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Abstract: Platelet derived growth factor is involved in the autocrine growth stimulation of malignant cells, the stimulation of angiogenesis and the recruitment and regulation of tumor fibroblasts. PDGF has been shown to physically interact with glycosaminoglycans which are abundant in the fibrosarcoma cell microenvironment. Aim of the present study was to examine the effects of glycosaminoglycans on the mitogenic function of platelet derived growth factor in two human fibrosarcoma cell lines (B6FS, HT1080). For this purpose exogenously added glycosaminoglycans, regulators of endogenous glycosaminoglycan synthesis (sodium chlorate as selective inhibitor and β-d-xyloside as a stimulator) and specific glycosidases to cleave cell-associated glycosaminoglycans, were utilized. Platelet derived growth factor demonstrated a growth stimulating effect on B6FS, whereas no effect was evident on HT1080 fibrosarcoma cells. β-d-Xyloside had no effect on the basal level or the platelet derived growth factor-induced cell proliferation, whereas sodium chlorate severely reduced the basal level of proliferation in both cell lines. Significant co-stimulatory effects of chondroitin sulfate A in combination with platelet derived growth factor BB on the growth of HT1080 and B6FS cells were found. The co-stimulatory effect of chondroitin sulfate A was not due to transcriptional up regulation of platelet derived growth factor receptors genes, but rather to more efficient signalling of tyrosine kinase receptors. In conclusion, this study shows that chondroitin sulfate A can enhance the mitogenic activity of platelet-derived growth factor in fibrosarcoma cells utilizing a pathway which involves tyrosine kinases. This result introduces a new modulating role for chondroitin sulfate in signalling pathways critical for cancer growth. [Copyright &y& Elsevier]

Abstract: Versican, a large chondroitin sulphate proteoglycan and hyaluronan (HA), a non-sulphated glycosaminoglycan are major constituents of the pericellular matrix. In many neoplastic tissues, changes in the expression of versican and HA affect tumour progression. Here, we analyse the synthesis of versican and hyaluronan by fibrosarcoma cells, and document how the latter is affected by PDGF-BB, bFGF and TGFB2, growth factors endogenously produced by these cells. Fibrosarcoma cell lines B6FS and HT1080 were utilised and compared with normal lung fibroblasts (DLF). The major versican isoforms expressed by DLF and B6FS cells were V0 and V1. Treatment of B6FS cells with TGFB2 showed a significant increase of V0 and V1 mRNAs. Versican expression in HT1080 cells was not significantly affected by any of the growth factors. In addition, TGFB2 treatment increased versican protein in DLF cells. HA, showed approximately a 2-fold and a 9-fold higher production in DLF cells compared to B6FS and HT1080 cells, respectively. In HT1080 cells, HA biosynthesis was significantly increased by bFGF, whereas, in B6FS cells it was increased by TGFB2 and PDGF-BB. Furthermore, analysis of HA synthases (HAS) expression indicated that HT1080 expressed similar levels of all three HAS isoforms in the following order: HAS2> HAS3> HAS1. bFGF shifted that balance by increasing the abundance of HAS1. The major HAS isoform expressed by B6FS cells was HAS2. PDGF-BB and TGFB2 showed the most prominent effects by increasing both HAS2 and HAS1 isoforms. In conclusion, these growth factors modulated, through upregulation of specific HAS isoforms, HA synthesis, secretion and net deposition to the pericellular matrix. [Copyright &y& Elsevier]

Background: The placenta acts as a buffer to regulate the degree of fetal exposure to maternal cortisol through the 11-Beta Hydroxysteroid Dehydrogenase isoenzyme type 2 (11-β HSD2) enzyme. We conducted a systematic review and meta-analysis to assess the effect of prenatal psychological distress (PPD) on placental 11-β HSD2 gene expression and explore the related mechanistic pathways involved in fetal neurodevelopment., Methods: We searched PubMed, Embase, Scopus, APA PsycInfo®, and ProQuest Dissertations for observational studies assessing the association between PPD and 11-β HSD2 expression in human placentas. Adjusted regression coefficients (β) and corresponding 95% confidence intervals (CIs) were pooled based on three contextual PPD exposure groups: prenatal depression, anxiety symptoms, and perceived stress., Results: Of 3159 retrieved records, sixteen longitudinal studies involving 1869 participants across seven countries were included. Overall, exposure to PPD disorders showed weak negative associations with the placental 11-β HSD2 gene expression as follows: prenatal depression (β -0.01, 95% CI 0.05-0.02, I2=0%), anxiety symptoms (β -0.02, 95% CI 0.06-0.01, I2=0%), and perceived stress (β -0.01 95% CI 0.06-0.04, I2=62.8%). Third-trimester PPD exposure was more frequently associated with lower placental 11-β HSD2 levels. PPD and placental 11-β HSD2 were associated with changes in cortisol reactivity and the development of adverse health outcomes in mothers and children. Female-offspring were more vulnerable to PPD exposures., Conclusion: The study presents evidence of a modest role of prenatal psychological distress in regulating placental 11-β HSD2 gene expression. Future prospective cohorts utilizing larger sample sizes or advanced statistical methods to enhance the detection of small effect sizes should be planned. Additionally, controlling for key predictors such as the mother's ethnicity, trimester of PPD exposure, mode of delivery, and infant sex is crucial for valid exploration of PPD effects on fetal programming., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: 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., (© 2022.)

Background and Aim of the Work: 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.

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 ( n  = 2), (2) health providers ( n  = 3), (3) academic institutions ( n  = 28), (4) other research institutions ( n  = 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.

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., (© 2019 The Obesity Society.)

We describe the design, implementation, and results of the Qatar Biobank (QBB) cohort study for the first 10,000 participants. QBB is a prospective, population-based cohort study in Qatar, established in 2012. QBB's primary goal was to establish a cohort accessible to the local and international scientific community, providing adequate health data and biological samples to enable evidence-based research. The study design is based on an agnostic hypothesis, collecting data using questionnaires, biological samples, imaging data, and -omics. QBB aims to recruit 60,000 participants, men and women, adult (aged ≥18 years) Qataris or long-term residents (≥15 years living in Qatar) and follow up with them every 5 years. Currently, QBB has reached 28% (n = 17,065) of the targeted enrollee population and more than 2 million biological samples. QBB is a multinational cohort including 33 different nationalities, with a relatively young population (mean age, 40.5 years) of persons who are highly educated (50% university-educated) and have high monthly incomes. The 4 main noncommunicable diseases found among the QBB population are dyslipidemia, diabetes, hypertension, and asthma with prevalences of 30.1%, 17.4%, 16.8%, and 9.1%, respectively. The QBB repository can provide data and biological samples sufficient to demonstrate valid associations between genetic and/or environmental exposure and disease development to scientists worldwide., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 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.

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.

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 & 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 (<50 nmol/L) during pregnancy were associated with increased MNBN frequency in cord blood [IRR = 1.32 (95%CI: 1.00, 1.72)]. This increase was higher for newborns with birth weight above the third quartile [≥3.500 kg; IRR = 2.21 (1.26, 3.89)]. Similarly, low levels of dietary vitamin D were associated with increased MNBN frequency in cord blood [middle tertile IRR = 1.08 (0.78, 1.47), lower tertile IRR = 1.51 (1.06, 2.14)]. Insufficient levels of vitamin D were not associated with MNBN in mothers., Conclusion: Our results suggest that vitamin D deficiency during pregnancy increases genotoxic risks in newborns. The prevalence of vitamin D deficiency globally is high and it is important to further investigate whether vitamin D supplementation or similar interventions during pregnancy could prevent DNA damage at early stages of life., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

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 28weeks 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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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 4years 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 4years 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 4years of age. High exposure to PCBs (≥90th percentile) during pregnancy was associated with a 4.62 points reduction in working memory score at 4years 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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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., Competing Interests: The authors declare that they have no conflict of interest. Ethical approval In the present study all procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee’s and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the present study.

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 1.2μg/g creatinine±7.9 in 1st trimester, 5.1μg/g±13.3 in 2.5 years and 1.9μg/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=3.7mm; 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Micronuclei (MN) are biomarkers of early genetic effects that have been used to investigate the association between environmental exposures and cancer. However, few studies have examined the association between environmental exposures during pregnancy and MN in mothers and newborns., Objectives: We examined MN frequency in maternal blood and in cord blood, in relation to maternal air pollution exposure, and the potential interaction with maternal vitamin C intake and maternal smoking., Methods: We used the cytokinesis-block micronucleus assay to assess MN frequency per 1000 bi-nucleated T-lymphocytes from 181 mothers and 183 newborns born in 2007-2008 in Heraklion (Crete, Greece). The ESCAPE land-use regression methods were used to estimate annual mean exposure to outdoor air pollution [particulate matter (PM), black carbon, nitrogen dioxide (NO2) and nitrogen oxides (NOx)] at maternal home addresses. Food frequency questionnaires were used to estimate maternal dietary vitamin C intake during pregnancy. Smoking habits were self-reported using questionnaires which were checked by measuring maternal urinary cotinine levels., Results: Exposure to PM2.5 was associated with increased MN frequencies in pregnant women [rate ratio [RR (95%CI)] per 5 µg/m(3)=1.53 (1.02, 2.29)]. This increase was considerably higher among women who did not fulfill the recommended vitamin C dietary allowances [RR=9.35 (2.77, 31.61); n=20]. Exposure to PM2.5-10, PM10, NO2 and NOx were also associated with a higher incidence of MN frequencies in smoker women (n=56). No associations were found for newborns., Conclusions: We found an association between air pollution, particularly PM2.5, and MN frequency in mothers but not in newborns. This association was more pronounced among women with a lower dietary intake of vitamin C during pregnancy and among women who smoked during pregnancy. While results are clear in mothers, the association between maternal carcinogenic exposures during pregnancy and biomarkers of early biologic effect in the newborn remains poorly understood., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., Conclusions: Prenatal exposure to DDE and HCB was associated with excess adiposity and higher blood pressure levels in early childhood.

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 < 0.01) were observed for di-ethyl phthalate (DEP), di-n-butyl phthalate (DnBP), butyl-benzyl phthalate (BBP) and ethyl paraben (EPB) between mothers and their children. We observed higher median daily intake (DIu) for mothers (e.g. di-ethyl phthalate 6.9 μg d(-1) kg(-1)) than for their children (1.4 μg d(-1) kg(-1)) for all examined compounds, except for di-2-ethylhexyl phthalate (DEHP) and bisphenol-A. Principal component analysis (PCA) indicated two main sources of exposure (plastic related and personal care-hygiene products) for phthalates, parabens and bisphenol-A. Differences in DEHP metabolism were observed among mothers-children and female-male children., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.

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., (© The Author 2014. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

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=-161.1g; 95% CI: -296.6, -25.7) and PCBs (β=-174.1g; 95% CI: -332.4, -15.9); after further adjustment for gestational weight gain these estimates were slightly reduced (β=-154.3g; 95% CI: -300.8, -7.9 for HCB and β=-135.7g; 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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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: Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development., Objectives: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored., Methods: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe., Results: Malondialdehyde DNA adducts (M1dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M1dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/2 and CYP2E1 were associated with MNBN., Conclusion: We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research.

Background: Water disinfection by-products have been associated with an increased cancer risk. Micronuclei (MN) frequency in lymphocytes is a marker of genomic damage and can predict adult cancer risk., Objective: We evaluated maternal exposure to drinking water brominated trihalomethanes (BTHM) in relation to MN frequency in maternal and cord blood lymphocytes., Methods: MN frequency was examined in 214 mothers and 223 newborns from the Rhea mother-child cohort in Crete, Greece, in 2007-2008. Residential BTHM water concentrations were estimated during pregnancy using tap water analyses and modeling. Questionnaires on water related habits were used to estimate BTHM exposure from all routes. Associations between BTHM and MN frequency were estimated using negative binomial regression., Results: BTHM concentrations in residential tap water during pregnancy ranged from 0.06 to 7.1 μg/L. MN frequency in maternal binucleated lymphocytes was found to increase with BTHM concentrations in residential water for exposure during the first [rate ratio (RR) for 1 μg/L=1.05; 95% CI: 1.00, 1.11] and second trimesters (RR for 1 μg/L=1.03; 95% CI: 1.00, 1.06), and through all routes of BTHM exposure during the first trimester (RR for 1 μg/week=3.14; 95% CI: 1.16, 8.50)., Conclusions: These findings suggest that exposure to BTHM may increase the frequency of MN in maternal binucleated lymphocytes.

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.

Background: Leptin is an adipocyte-secreted hormone that regulates energy homeostasis, while its role in fetal programming remains poorly understood. We aimed to evaluate the effect of maternal weight status on cord blood leptin levels and their combined effect on fetal growth., Methods: We included 638 mother-child pairs from the prospective mother-child cohort 'Rhea' study in Crete, Greece with singleton pregnancies, providing cord blood serum samples for leptin analysis and complete data on birth outcomes. Multivariable logistic and linear regression models were used adjusting for confounders. Generalised additive models were used to explore the form of the relationship between cord leptin and continuous birth outcomes., Results: Log cord leptin was positively associated with birthweight {β-coef: 176.5 [95% confidence interval (CI): 133.0, 220.0] }, ponderal index (β-coef: 1.0 [95% CI: 0.6, 1.4] ) and gestational age (β-coef: 0.7 [95% CI: 0.5, 0.8] ). Excessive weight gain during pregnancy was associated with a threefold increased risk for cord hyperleptinaemia {relative risk (RR): 3.0, [95% CI: 1.5, 6.3] }. Maternal pre-pregnancy overweight/obesity [body mass index (BMI) ≥25 kg/m(2) ] increased the risk of giving birth to a hyperleptinaemic neonate (RR: 2.1 [95% CI: 1.4, 3.2] and the effect of log leptin on birthweight (β-coef: 219.1 [95% CI: 152.3, 285.9] compared with women with a BMI <25 kg/m(2) (β-coef: 150.5 [95% CI: 93.1, 207.9]., Conclusions: Higher cord blood leptin levels are associated with increased size at birth and gestational age, while maternal pre-pregnancy BMI and weight gain during pregnancy represent significant indicators of cord blood leptin., (© 2013 John Wiley & Sons Ltd.)

Background: To date, no research exists on the role that different sources of exposure to second-hand smoke (SHS) have on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and nicotine uptake, assessed via urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and cotinine concentrations of non-smoking pregnant women, nor the differences in NNAL concentrations among pregnant women who quit smoking in comparison to those who do not., Methods: As part of the 'Rhea' mother childbirth cohort in Crete, Greece, 1317 mother-child pairs were followed-up until delivery, while among a subsample, maternal urine was assessed for its NNAL (n=117) and cotinine concentrations (n=377)., Results: Pregnant women who continued to smoke during pregnancy were found to have geometric mean urinary NNAL concentrations of 0.612 pmol/ml, in comparison to the 0.100 pmol/ml of ex-smokers and 0.0795 pmol/ml of non-smokers exposed to SHS. Exposure to SHS in the home was associated with a 4.40 ng/ml increase in urinary cotinine levels, while reported exposure to SHS in cars was associated with an even higher (8.73 ng/ml) increase in cotinine concentrations and was strongly related to NNAL concentrations. Exposure to SHS in the workplace and in public places was also shown to increase cotinine and NNAL concentrations. The NNAL:cotinine ratio was found to be higher among pregnant women who were exposed to SHS but did not smoke (p<0.001)., Conclusions: Using cotinine levels as an indicator of NNK, exposure due to SHS during pregnancy leads to an underestimation of exposure to NNK uptake. Moreover, each source of exposure contributed to the increase in cotinine levels, indicating the importance of avoiding SHS exposure from any source.

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 thyroid hormones (TSH, free T(4), and free T(3)) 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.

Background: Acrylamide is a common dietary exposure that crosses the human placenta. It is classified as a probable human carcinogen, and developmental toxicity has been observed in rodents., Objectives: We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother-child study., Methods: Hemoglobin (Hb) adducts of acrylamide and its metabolite glycidamide were measured in cord blood (reflecting cumulated exposure in the last months of pregnancy) from 1,101 singleton pregnant women recruited in Denmark, England, Greece, Norway, and Spain during 2006-2010. Maternal diet was estimated through food-frequency questionnaires., Results: Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference. The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was -132 g (95% CI: -207, -56); the corresponding difference for head circumference was -0.33 cm (95% CI: -0.61, -0.06). Findings were similar in infants of nonsmokers, were consistent across countries, and remained after adjustment for factors associated with reduced birth weight. Maternal consumption of foods rich in acrylamide, such as fried potatoes, was associated with cord blood acrylamide adduct levels and with reduced birth weight., Conclusions: Dietary exposure to acrylamide was associated with reduced birth weight and head circumference. Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero. If confirmed, these findings suggest that dietary intake of acrylamide should be reduced among pregnant women.

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 γH2AX 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; γH2AX 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.

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., (Copyright © 2012 S. Karger AG, Basel.)

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 < 0.001), and we found a moderate correlation between MNMONO in mothers and newborns (r = 0.26, p < 0.001). MNMONO frequencies in newborns were positively associated with the mother's body mass index and inversely associated with gestational age and mother's age, but we found no significant predictors of MNBN or CBPI in newborns., Conclusions: Although confirmation is needed by a larger study population, the results indicate the importance of taking into account both mono- and binucleated T lymphocytes for biomonitoring of newborns, because the first reflects damage expressed during in vivo cell division and accumulated in utero, and the latter includes additional damage expressed as MN during the in vitro culture step.

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<0.01), and enhanced the presence of vitamin C radicals in seminal plasma. In vitro, vitamin C protected mature spermatozoa against DNA damage, but this protection appeared to be insufficient in vivo. CAT and DDIT4 expression in spermatozoa were higher in smokers than in nonsmokers, but were not related to DNA damage. CAT and DDIT4 expression were inversely related with sperm count (P=0.039 and 0.024 resp.), but no effect was observed for SOD2 expression. These data indicate that spermatozoa of smokers encounter higher levels of oxidative stress. Expression of antioxidant enzymes and seminal vitamin C were insufficient to provide full protection of spermatozoa against DNA damage., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.