holds College of American Pathologists (CAP) accreditation and International Organization for Standardization (ISO) certification for Quality Management (9001:2105) and Information Security Management Systems (27001: 2013)1. These standards helped to effectively convert its operations to facilitate the COVID-19 national project2. The COVID-19 Biorepository is a National Disease-based study aiming to collect adequate health information and biological samples from Qatar residents infected by SARS-CoV-2 virus to enable evidence-based research towards the discovery and development of novel healthcare interventions and to facilitate research projects related to the COVID-19 pandemic. QBB IT Department used open-source Onyx (ObiBa) software to newly develop a COVID-19 electronic system and interface for various clinical devices and Laboratory Information Management System. QBB operational services were adapted to accommodate the COVID-19 project by providing training to the personnel (n = 20; i.e. nurses, research assistants etc.) and developing work instructions (n>5) for the participants’ recruitment process, data and specimen collection in the different hospitals. A COVID-19 portal was also developed by QBB to facilitate data access for researchers from Qatar and worldwide4. Results: Within 5 weeks QBB transformed to accommodate a disease/virus-based biorepository. At an operational level, multi-adjustments were implemented. QBB IT department developed an electronic system for the data collection and specimen traceability3. Clinically trained staff were transferred to different healthcare facilities to recruit COVID-19 positive patients. QBB laboratory designed special collection kits. QBB Medical Review Office and Scientific and Education departments managed the recruitment process, set up of the study and provided training to the staff. The Communications and Participants Recruitment Department transformed its operations to fit the needs of the COVID-19 initiative. The Research Access Office designed the COVID-19 access portal and supported the project through purchasing of personal protective equipment and other administrative tasks. Conclusion: It is now time to consider lessons learned, as many countries have been affected by this pandemic, and to understand that biobanks are an asset for a country and there is a need to integrate them into a new standard with their sustainability in mind. Qatar Biobank is a good showcase of how a biobank can successfully assist in the collection of important data related to different health crises such as the COVID-19 pandemic.

Background: The rapid spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its resulting disease (COVID-19) is one of the greatest global public health crisis of the recent decades1. The COVID-19 Biorepository is a national project aimed to support the high demand of biomedical research by multiple groups and the need to have access to high quality, curated clinical data, and specimens contributing to the understanding of, and response to, the COVID-19 pandemic and its impacts in Qatar2, 3. Methods/Case presentation: Patients with a laboratory diagnosis of COVID-19, who were Qatar residents that could communicate in Arabic, English, Hindi, and Urdu were eligible to participate in the study. COVID-19 diagnosed patients were recruited at the time of their disease period from the main three public hospitals (Communicable Disease Center, Cuban, and Hazm Mebaireek Hospitals) serving as isolation facilities of symptomatic patients in Qatar, during a 7-month period from March 2020 until September 2020. Consented participants were followed up on a weekly basis until recovery, and then monthly for a year. Sociodemographic and clinical data were collected in electronic questionnaires via a face-to-face interview by trained Qatar Biobank (QBB) staff. Results: A total of 2097 consented participants were recruited up to September 2020, males (N = 1050) and females (N = 1047), with a mean age of 41 years (SD: 15.5). 61.0% of the participants had at least one follow up while 27% adhered to monthly follow up visits. Data was collected for 99.7% of the participants, while the follow up process is still ongoing. In total there are 107,171 high quality specimens in the biorepository including plasma, erythrocytes, buffy coat, serum, PAXgene whole blood, nasopharyngeal secretions, and DNA. Conclusion: The COVID-19 Biorepository is a national asset to illuminate the pathophysiological and identify markers of disease prognosis as well as to describe the clinical features and epidemiology of COVID-19 in Qatar and worldwide.

Funding Information: The work of the contributing biobanks was supported by numerous grants from governmental and charitable bodies. Biobank-specific acknowledgments and more detailed acknowledgments are included in Data S2. Initiative management, S.B.C. J.C. N.J.C. M.J.D. E.E.K. A.R.M. B.M.N. Y.O. A.V.P. D.A.v.H. R.G.W. C.J.W. W.Z. and S.Z.; individual biobank analysis, A.B. Y.B. B.M.B. C.D.B. S.C. T.-T.C. K.C. S.M.D. M.D. G.H.d.B. Y.D. N.J.D. M.-J.F. Y.-C.A.F. S.F. V.L.F. L.G.F. E.R.G. T.R.G. D.H.G. C.R.G. G.G.-A. S.E.G. L.A.G. C.H. J.B.H. W.E.H. H.H. K.H. N.I. A.I. R.J. M. Kurki, J.K. N.K. E.E.K. J.T.K. M. Kanai, T.L. K.L. M.H.L. S.L. K.L. Y.-F.L. V.L.F. R.J.F.L. E.A.L.-M. A.R.-M. S.M.-G. R.M. R.E.M. H.C.M. A.R.M. Y.M. H.M. S.E.M. I.Y.M. B.M. S.M. K.N. S.N. M.A.N.-A. K.N. Y.O. P.P. A.L.-P. A.P. B.P. S.P. M.H.P. D.J.R. N.R. M.D.R. A.R. C.S. S.S. S.S.S. J.A.S. P.S. I.S. T.T. R.T. K.T. J.U. D.A.v.H. B.V. M.V. Y.V. J.M.V. R.G.W. Y.W. S.J.W. B.N.W. K.-H.H.W. M.Z. X.Z. and S.Z.; individual biobank management, N.A. A.A.T. K.M.A.-D. P.A. K.C.B. M. Boehnke, M. Boezen, C.D.B. A.C. Z.C. C.-Y.C. J.C. N.J.C. S.M.D. S.F. Y.-C.A.F. S.F. E.F. T.G. C.R.G. C.J.G. Y.G. H.H. K.A.H. K.H. S.I.I. N.M.J. N.K. E.E.K. J.T.K. C.L. M.H.L. M.T.M.L. L.L. K.L. Y.-F.L. R.J.F.L. J.L. S.M. Y.M. K.M. I.Y.M. Y.O. C.M.O. A.V.P. B.P. D.J.P. D.J.R. M.D.R. S.S. J.W.S. H.S. K.S. T.T. U.T. R.C.T. D.A.v.H. M.V. R.G.W. D.C.W. C.W. J.W. M.Z. X.Z. and S.Z.; study design and interpretation of results, A.B. M. Boehnke, M. Boezen, B.M.B. T.-T.C. C.-Y.C. M.J.D. G.D.S. N.J.D. S.F. M.-J.F. H.K.F. E.R.G. A.G. T.G. J.B.H. J.H. K.H. R.J. M.K. E.E.K. T.K. C.M.L. V.L.F. E.A.L.-M. A.R.M. S.N. B.M.N. C.M.O. J.J.P. B.P. N.R. H.R. J.A.S. I.S. K.T. D.A.v.H. R.G.W. Y.W. D.C.W. S.J.W. C.J.W. B.N.W. J.W. K.-H.H.W. M.Z. H.Z. J.Z. W.Z. X.Z. and S.Z.; drafted and edited the paper, A.B. M. Boehnke, M. Boezen, M.J.D. G.H.d.B. N.J.D. T.R.G. J.B.H. N.I. N.M.J. M.K. V.L.F. S.M. A.R.M. H.M. S.N. B.M.N. C.M.O. B.P. H.R. C.S. J.A.S. J.W.S. K.T. Y.W. D.C.W. C.J.W. K.-H.H.W. H.Z. J.Z. W.Z. and S.Z.; primary meta-analysis and quality control, M.J.D. H.K.F. M. Kanai, J.K. J.T.K. M. Kurki, M.M. B.M.N. C.J.W. K.-H.H.W. and W.Z.; drug discovery: S.N. T.K. K.-H.H.W. W.Z. and Y.O.; fine mapping, M. Kanai, W.Z. M.J.D. and H.K.F.; polygenic risk score, Y.W. S.N. E.A.L.-M. S.K. K.T. K.L. M. Kanai, W.Z. K.W. M.-J.F. L.B. P.A. P.D. V.L.F. R.M. Y.M. B.B. S.S. J.U. E.R.G. N.J.C. I.S. Y.O. A.R.M. and J.B.H.; proteome-wide Mendelian randomization, H.Z. H.R. A.B. G.H. G.D.S. B.M.B. W.Z. B.M.N. T.R.G. and J.Z.; transcriptome-wide association study, A.B. J.B.H. W.Z. J.Z. M. Kanai, B.P. E.R.G. and N.J.C.; asthma, K.T. W.Z. Y.W. M. Kanai, S.N. Y.O. B.M.N. M.J.D. and A.R.M.; heart failure, K.-H.H.W. N.J.D. B.N.W. I.S. S.E.G. J.B.H. N.J.C. M.P. R.J.F.L. M.J.D. B.M.N. W.Z. W.E.H. and C.J.W.; idiopathic pulmonary fibrosis, J.J.P. W.Z. M.J.D. J.T.K. N.J.C. and J.B.H.; primary open-angle glaucoma, V.L.F. A.B. W.Z. Y.W. K.L. M. Kanai, E.A.L.-M. P.S. R.T. X.Z. S.N. S.S. Y.O. N.I. S.M. H.S. I.S. C.W. A.R.M. E.R.G. N.M.J. N.J.C. and J.B.H.; stroke, I.S. K.-H.H.W. W.H. B.N.W. W.Z. J.E.H. A.P. B.B. A.H.S. M.E.G. R.G.W. K.H. C.K. S.Z. M.J.D. B.M.N. and C.J.W.; venous thromboembolism, B.N.W. I.S. K.-H.H.W. B.B. V.L.F. K.T. M.D. B.N. W.Z. J.A.S. and C.J.W. All authors reviewed the manuscript. M.J.D. is a founder of Maze Therapeutics. B.M.N. is a member of the scientific advisory board at Deep Genomics and a consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. The spouse of C.J.W. works at Regeneron Pharmaceuticals. C.-Y.C. is employed by Biogen. C.R.G. owns stock in 23andMe, Inc. T.R.G. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. E.E.K. has received speaker fees from Regeneron, Illumina, and 23andMe and is a member of the advisory board for Galateo Bio. R.E.M. has received speaker fees from Illumina and is a scientific advisor to the Epigenetic Clock Development Foundation. G.D.S. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. K.S. and U.T. are employed by deCODE Genetics/Amgen, Inc. J.Z. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. S.M. is a co-founder of and holds stock in Seonix Bio. Publisher Copyright: © 2022 Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)—a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.

Qatar Biobank (QBB) is actively acquiring data on the range of short- and long-term health impacts associated with COVID-19. This is performed through the COVID-19 biorepository National project. In this report, we describe the most common indications for the referral to Qatar's healthcare system of COVID-19 biorepository participants in comparison with the Qatar Biobank (QBB) general population study. Methods Patients with a laboratory diagnosis of COVID-19, who were Qatar residents that could communicate in Arabic, English, Hindi and Urdu were eligible to participate in the COVID-19 biorepository project. Biological samples of Consented participants were collected on a weekly basis until recovery, and then monthly for a year. Participants were also offered a bone density scan three months after recovery and non-contrast MRI brain and whole-body scan six months after recovery. Number of participants requiring referral for medical follow up after recovery for any abnormal clinically significant findings were recorded and statistically compared to general population referred participants Results: The majority of referrals for the general population study was for osteopenia versus diabetes for the COVID-19 biorepository project Conclusion Descriptive analysis of the referral data of the COVID-19 participants and QBB general population (not previously affected by the virus) shows a clear difference between the two populations' reasons for referrals. Diabetes for COVID 19 recovered participants versus osteopenia for general population Keywords: COVID19, Reason for Referrals, Diabetes, Qatar biobank.

Prenatal cadmium exposure has been associated with impaired fetal growth; much less is known about the impact during later childhood on growth and cardiometabolic traits. To elucidate the associations of prenatal cadmium exposure with child growth, adiposity, and cardiometabolic traits in 515 mother-child pairs in the Rhea Mother-Child Study cohort (Heraklion, Greece, 2007-2012), we measured urinary cadmium concentrations during early pregnancy and assessed their associations with repeated weight and height measurements (taken from birth through childhood), waist circumference, skinfold thickness, blood pressure, and serum lipid, leptin, and C-reactive protein levels at age 4 years. Adjusted linear, Poisson, and mixed-effects regression models were used, with interaction terms for child sex and maternal smoking added. Elevated prenatal cadmium levels (third tertile of urinary cadmium concentration (0.571-2.658 μg/L) vs. first (0.058-0.314 μg/L) and second (0.315-0.570 μg/L) tertiles combined) were significantly associated with a slower weight trajectory (per standard deviation score) in all children (β = -0.17, 95% confidence interval (CI): -0.32, -0.02) and a slower height trajectory in girls (β = -0.30, 95% CI: -0.52,-0.09; P for interaction = 0.025) and in children born to mothers who smoked during pregnancy (β = -0.48, 95% CI: -0.83, -1.13; P for interaction = 0.027). We concluded that prenatal cadmium exposure was associated with delayed growth in early childhood. Further research is needed to understand cadmium-related sex differences and the role of coexposure to maternal smoking during early pregnancy. The Rhea Mother-Child Cohort Study was financially supported by European Union projects (FP6-2003-Food-3-A NewGeneris, Food-CT-2006-036224 Hiwate, FP7/2007- 2011-GA-211250 ESCAPE Project, FP7-2008-226756 Envirogenomarkers, FP7-HEALTH-2009 single-stage 241604 CHICOS, and FP7-ENV.2008.1.2.1.6 proposal 226285 ENRIECO) and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, Heraklion District, Crete, Greece, 2011–2014; and “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health and Child Health, 2012–2015). The present study was also funded by the Karolinska Institutet, the Swedish Research Council Formas (project 210-2013-751), and the Swedish Research Council (project 2015-03655).

Biobank science is progressively becoming indispensable for the development of novel diagnostic tools in health care, by pairing standardized high-quality biological samples, phenotypic, and omics data required to best characterize the underlying biological mechanisms of response to therapy and survival. Qatar Biobank (QBB), Qatar's National Repository Centre for biological samples and health information, aligning with these endeavors, has developed a strategic framework to enable biobanking science that can be transformed into tangible health care diagnostic tools. In this concept, QBB works closely with multidisciplinary stakeholders: (1) governmental authorities ( = 2), (2) health providers ( = 3), (3) academic institutions ( = 28), (4) other research institutions ( = 6), and (5) the Qatar National Research Fund, by providing data and biospecimens to research projects. The local community organizes campaigns through social media and interactive events, spreading the concept of biobanking to inform and encourage people to participate. Up to now, QBB has recruited up to 30% of the targeted population and collaborated with 35 national and international research entities contributing to more than 170 research projects. QBB is referring about 53% of its participants to the Hamad general hospital through the integrated information system, revealing the need of new health screening approaches for public health policy makers. QBB contributed to the development of a customized genetic screening microarray tailored to the Qatari population that will be used in research as well as for the screening of variants of medical relevance in Qatar, promoting precision medicine in Qatar's health care system. The QBB strategic plan is a paradigm for the optimal utilization of resources, infrastructure, and investments engaging the local authorities and the research entities, and committing them to data sharing and working together toward the discovery of evidence-based health care interventions.

The overall goal of the Qatar Biobank (QBB) is to collect, manage, and distribute high-quality human biospecimens with appropriate clinical and/or research annotation and associated phenotypic data, aiming to be an important and essential resource of medical research and evidence-based health care system policies in Qatar. To manage and collect large volumes of data, the QBB has been investing in a number of information management solutions, trying to avoid inflexibility of traditional systems and accommodate changes in data sources and workflows. This article aims to present the information technology solutions of QBB based on a free, open-source software solution, considered a reliable alternative to commercial solutions. After evaluating the free, open-source software solutions available for biobanks, Onyx from ObiBa was utilized to develop custom components to interface various clinical devices, LIMS and Picture Archiving and Communication System, which has varying integration capabilities. This is a showcase for biobanks to carefully evaluate and select hardware and software to automate their operations providing the functions required for business continuity.

Purpose: The study assessed whether diet and adherence to cancer prevention guidelines during pregnancy were associated with micronucleus (MN) frequency in mothers and newborns. MN is biomarkers of early genetic effects that have been associated with cancer risk in adults. Methods: A total of 188 mothers and 200 newborns from the Rhea cohort (Greece) were included in the study. At early-mid pregnancy, we conducted personal interviews and a validated food frequency questionnaire was completed. With this information, we constructed a score reflecting adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention guidelines on diet, physical activity and body fatness. At delivery, maternal and/or cord blood was collected to measure DNA and hemoglobin adducts of dietary origin and frequencies of MN in binucleated and mononucleated T lymphocytes (MNBN and MNMONO). Results: In mothers, higher levels of red meat consumption were associated with increased MNBN frequency [2nd tertile IRR = 1.34 (1.00, 1.80), 3rd tertile IRR = 1.33 (0.96, 1.85)] and MNMONO frequency [2nd tertile IRR = 1.53 (0.84, 2.77), 3rd tertile IRR = 2.69 (1.44, 5.05)]. The opposite trend was observed for MNBN in newborns [2nd tertile IRR = 0.64 (0.44, 0.94), 3rd tertile IRR = 0.68 (0.46, 1.01)], and no association was observed with MNMONO. Increased MN frequency in pregnant women with high red meat consumption is consistent with previous knowledge. Conclusions: Our results also suggest exposure to genotoxics during pregnancy might affect differently mothers and newborns. The predictive value of MN as biomarker for childhood cancer, rather than adulthood, remains unclear. With few exceptions, the association between maternal carcinogenic exposures during pregnancy and childhood cancer or early biologic effect biomarkers remains poorly understood. The Rhea cohort was funded by the following European projects NewGeneris (FP-6-FOOD-CT-2005-016320), ESCAPE (FP7-2007-211250), HiWATE (FP-6-FOOD-CT-2006-036224), Envirogenomarkers (FP7-2008-ENV-1.2.1.4), CHICOS (FP7-2009-GA 241604), and ENRIECO (FP7-2008-GA 226285). COG holds a Sara Borrell postdoctoral fellowship awarded from the Carlos III National Institute of Health (CD13/00072). MP held a Juan de la Cierva postdoctoral fellowship awarded from the Spanish Ministry of Ministry of Economy and Competitiveness (JCI-2011-09479). DFM received support from the Italian Ministry of Health, 5x1000 Grant-2011.

BACKGROUND & AIMS: Vitamin D deficiency is common among pregnant women and may be associated with several adverse health outcomes including cancer. Micronuclei frequency is a biomarker of early genetic effects and has been used to examine the association between genotoxic exposures and cancer. We examined maternal vitamin D levels during pregnancy in associations with micronuclei frequency in maternal blood and in cord blood. METHODS: 173 mothers and 171 newborns born between 2007 and 2008 in Heraklion (Crete, Greece) were included in the study. Between 14th and 18th weeks of gestation we collected information on maternal diet using food frequency questionnaires (FFQs). We measured maternal serum concentrations of 25-hydroxyvitamin D [25(OH)D] between the first and second trimester of pregnancy. We estimated dietary vitamin D intake using information from FFQ. After delivery we collected cord blood and maternal peripheral blood. We used the cytokinesis-block micronucleus (CBMN) assay to assess the frequencies of micronucleated cells in binucleated T lymphocytes (MNBN). RESULTS: Maternal insufficient serum levels of 25(OH)D (

Background: Persistent organic pollutants (POPs) are a group of diverse substances, including polychlorinated biphenyls (PCBs) and organochlorine pesticides that are resistant to biodegradation and ubiquitously present in our environment. Exposure to endocrine disrupting chemicals such as POPs has been linked to type 2 diabetes and metabolic disturbances in epidemiological and animal studies, but little is known about POPs exposure during pregnancy and the development of gestational diabetes mellitus (GDM). The purpose of this study was to determine the extent to which exposure to current low levels of different POPs in the first trimester of pregnancy is associated with GDM risk in 939 women from the “Rhea” pregnancy cohort in Crete, Greece. Methods: Concentrations of several PCBs, dichlorodiphenyldichloroethene (DDE), and hexachlorobenzene (HCB) were determined in first trimester maternal serum by triple quadrupole mass spectrometry. We defined total PCBs as the sum of all congeners, nondioxin-like PCBs as the sum of PCB 153, 138, 170 and 180, and dioxin-like PCBs as the sum of PCB 118 and 156. Pregnant women were screened for gestational diabetes mellitus (GDM) between 24 and 28 weeks of gestation, and GDM was defined by the criteria proposed by Carpenter and Coustan. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression models. Results: Of the 939 women, 68 (7%) developed GDM. Serum concentrations of POPs were higher in women with GDM. Women in the medium and high tertiles of PCBs had 3.90 (95% CI: 1.37, 11.06) and 3.60 (95% CI: 1.14, 11.39) fold respectively higher odds of developing GDM compared to women in the lowest tertile of PCB exposure after adjusting for pre-pregnancy BMI and several other confounders. Odds of GDM for women in the medium and high tertiles of dioxin-like PCBs was 5.63 (95% CI: 1.81, 17.51) and 4.71 (95% CI: 1.38, 16.01) and for nondioxin-like PCBs 2.36 (95% CI: 0.89, 6.23) and 2.26 (95% CI: 0.77, 6.68) respectively. Prenatal DDE and HCB exposure were not significantly associated GDM risk. Conclusions: These findings suggest that women with high PCBs levels in early pregnancy had higher risk for GDM. Further studies are needed to replicate these results and to evaluate potential biological mechanisms underlying the observed associations. Keywords: Gestational diabetes mellitus, Persistent organic pollutants, Polychlorinated biphenyls (PCBs), Organochlorine pesticides, Pregnancy

Background: Persistent Organic Pollutants (POPs) are highly-resistant compounds to environmental degradation and due to fat solubility they bioaccumulate through the food chain. As they cross the placenta, in utero exposure to POPs could disrupt child neurodevelopment as they are considered to be neurotoxic. Aims: We examined whether in utero exposure to levels of different POPs is associated with offspring cognitive and behavioral outcomes at 4 years of age in a mother-child cohort in Crete, Greece (Rhea study). Methods: We included 689 mother-child pairs. Concentrations of several polychlorinated biphenyls (PCBs) and other organochlorine compounds (dichlorodiphenyl dichloroethene [DDE], hexachlorobenzene [HCB]) were determined in maternal serum collected in the first trimester of pregnancy by triple quadrupole mass spectrometry. Neurodevelopment at 4 years was assessed by means of the McCarthy Scales of Children's Abilities. Behavioral difficulties were assessed by Strengths and Difficulties Questionnaire and Attention Deficit Hyperactivity Disorder Test. Linear regression analyses were used to estimate the associations between the exposures and outcomes of interest after adjustment for potential confounders. Results: Children with “high” HCB concentrations (≥90th percentile) in maternal serum, demonstrated decreased scores in perceptual performance (adjusted β = −6.07; 95% CI: −10.17, −1.97), general cognitive (adjusted β = −4.97; 95% CI: −8.99, −0.96), executive function (adjusted β = −6.24; 95% CI: −10.36, −2.11) and working memory (adjusted β = −4.71; 95% CI: −9.05, −0.36) scales at 4 years of age. High exposure to PCBs (≥90th percentile) during pregnancy was associated with a 4.62 points reduction in working memory score at 4 years of age (95% CI: −9.10, −0.14). Prenatal exposure to DDE, HCB and PCBs was not associated with child behavioral difficulties. Conclusions: The findings suggest that prenatal exposure to HCB and PCBs may contribute to reduced cognitive development at preschool age. Our results raise the possibility that exposure to HCB may play a more important role in child cognition than previously considered. Keywords: Persistent organic pollutants, PCBs, HCB, Neuropsychological development, Cognition, McCarthy Scales for Children’s Abilities

Objective Leptin is critical for central nervous system development and maturation. This study aimed to evaluate the potential regulatory role of cord leptin in the neuropsychomotor development of children ages 18 months to 6 years. Methods This study included 424 children from a prospective mother-child cohort (Rhea Study; Crete, Greece) with available cord leptin levels and data on neurodevelopmental outcomes at 18 months (Bayley Scales of Infant and Toddler Development, Third Edition), 4 years (McCarthy Scales of Children's Abilities), and 6 years (Raven's Coloured Progressive Matrices and Trail Making Test). Multivariable linear regression models were used to explore the associations. Results Each 10-ng/mL increase in the cord leptin level was associated with increased scores on the gross motor scale at 18 months (β coefficient: 3.8; 95% CI: 0.0-7.5), with decreased scores in the general cognitive performance (β coefficient: -3.0; 95% CI: -5.5 to -0.4), perceptual performance (β coefficient: -3.4; 95% CI: -6.0 to -9.9), working memory (β coefficient: -3.1; 95% CI: -5.7 to -0.4), executive function (β coefficient -3.1; 95% CI: -5.7 to -0.5), and functions of the posterior cortex (β coefficient: -2.7; 95% CI: -5.2 to -0.1) scales at 4 years, and with a 3.7-unit decrease in the Raven's Coloured Progressive Matrices score at 6 years (β coefficient: -3.7; 95% CI: -6.9 to -0.5). Conclusions Increased cord leptin levels are associated with enhanced gross motor development at 18 months but decreased cognitive performance in early and middle childhood.

Mother-Child and Birth cohort studies offer an excellent opportunity to evaluate the effects of ’early life’ exposures providing an insight in the etiology of chronic diseases. To our knowledge, this is the first study that aims to provide a comprehensive review of these studies in the Middle East Area (MEA). Authors searched to relevant registries, the Pubmed interface, internet search tools and had personal contact with study PIs. The search revealed 117 mother-child and birth cohort studies from 9 MEA region countries (Iran, Israel, Jordan, Kuwait, Lebanon, Palestine, Saudi Arabia, United Arab Emirates and Qatar). Variability in the identified studies refers to the study design, objectives and the years of recruitment. Biological samples and data on environmental exposures were absent with the exception of limited studies (n = 44). This review revealed a sufficient number of available cohorts, however few have followed up children beyond the age of 2 years. Improved study designs focused on molecular and environmental data acquisition are required in a region that shares a set of unique characteristics in terms of landscape, climate, culture, and lifestyle. This review provides valuable information for planning future studies and set the grounds for collaborationswithin the MEA region and internationally.

The evidence regarding a potential link of low-to-moderate iodine deficiency, selenium status, and cadmium exposure during pregnancy with neurodevelopment is either contradicting or limited. We aimed to assess the prenatal impact of cadmium, selenium, and iodine on children's neurodevelopment at 4 years of age. The study included 575 mother-child pairs from the prospective "Rhea" cohort on Crete, Greece. Exposure to cadmium, selenium and iodine was assessed by concentrations in the mother's urine during pregnancy (median 13 weeks), measured by ICPMS. The McCarthy Scales of Children's Abilities was used to assess children's general cognitive score and seven different sub-scales. In multivariable-adjusted regression analysis, elevated urinary cadmium concentrations (≥0.8 µg/L) were inversely associated with children's general cognitive score [mean change: -6.1 points (95 % CI -12; -0.33) per doubling of urinary cadmium; corresponding to ~0.4 SD]. Stratifying by smoking status (p for interaction 0.014), the association was restricted to smokers. Urinary selenium was positively associated with children's general cognitive score [mean change: 2.2 points (95 % CI -0.38; 4.8) per doubling of urinary selenium; ~0.1 SD], although the association was not statistically significant. Urinary iodine (median 172 µg/L) was not associated with children's general cognitive score. In conclusion, elevated cadmium exposure in pregnancy of smoking women was inversely associated with the children's cognitive function at pre-school age. The results indicate that cadmium may adversely affect neurodevelopment at doses commonly found in smokers, or that there is an interaction with other toxicants in tobacco smoke. Additionally, possible residual confounding cannot be ruled out. 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 211250 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 226285 ENRIECO, EU-FP7-HEALTH-2012 Proposal No 308333 HELIX) 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: 2012–2015). The present study was also funded by Karolinska Institutet, the Swedish Research Council Formas (Project No. 210-2013-751), and Swedish Research Council

The intentional or accidental release of airborne toxics poses great risk to the public health. During these incidents, the greatest factor of uncertainty is related to the location and rate of released substance, therefore, an information of high importance for emergency preparedness and response plans. A novel computational algorithm is proposed to estimate, efficiently, the location and release rate of an airborne toxic substance source based on health effects observations; data that can be readily available, in a real accident, contrary to actual measurements. The algorithm is demonstrated by deploying a semi-empirical dispersion model and Monte Carlo sampling on a simplified scenario. Input data are collected at varying receptor points for toxics concentrations (C; standard approach) and two new types: toxic load (TL) and health effects (HE; four levels). Estimated source characteristics are compared with scenario values. The use of TL required the least number of receptor points to estimate the release rate, and demonstrated the highest probability (>90%). HE required more receptor points, than C, but with lesser deviations while probability was comparable, if not better. Finally, the algorithm assessed very accurately the source location when using C and TL with comparable confidence, but HE demonstrated significantly lower confidence.

Background: Bulky DNA adducts reflect genotoxic exposures, have been associated with lower birth weight, and may predict cancer risk. Objective: We selected factors known or hypothesized to affect in utero adduct formation and repair and examined their associations with adduct levels in neonates. Methods: Pregnant women from Greece, Spain, England, Denmark, and Norway were recruited in 2006–2010. Cord blood bulky DNA adduct levels were measured by the 32P-postlabeling technique (n = 511). Diet and maternal characteristics were assessed via questionnaires. Modeled exposures to air pollutants and drinking-water disinfection by-products, mainly trihalomethanes (THMs), were available for a large proportion of the study population. Results: Greek and Spanish neonates had higher adduct levels than the northern European neonates [median, 12.1 (n = 179) vs. 6.8 (n = 332) adducts per 108 nucleotides, p < 0.001]. Residence in southern European countries, higher maternal body mass index, delivery by cesarean section, male infant sex, low maternal intake of fruits rich in vitamin C, high intake of dairy products, and low adherence to healthy diet score were statistically significantly associated with higher adduct levels in adjusted models. Exposure to fine particulate matter and nitrogen dioxide was associated with significantly higher adducts in the Danish subsample only. Overall, the pooled results for THMs in water show no evidence of association with adduct levels; however, there are country-specific differences in results with a suggestion of an association in England. Conclusion: These findings suggest that a combination of factors, including unknown country-specific factors, influence the bulky DNA adduct levels in neonates. Citation: Pedersen M, Mendez MA, Schoket B, Godschalk RW, Espinosa A, Landström A, Villanueva CM, Merlo DF, Fthenou E, Gracia-Lavedan E, van Schooten FJ, Hoek G, Brunborg G, Meltzer HM, Alexander J, Nielsen JK, Sunyer J, Wright J, Kovács K, de Hoogh K, Gutzkow KB, Hardie LJ, Chatzi L, Knudsen LE, Anna L, Ketzel M, Haugen M, Botsivali M, Nieuwenhuijsen MJ, Cirach M, Toledano MB, Smith RB, Fleming S, Agramunt S, Kyrtopoulos SA, Lukács V, Kleinjans JC, Segerbäck D, Kogevinas M. 2015. Environmental, dietary, maternal, and fetal predictors of bulky DNA adducts in cord blood: a European mother–child study (NewGeneris). Environ Health Perspect 123:374–380; http://dx.doi.org/10.1289/ehp.1408613

BACKGROUND: The latest scientific reports raise concerns about the rapidly increasing burden of chronic diseases in the state of Qatar. Pregnant Qatari women often confront complications during pregnancy including gestational diabetes, hypertension, abortion and stillbirth. The investigation of early life environmental, genetic, nutritional and social factors that may affect lifelong health is of great importance. Birth cohort studies offer a great opportunity to address early life hazards and their possible long lasting effects on health. METHODS/DESIGN: The Qatari Birth Cohort study is the first mother-child cohort study in the Middle East Area that aims to assess the synergetic role of environmental exposure and genetic factors in the development of chronic disease and monitor woman and child health and/or obstetric characteristics with high prevalence. The present manuscript describes the recruitment phase of the study (duration: 2 years; expected number: 3000 families), where the pregnant Qatari women and their husbands are being contacted before the 15th week of gestation at the Primary Health Care Centers. The consented participants are interviewed to obtain information on several factors (sociodemographic characteristics, dietary habits, occupational/environmental exposure) and maternal characteristics are assessed based on anthropometric measurements, spirometry, and blood pressure. Pregnant women are invited to provide biological samples (blood and urine) in each trimester of their pregnancy, as well as cord blood at delivery. Fathers are also asked to provide biological samples. DISCUSSION: The present study provides invaluable insights into a wide range of early life factors affecting human health. With a geographical focus on the Middle East, it will be a resource for information to the wider scientific community and will allow the formulation of effective policies with a primary focus on public health interventions for maternal and child health.

Background: Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and pesticides bioaccumulate through the food chain and cross the placenta. POPs are developmental toxicants in animals but the epidemiological evidence on pregnancy outcomes is inconsistent. Maternal gestational weight gain has been recently suggested as a key factor explaining the association between PCBs with lower birth weight. Aims: We examined whether in utero exposure to current low levels of different POPs is associated with fetal growth and gestational age in a mother–child cohort in Crete, Greece (Rhea study), and evaluated specifically whether maternal gestational weight gain may affect this association. Methods: We included 1117 mothers and their newborns from the Rhea study. Mothers were interviewed and blood samples collected during the first trimester of pregnancy. Information on birth outcomes was retrieved from medical records. Concentrations of several PCBs, other organochlorine compounds (dichlorodiphenyl dichloroethene [DDE], dichlorodiphenyl trichloroethane [DDT] and hexachlorobenzene [HCB]) and one polybrominated diphenyl ether congener (tetra-bromodiphenyl ether [BDE-47]), were determined in maternal serum by triple quadrupole mass spectrometry. Multiple linear regression models were used to investigate the associations of birth weight, gestational age, and head circumference with each compound individually on the log10 scale, and with combined exposures through the development of an exposure score. Results: In multivariate models, birth weight was negatively associated with increasing levels of HCB (β = −161.1 g; 95% CI: −296.6, −25.7) and PCBs (β = −174.1 g; 95% CI: −332.4, −15.9); after further adjustment for gestational weight gain these estimates were slightly reduced (β = −154.3 g; 95% CI: −300.8, −7.9 for HCB and β = −135.7 g; 95% CI: −315.4, 43.9 for PCBs). Furthermore, in stratified analysis, the association between POPs and birth weight was only observed in women with inadequate or excessive gestational weight gain. Small, negative associations were observed with head circumference while no association was observed with gestational age. Conclusions: The findings suggest that prenatal exposure to PCBs and HCB impairs fetal growth and adds to the growing literature that demonstrates an association between low-level environmental pollutant exposure and fetal growth. Furthermore our results suggest that the association of POPs, maternal gestational weight gain and birth weight is probably more complex than that previously hypothesized. Keywords: Persistent organic pollutants, PCBs, HCB, Birth outcomes, Gestational weight gain, Cohort studies

Background: Maternal exposure to dioxins and dioxin-like compounds may affect fetal growth and development. We evaluated the association between in utero dioxin-like activity and birth outcomes in a prospective European mother-child study. Methods: We measured dioxin-like activity in maternal and cord blood plasma samples collected at delivery using the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX) bioassay in 967 mother-child pairs, in Denmark, Greece, Norway, Spain, and England. Multiple linear regression models were used to investigate the associations with birth weight, gestational age, and head circumference. Results: Plasma dioxin-like activity was higher in maternal sample than in cord samples. Birth weight was lower with medium (-58 g [95% confidence interval (CI) = -176 to 62]) and high (-82 g [-216 to 53]) tertiles of exposure (cord blood) compared with the lowest tertile. Gestational age was shorter by approximately half a week in the highest compared with the lowest (-0.4 weeks [95% CI = -0.8 to -0.1]). This association was stronger in boys than in girls, although the statistical evidence for interaction was weak (P = 0.22). Analysis based on CALUX-toxic equivalents expressed per milliliter of plasma showed similar trends. We found no association between dioxin-like activity in maternal plasma and birth outcomes. Conclusions: Results from this international general population study suggest an association between low-level prenatal dioxin-like activity and shorter gestational age, particularly in boys, with weaker associations for birth weight.

Background: Tobacco-smoke, airborne, and dietary exposures to polycyclic aromatic hydrocarbons (PAHs) have been associated with reduced prenatal growth. Evidence from biomarker-based studies of low-exposed populations is limited. Bulky DNA adducts in cord blood reflect the prenatal effective dose to several genotoxic agents including PAHs. Objectives: We estimated the association between bulky DNA adduct levels and birth weight in a multicenter study and examined modification of this association by maternal intake of fruits and vegetables during pregnancy. Methods: Pregnant women from Denmark, England, Greece, Norway, and Spain were recruited in 2006–2010. Adduct levels were measured by the 32P-postlabeling technique in white blood cells from 229 mothers and 612 newborns. Maternal diet was examined through questionnaires. Results: Adduct levels in maternal and cord blood samples were similar and positively correlated (median, 12.1 vs. 11.4 adducts in 108 nucleotides; Spearman rank correlation coefficient = 0.66, p < 0.001). Cord blood adduct levels were negatively associated with birth weight, with an estimated difference in mean birth weight of –129 g (95% CI: –233, –25 g) for infants in the highest versus lowest tertile of adducts. The negative association with birth weight was limited to births in Norway, Denmark, and England, the countries with the lowest adduct levels, and was more pronounced in births to mothers with low intake of fruits and vegetables (–248 g; 95% CI: –405, –92 g) compared with those with high intake (–58 g; 95% CI: –206, 90 g). Conclusions: Maternal exposure to genotoxic agents that induce the formation of bulky DNA adducts may affect intrauterine growth. Maternal fruit and vegetable consumption may be protective. The NewGeneris (Newborns and Genotoxic exposure risks) study was funded by the European Union (EU contract FOOD-CT-2005-016320). The study was also supported by the National Institute for Health Research, United Kingdom (programme grant RP-PG-0407-10044), the Norwegian Ministry of Health, the Norwegian Ministry of Education and Research, the Norwegian Research Council/FUGE (grant 151918/S10), the EU funded HiWATE (contract Food-CT-2006-036224), the U.S. National Institutes of Health (NIH)/National Institute of Environmental Health Sciences (contract NO-ES-75558), and the U.S. NIH/National Institute of Neurological Disorders and Stroke (grant 1 UO1 NS 047537-01). M.P. holds a Juan de la Cierva postdoctoral fellowship awarded from the Spanish Ministry of Science and Innovation (JCI-2011-09479) The NewGeneris (Newborns and Genotoxic exposure risks) study was funded by the European Union (EU contract FOOD-CT-2005-016320). The study/nwas also supported by the National Institute for Health Research, United Kingdom (programme grant RP-PG-0407-10044), the Norwegian Ministry of/nHealth, the Norwegian Ministry of Education and Research, the Norwegian Research Council/FUGE (grant 151918/S10), the EU funded HiWATE (contract Food-CT-2006-036224), the U.S. National Institutes of Health (NIH)/National Institute of Environmental Health Sciences (contract NO-ES-75558), and the U.S. NIH/National Institute of Neurological Disorders and Stroke (grant 1 UO1 NS 047537-01). M.P. holds a Juan de la Cierva postdoctoral fellowship awarded from the Spanish Ministry of Science and Innovation (JCI-2011-09479)

Context: Maternal thyroid dysfunction, especially in early pregnancy, may lead to pregnancy complications and adverse birth outcomes. Few population-based prospective studies have evaluated these effects and results are discrepant. Objective: We examined the association of thyroid function and autoimmunity in early pregnancy with adverse pregnancy and birth outcomes. Setting and Participants: The study used data from the prospective mother-child cohort >Rhea> study in Crete, Greece. A total of 1170 women with singleton pregnancies participated in this analysis. Maternal serum samples in the first trimester of pregnancy were tested for thyroidhormones (TSH, free T4, and free T3) and thyroid antibodies (thyroid peroxidase antibody and thyroglobulin antibody). Multivariable log-Poisson regression models were used adjusting for confounders. Main Outcome Measures: Outcomes included gestational diabetes, gestational hypertension/preeclampsia, cesarean section, preterm delivery, low birth weight, and small-for-gestational-age neonates. Results: The combination of high TSH and thyroid autoimmunity in early pregnancy was associated with a 4-fold increased risk for gestational diabetes [relative risk (RR) 4.3, 95% confidence interval (CI) 2.1- 8.9)] and a 3-fold increased risk for low birth weight neonates (RR 3.1,95%CI 1.2- 8.0) after adjustment for several confounders. Women positive for thyroid antibodies without elevated TSH levels in early pregnancy were at high risk for spontaneous preterm delivery (RR 1.7, 95% CI 1.1-2.8), whereas the combined effect of high TSH and positive thyroid antibodies did not show an association with preterm birth. Conclusions: High TSH levels and thyroid autoimmunity in early pregnancy may detrimentally affect pregnancy and birth outcomes. Copyright © 2012 by The Endocrine Society., This work was supported by the European Uniuon Integrated Projects NewGeneris, Sixth Framework Programme (Contract FOOD-CT-2005-016320), and Chicos, Seventh Framework Programme (Contract Health-F2-2009-241604).

BackgroundQatar demonstrated high incidence of low birth weight (8.8%), preterm deliveries (8.5%), and stillbirths rate (6.85) (Rahman et all, 2013). In addition, Qatari pregnant women are 1.2 times more likely to have a low birth weight newborn compared to other Arab women, where Gestational Diabetes (13.4%–20.8%) and Gestational Hypertension (15.2%–21.6%) were the leading maternal complications observed.). The WHO Qatar STEPS survey (2012) on chronic disease risk factors reported that 42.5% of the women in reproductive age have high risk factor for developing chronic diseases, while 68% are overweight with high blood pressure, elevated total cholesterol levels and fasting glucose. In addition to these data, the International Association of the study of Obesity has ranked Qatar sixth globally for prevalence of obesity.Methods/DesignThis is a prospective five year cohort study developed by SCH. Pregnant women (n = 2500) and offspring will be, respectively, recruited during certain critical periods of fetal development and the first years of life. The genetic, environmental exposures and potential human health risks (including cancer, immune, metabolic and cardiovascular diseases, neurodevelopmental abnormalities, asthma, and birth outcomes) will be investigated via specific questionnaires and collection of biological samples. The study comprises an extensive range of “omics” analyses for the in-depth investigation of the impact of the genome-exposome synergy in the establishment of adverse birth outcomes and early childhood diseases. This is a multidisciplinary study where SCH is collaborating with various research institutions such as PHCC, QU, WCMC-Q, QBRI, QBB, QEERI, TAMU-Q, Sidra, and HMC.DiscussionHuman epidemiological studies and animal research data propose a concept of fetal developmental programming whereby intrauterine environment is believed to trigger adaptations preparing the fetus in a particular range of environments. In this context intrauterine exposures have been referred to as the “fourth factor” in the causation of human disease. Consequently, the design of birth-cohort study is crucial for investigating the complex multidimensional molecular mechanisms associated with genetic, environmental and socioeconomic determinants, and their contribution to the development of chronic diseases and birth defects. This first birth-cohort in the state of Qatar has been launched by SCH with the main objective of evaluating the association of these exposures with the fetal development, reproductive outcomes, endocrine related outcomes, neurodevelopment, and obesity and with the occurrence of chronic diseases including asthma and allergies, metabolic syndrome and endocrine disorders that appear first in childhood but may perpetuate to future health problems. The main outcome of this multi-disciplinary project is to address the national concern of low reproductive health. The identification and quantification of the gene-environmental interaction affecting fetal growth and child health, shall provide evidence-based data to assist policy makers at SCH to develop better primary prevention programs and evidence based healthcare policies concerning Maternal Health, Reproductive Health, Pregnancy and Child Health in Qatar.

It is a fact that people spend 60-90% of their lifetime indoors; nevertheless, in case of Middle Eastern countries this percentage can reach 100%, especially during summer and dust storms periods. Indoor air quality (IAQ) is of great importance for peoples’ health, especially for vulnerable population groups. To the best of our knowledge, recent air quality studies in areas with hot and arid climate such as Qatar (or Middle East Area in general), are limited. Especially for the indoor environment, there is lack of indoor sources identification and consequently there are insufficient mitigation actions. This study aimed to assess the IAQ in an air-tight public building during warm season. For this scope, a monitoring campaign of particulate matter (PM2.5 and PM10) and volatile organic compounds (VOCs) for both indoor/outdoor measurements was performed at the Supreme Council of Health building in Doha, Qatar. The duration of the campaign was from 22/4/2015 to 21/6/2015. Chemical analysis for organic/elemental carbon (OC/EC), ions (NO3 − , SO4 2 − , Cl− , Br − , NH4 +, Na+, K+, Mg2+, Ca2+) and elements (Cu, Pb, Cr, Ni, Cd, Zn, Fe, Al) was conducted on the collected particle mass. Results showed that OC and EC outdoor values were higher (by 3-4 times) than the indoor ones for both PM fractions. Outdoor average OC value was 12.7 and 16.3 μgm− 3 for PM2.5 and PM10 respectively. Among the elements analyzed, Zn dominated in indoor samples followed by Mn, Ba, Pb while outdoors, Sr and Mn were the most abundant species. Concerning ions, indoor to outdoor ratio (I/O), was in all cases lower than unity implying the prevalence of outdoor sources emissions. Finally, I/O was close to unity for VOCs except for xylene and dlimonene, which were significantly higher indoors implying the existence of internal emission sources.

Cord leptin is a biomarker of fetal growth and adiposity with a role in predicting weight gain during the first months of life and childhood obesity. Our objective was to calculate gender-specific reference intervals for cord blood leptin in healthy neonates in Crete, Greece. We used data from the prospective mother–child cohort (“Rhea” study) in Crete, Greece. The analysis included 398 neonates chosen with strict inclusion criteria based on maternal and fetal characteristics. Cord leptin reference intervals for male neonates were 1.4–18.2 ng/mL and for females 2.0–25.8 ng/mL. Females had higher leptin levels (median 7.4; IQR 4.7–10.9) compared to males (median 4.9; IQR 3.2–7.6) (p < 0.001). Conclusion Gender-specific reference ranges are essential in clinical practice for correct interpretation of leptin values in cord blood and early detection of childhood obesity.

The relevance of preconceptional and prenatal toxicant exposures for genomic stability in offspring is difficult to analyze in human populations, because gestational exposures usually cannot be separated from preconceptional exposures. To analyze the roles of exposures during gestation and conception on genomic stability in the offspring, stability was assessed via the Comet assay and highly sensitive, semiautomated confocal laser scans of gammaH2AX foci in cord, maternal, and paternal blood as well as spermatozoa from 39 families in Crete, Greece, and the United Kingdom. With use of multivariate linear regression analysis with backward selection, preconceptional paternal smoking (% tail DNA: P>0.032; gammaH2AX foci: P>0.018) and gestational maternal (% tail DNA: P>0.033) smoking were found to statistically significantly predict DNA damage in the cord blood of F1 offspring. Maternal passive smoke exposure was not identified as a predictor of DNA damage in cord blood, indicating that the effect of paternal smoking may be transmitted via the spermatozoal genome. Taken together, these studies reveal a role for cigarette smoke in the induction of DNA alterations in human F1 offspring via exposures of the fetus in utero or the paternal germline. Moreover, the identification of transgenerational DNA alterations in the unexposed F1 offspring of smoking-exposed fathers supports the claim that cigarette smoke is a human germ cell mutagen.-Laubenthal, J., Zlobinskaya, O., Poterlowicz, K., Baumgartner, A., Gdula, M. R., Fthenou, E., Keramarou, M., Hepworth, S. J., Kleinjans, J. C. S., van Schooten, F.-J., Brunborg, G., Godschalk, R. W., Schmid, T. E., Anderson, D. Cigarette smoke-induced transgenerational alterations in genome stability in cord blood of human F1 offspring.

Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.

Background Bisphenol A (BPA) is a chemical used extensively worldwide in the manufacture of plastic polymers. The environmental obesogen hypothesis suggests that early life exposure to endocrine disrupting chemicals such as BPA may increase the risk for wt gain later in childhood but few prospective epidemiological studies have investigated this relationship. Objectives We examined the association of early life BPA exposure with offspring obesity and cardiometabolic risk factors in 500 mother-child pairs from the RHEA pregnancy cohort in Crete, Greece. Methods BPA concentrations were measured in spot urine samples collected at the 1st trimester of pregnancy) and from children at 2.5 and 4 years of age. We measured birth wt, body mass index (BMI) from 6 months to 4 years of age, waist circumference, skinfold thickness, blood pressure, serum lipids, C-reactive protein, and adipokines at 4 years of age. BMI growth trajectories from birth to 4 years were estimated by mixed effects models with fractional polynomials of age. Adjusted associations were obtained via multivariable regression analyses. Results The prevalence of overweight/obesity was 9% at 2, 13% at 3% and 17% at 4 years of age. Geometric mean BPA concentrations were 1.2 μg/g creatinine±7.9 in 1st trimester, 5.1 μg/g±13.3 in 2.5 years and 1.9 μg/g±4.9 in 4 years. After confounder adjustment, each 10-fold increase in BPA at 4 years was associated with a higher BMI z-score (adj. β=0.2; 95% CI: 0.01, 0.4), waist circumference (adj. β=1.2; 95% CI: 0.1, 2.2) and sum of skinfold thickness (adj. β=3.7 mm; 95% CI: 0.7, 6.7) at 4 years. Prenatal BPA was negatively associated with BMI and adiposity measures in girls and positively in boys. We found no associations of early life exposure to BPA with other offspring cardiometabolic risk factors. Conclusions Prenatal BPA exposure was not consistently associated with offspring growth and adiposity measures but higher early childhood BPA was associated with excess child adiposity.

BACKGROUND: The use of cancer-related biomarkers in newborns has been very limited. OBJECTIVE: We investigated the formation of micronuclei (MN) in full-term and preterm newborns and their mothers from the Rhea cohort (Crete), applying for the first time in cord blood a validated semiautomated analysis system, in both mono-and binucleated T lymphocytes. METHODS: We assessed MN frequencies in peripheral blood samples from the mothers and in umbilical cord blood samples. We calculated MN in mononucleated (MNMONO) and binucleated (MNBN) T lymphocytes and the cytokinesis block proliferation index (CBPI) in 251 newborns (224 full term) and 223 mothers, including 182 mother-child pairs. Demographic and lifestyle characteristics were collected. RESULTS: We observed significantly higher MNBN and CBPI levels in mothers than in newborns. In newborns, MNMONO and MNBN were correlated (r = 0.35, p

Exposure to toxic metals during pregnancy may have detrimental effects on foetal development. We assessed the role of sociodemographic characteristics and active and passive smoking on blood concentrations of metals (As, Cd, Pb, Hg, Sb, U, Mn and Mo). Venous blood drawn from 50 pregnant women, randomly selected from the mother-child birth cohort 'Rhea'. Extensive questionnaire data on active and passive smoking were collected. Urinary cotinine was measured to validate self-reported exposure and non-smoking status. Smokers had higher concentrations of Cd (1.0 µg/L) as compared with non-smokers (0.29 µg/L, P 0.001) and a tendency for higher As and Hg. Among non-smokers, blood As and Hg concentrations were also associated with exposure to passive smoking in public venues and the family home and to overall greater secondhand smoke (SHS) exposure (As: 0.97µg/L among heavy-exposed compared with 0.20 µg/L among the low-exposed, P 0.05; Hg: 2.1 µg/L vs. 0.9 µg/L respectively, P 0.05). Controlling for fish and seafood intake altered the statistical significance but not the direction of the above associations. Smoking was associated with higher Cd concentrations in pregnant women, although the association between passive smoking and elevated As and Hg concentrations was indicative, however inconclusive.

Although DNA damage in human spermatozoa is associated with adverse health effects, its origin is not fully understood. Therefore, we assessed biomarkers in ejaculates that retrospectively reflect processes that occurred in the epididymis or testis. Smoking increased the amount of DNA strand breaks (P

Background: Investigations of the presence of the precarcinogenic DNA adduct O6-methylguanine (O6-meG) in humans and its association with exposure or cancer risk have been hindered by the absence of analytic methods of adequate sensitivity and throughput. We report the development, validation, and application of an ELISA-type assay for O6-meG appropriate for large-scale population studies. Methods: In the new analytic method, restriction enzymes are used to digest DNA to fragments of size expected to contain no more than one O6-meG residue. Anti-adduct antisera are used to transfer O6-meG–containing fragments to a solid surface, where they are detected using anti-ssDNA antisera, the high ratio of normal nucleotides to adducts providing a strong signal enhancement. Results: An assay with a limit of detection of 1.5 adducts/109 nucleotides using 10 μg of DNA, a dynamic range of approximately two orders of magnitude and satisfactory precision and accuracy characteristics was established and validated. Analysis of samples from 120 subjects from the Rhea mother–child cohort in Crete led to the detection of O6-meG in 70% of maternal and 50% of cord blood buffy coat samples at mean levels of 0.65 and 0.38 adducts/108 nucleotides, respectively. Conclusions: The frequent observation of O6-meG in human DNA is compatible with dietary compounds (e.g. N-nitroso compounds or their precursors), or endogenous processes being responsible for the formation of this adduct. Impact: The new assay opens the way for large-scale population studies of O6-meG as a biomarker of exposure or risk. The approach used in this assay can, in principle, be extended to any DNA adduct for which suitable antisera are available. Cancer Epidemiol Biomarkers Prev; 20(1); 82–90. ©2011 AACR.

Platelet-derived growth factor (PDGF) is a major polypeptide mitogen for cells of mesenchymal origin such as fibroblasts. Chondroitin sulfate chains (CS), which are abundant in the extracellular matrix have been shown to physically interact with PDGF-BB modulating its biological function. The aim of the present study was to examine the involvement of CS on PDGF-BB induced proliferative responses and receptor activation in human lung fibroblasts. The addition of exogenous free CS chains caused a significant downregulation of the PDGF-BB mediated mitogenic and chemotactic responses. Similar results were obtained by the increase of endogenous CS biosynthesis after beta-D-xyloside treatment. Furthermore, removal of the membrane-bound CS chains by selective enzymatic treatment significantly increased the proliferative capacity of human fibroblasts. Analysis of PDGF-R phosphorylation in the presence of CS or beta-D-xyloside, revealed a reduction of PDGF-Rbeta phosphorylation in the tyrosine residue 1021. These results demonstrate, for the first time, that CS either soluble or surface bound downregulates the mitogenic responses of PDGF-BB in normal human lung fibroblasts through the reduction of PDGF-Rbeta phosphorylation.

Introduction: Micronuclei (MN) are markers of pre-carcinogenic events and have been associated with cancer risk in adults. Few studies have examined MN frequencies in pregnant women and newborns. W...

Introduction: Bisphenol A (BPA) is a chemical used extensively worldwide in the manufacture of plastic polymers. The environmental obesogen hypothesis suggests that early life exposure to endocrine...

Exposure to endocrine disruptors, used as additives, preservatives, plasticisers and solvents in numerous consumer products, might cause adverse health effects. Humans exposed to these chemicals, metabolise and excrete them mostly via urine. Urinary metabolite concentrations are used as biomarkers of exposure. We evaluated the exposure of 4-month pregnant women and their children at 2 years of age to phthalates, parabens and bisphenol-A. Concentrations of eight phthalate metabolites, six parabens and bisphenol-A were measured in 239 mother–child pairs of the “Rhea” cohort in Greece. Concentration levels in mother and children were comparable with corresponding concentrations in other countries worldwide. Low Spearman correlation coefficients (CC 0.1–0.2, p-value

BACKGROUND: Prenatal exposure to endocrine-disrupting chemicals such as persistent organic pollutants (POPs) may increase risk of obesity later in life. OBJECTIVE: We examined the relation of in utero POPs exposure to offspring obesity and cardiometabolic risk factors at 4 years of age in the Rhea mother-child cohort in Crete, Greece (n = 689). METHODS: We determined concentrations of polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), and hexachlorobenzene (HCB) in first-trimester maternal serum. We measured child weight, height, waist circumference, skinfold thicknesses, blood pressure (BP), blood levels of lipids, C-reactive protein, and adipokines at 4 years of age. Childhood obesity was defined using age- and sex-specific cut points for body mass index (BMI) as recommended by the International Obesity Task Force. RESULTS: On multivariable regression analyses, a 10-fold increase in HCB was associated with a higher BMI z-score (adjusted β = 0.49; 95% CI: 0.12, 0.86), obesity [relative risk (RR) = 8.14; 95% CI: 1.85, 35.81], abdominal obesity (RR = 3.49; 95% CI: 1.08, 11.28), greater sum of skinfold thickness (β = 7.71 mm; 95% CI: 2.04, 13.39), and higher systolic BP (β = 4.34 mmHg; 95% CI: 0.63, 8.05) at 4 years of age. Prenatal DDE exposure was associated with higher BMI z-score (β = 0.27; 95% CI: 0.04, 0.5), abdominal obesity (RR = 3.76; 95% CI: 1.70, 8.30), and higher diastolic BP (β = 1.79 mmHg; 95% CI: 0.13, 3.46). PCBs were not significantly associated with offspring obesity or cardiometabolic risk factors./nCONCLUSIONS: Prenatal exposure to DDE and HCB was associated with excess adiposity and higher blood pressure levels in early childhood. The Rhea project was financially supported by European Union (EU) grants for specific projects (EU FP6-2003-Food-3-NewGeneris; EU FP6. STREP HiWATE; EU FP7 ENV.2007.1.2.2.2. Project no. 211250 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. 226285 ENRIECO; EU-FP7-HEALTH-2012 Proposal no. 308333 HELIX), MeDALL (FP7 European Union project, no. 264357), 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). E.O. was supported by the U.S. National Institutes of Health (K24 HD069408).

The use of biomarkers of early genetic effects, predictive for cancer, such as micronuclei (MN) in lymphocytes, may help to investigate the association between diet and cancer. We hypothesised that the presence of mutagens in the diet may increase MN formation. A 'pooled' standardised analysis was performed by applying the same experimental protocol for the cytokinesis block micronucleus assay in 625 young healthy women after delivery from five European study populations (Greece, Denmark, UK, Spain and Norway). We assessed MN frequencies in mono- and binucleated T-lymphocytes (MNMONO and MNBN) and the cytokinesis blocked proliferation index using a semi-automated image analysis system. Food frequency questionnaires (FFQs) were used to estimate intake of fatty acids and a broad range of immunotoxic and genotoxic/carcinogenic compounds through the diet. Pooled difference based on delivery type revealed higher MNMONO frequencies in caesarean than in vaginal delivery (P = 0.002). Statistical analysis showed a decrease in MNMONO frequencies with increasing calculated omega-6 PUFA concentrations and a decrease in MNBN frequencies with increasing calculated omega-3 PUFA concentrations. The expected toxic compounds estimated by FFQs were not associated with MN formation in mothers after delivery. In pregnant women, an omega-3 and -6 rich diet estimated by FFQ is associated with lower MN formation during pregnancy and delivery.

Background: The environmental obesogen hypothesis suggests that prenatal or early life exposure to certain endocrine disrupting chemicals such as persistent organic pollutants (POPs) may cause perm...

Background: Incidence of childhood cancer has increased in recent decades. The causes of childhood cancer are poorly understood. High micronuclei (MN) frequency has been associated in adults with f...

Background Preterm birth (PB) and fetal growth restriction (FGR) convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. Identifying early in pregnancy the unfavourable maternal conditions that can predict poor birth outcomes could help their prevention and management. Here we used an exploratory metabolic profiling approach (metabolomics) to investigate the association between birth outcomes and metabolites in maternal urine collected early in pregnancy as part of the prospective mother–child cohort Rhea study. Metabolomic techniques can simultaneously capture information about genotype and its interaction with the accumulated exposures experienced by an individual from their diet, environment, physical activity or disease (the exposome). As metabolic syndrome has previously been shown to be associated with PB in this cohort, we sought to gain further insight into PB-linked metabolic phenotypes and to define new predictive biomarkers. Methods Our study was a case–control study nested within the Rhea cohort. Major metabolites (n = 34) in maternal urine samples collected at the end of the first trimester (n = 438) were measured using proton nuclear magnetic resonance spectroscopy. In addition to PB, we used FGR in weight and small for gestational age as study endpoints. Results We observed significant associations between FGR and decreased urinary acetate (interquartile odds ratio (IOR) = 0.18 CI 0.04 to 0.60), formate (IOR = 0.24 CI 0.07 to 0.71), tyrosine (IOR = 0.27 CI 0.08 to 0.81) and trimethylamine (IOR = 0.14 CI 0.04 to 0.40) adjusting for maternal education, maternal age, parity, and smoking during pregnancy. These metabolites were inversely correlated with blood insulin. Women with clinically induced PB (IPB) had a significant increase in a glycoprotein N-acetyl resonance (IOR = 5.84 CI 1.44 to 39.50). This resonance was positively correlated with body mass index, and stratified analysis confirmed that N-acetyl glycoprotein and IPB were significantly associated in overweight and obese women only. Spontaneous PB cases were associated with elevated urinary lysine (IOR = 2.79 CI 1.20 to 6.98) and lower formate levels (IOR = 0.42 CI 0.19 to 0.94). Conclusions Urinary metabolites measured at the end of the first trimester are associated with increased risk of negative birth outcomes, and provide novel information about the possible mechanisms leading to adverse pregnancies in the Rhea cohort. This study emphasizes the potential of metabolic profiling of urine as a means to identify novel non-invasive biomarkers of PB and FGR risk.