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The hypothesis of whether early life exposure (both pre- and early postnatal) to endocrine-disrupting chemicals (EDCs) may be a risk factor for obesity and related metabolic diseases later in life will be tested in the European research project OBELIX (OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life). OBELIX is a 4-y project that started in May 2009 and which has the following 5 main objectives: 1) to assess early life exposure in humans to major classes of EDCs identified as potential inducers of obesity (ie, dioxin-like compounds, non-dioxin-like polychlorinated biphenyls, organochlorine pesticides, brominated flame retardants, phthalates, and perfluorinated compounds) by using mother-child cohorts from 4 European regions with different food-contaminant exposure patterns; 2) to relate early life exposure to EDCs with clinical markers, novel biomarkers, and health-effect data related to obesity; 3) to perform hazard characterization of early life exposure to EDCs for the development of obesity later in life by using a mouse model; 4) to determine mechanisms of action of obesogenic EDCs on developmental programming with in vivo and in vitro genomics and epigenetic analyses; and 5) to perform risk assessments of prenatal exposure to obesogenic EDCs in food by integrating maternal exposure through food-contaminant exposure and health-effect data in children and hazard data in animal studies. [ABSTRACT FROM AUTHOR]

Background and aims There is evidence that endocrine disrupting chemicals (EDCs) have developmental effects at environmental concentrations. We investigated whether some EDCs are associated with the adverse birth outcome Small for Gestational Age (SGA). Methods We used PCB 153, p,p' -DDE, HCB, PFOS and PFOA measured in maternal, cord blood or breast milk samples of 5446 mother-child pairs (subset of 693 for the perfluorinated compounds) from seven European birth cohorts (1997–2012). SGA infants were those with birth weight below the 10th percentile for the norms defined by gestational age, country and infant's sex. We modelled the association between measured or estimated cord serum EDC concentrations and SGA using multiple logistic regression analyses. We explored effect modification by child's sex and maternal smoking during pregnancy. Results Among the 5446 newborns, 570 (10.5%) were SGA. An interquartile range (IQR) increase in PCB 153 was associated with a modestly increased risk of SGA (odds ratio (OR) of 1.05 [95% CI: 1.04–1.07]) that was stronger in girls (OR of 1.09 [95% CI: 1.04–1.14]) than in boys (OR of 1.03 [95% CI: 1.03–1.04]) ( p -interaction = 0.025). For HCB, we found a modestly increased odds of SGA in girls (OR of 1.04 [95% CI: 1.01–1.07] per IQR increase), and an inverse association in boys (OR of 0.90 [95% CI: 0.85–0.95]) ( p -interaction = 0.0003). Assessment of the HCB-sex-smoking interaction suggested that the increased odds of SGA associated with HCB exposure was only in girls of smoking mothers (OR of 1.18 [95% CI: 1.11–1.25]) ( p -interaction = 0.055). Higher concentrations of PFOA were associated with greater risk of SGA (OR of 1.64 [95% CI: 0.97–2.76]). Elevated PFOS levels were associated with increased odds of SGA in newborns of mothers who smoked during pregnancy (OR of 1.63 [95% CI: 1.02–2.59]), while an inverse association was found in those of non-smoking mothers (OR of 0.66 [95% CI: 0.61–0.72]) ( p -interaction = 0.0004). No significant associations were found for p,p' -DDE. Conclusions Prenatal environmental exposure to organochlorine and perfluorinated compounds with endocrine disrupting properties may contribute to the prevalence of SGA. We found indication of effect modification by child's sex and smoking during pregnancy. The direction of the associations differed by chemical and these effect modifiers, suggesting diverse mechanisms of action and biological pathways. [ABSTRACT FROM AUTHOR]

Abstract Background Perfluoroalkyl substances (PFASs) are man-made fluorinated compounds with endocrine-disrupting properties, detected in 99% of serum samples worldwide and associated with adverse childhood health outcomes. The aim of this study was to describe determinants of prenatal exposure to PFASs in Slovakia. Methods This study was based on Slovak multicentric prospective mother-child cohort PRENATAL (N = 796). Cord blood samples were collected within 2010–2012 and PFASs were analyzed in a subpopulation of 322 newborns. Concentrations of perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) were measured in the samples of cord blood using an ultrahigh-performance liquid chromatography- mass spectrometry (U-HPLC−MS) method. From questionnaires, we obtained information on medical history of mother, socio-demographic factors, nutrition and environmental factors. Association between maternal characteristics and PFASs exposure was analyzed using multivariable linear regression models. Results The highest cord blood concentration (geometric mean ± SD) was observed for PFOA (0.79 ± 2.21 ng/ml) followed by PFOS (0.36 ± 2.56 ng/ml), PFNA (0.20 ± 2.44 ng/ml) and PFHxS (0.07 ± 2.36 ng/ml). Primiparity was associated with higher levels of all four PFAS: PFOS (exp. β = 1.25; 95%CI[1.03; 1.53]), PFOA (exp. β = 1.49; 95%CI[1.18; 1.89]), PFNA (exp. β = 1.30; 95%CI[1.05; 1.60]) and PFHxS (exp. β = 1.49; 95%CI [1.20; 1.86]). In addition, maternal age category 29 years and more was associated with higher PFNA and PFHxS levels (exp. β = 1.27; 95%CI[1.04; 1.55] and exp. β = 1.30; 95%CI[1.06; 1.60], respectively) and higher educational level of mother was associated with higher PFNA levels (exp. β = 1.32; 95%CI[1.04; 1.68]). Higher fish consumption was associated with lower PFNA levels (exp. β = 0.49; 95%CI[0.26; 0.92]). Conclusions We observed that PFASs cord blood concentrations were comparable or lower than those measured in western or northern European countries. We identified parity as the main determinant of PFASs exposure in our population and maternal age and education as factors that might be associated with exposure to certain PFASs. Highlights • The highest mean cord blood concentration was observed for PFOA. • This study points out parity as the main determinant of PFASs exposure in our population. • PFNA levels in cord blood were associated with higher educational level of mother. • PFNA and PFHxS in cord blood were associated with maternal age. [ABSTRACT FROM AUTHOR]

Background Dioxins and dioxin-like compounds are endocrine disrupting chemicals (EDCs). Experimental studies suggest perinatal exposure to EDCs results in later obesity. However, the few epidemiological investigations on dioxins are inconclusive. We investigated perinatal exposure to dioxins and dioxin-like compounds, infant growth and body mass index (BMI) in childhood. Methods We pooled data from 3 European birth cohorts (Belgian, Norwegian, Slovak) with exposure assessment in cord blood or breast milk. Two cohorts had dioxin-like toxicity assessed using dioxin-responsive chemical-activated luciferase expression (DR-CALUX) bioassay and one cohort had measured concentrations of dioxins, furans and dioxin-like polychlorinated biphenols with CALUX relative potency values applied. Growth was cohort- and sex-specific change in weight-for-age z-score between birth and 24 months (N = 367). BMI was calculated at around 7 years (median 7.17, interquartile range [IQR] 7.00–7.37 years, N = 251), and overweight defined according to international standards for children equivalent to adult BMI > 25 kg/m 2 (Cole and Lobstein, 2012). We fitted multivariate models using generalized estimating equations, and tested effect modification by sex, breastfeeding and cohort. Results per 10 pg CALUX TEQ/g lipid increase in exposure. Results Dioxin exposure was highest in the Belgian and lowest in the Norwegian cohort; median (IQR) of the pooled sample 13 (12.0) pg CALUX TEQ/g lipid. Perinatal exposure to dioxins and dioxin-like compounds appeared associated with increased growth between 0 and 24 months (adjusted estimate for change in z-score: β = 0.07, 95% CI: − 0.01, 0.14). At 7 years, dioxins exposure was associated with a statistically significant increase in BMI in girls (adjusted estimate for BMI units β = 0.49, 95% CI: 0.07, 0.91) but not in boys (β = − 0.03, 95% CI: − 0.55, 0.49) ( p -interaction = 0.044). Furthermore, girls had a 54% (− 6%, 151%) increased risk of overweight at 7 years ( p -interaction = 0.023). Conclusion Perinatal exposure to dioxin and dioxin-like compounds was associated with increased early infant growth, and increased BMI in school age girls. Studies in larger sample sizes are required to confirm these sex-specific effects. [ABSTRACT FROM AUTHOR]

Abstract: The goal of the present study is to understand the probable molecular mechanism of toxicities and the associated pathways related to observed pathophysiology in high PCB-exposed populations. We have performed a microarray-based differential gene expression analysis of children (mean age 46.1months) of Central European descent from Slovak Republic in a well-defined study cohort. The subset of children having high blood PCB concentrations (>75 percentile) were compared against their low PCB counterparts (<25 percentile), with mean lipid-adjusted PCB values of 3.02±1.3 and 0.06±0.03ng/mg of serum lipid, for the two groups, respectively (18.1±4.4 and 0.3±0.1ng/ml of serum). The microarray was conducted with the total RNA from the peripheral blood mononuclear cells of the children using an Affymetrix platform (GeneChip Human genome U133 Plus 2.0 Array) and was analyzed by Gene Spring (GX 10.0). A highly significant set of 162 differentially expressed genes between high and low PCB groups (p value <0.00001) were identified and subsequently analyzed using the Ingenuity Pathway Analysis tool. The results indicate that Cell-To-Cell Signaling and Interaction, Cellular Movement, Cell Signaling, Molecular Transport, and Vitamin and Mineral Metabolism were the major molecular and cellular functions associated with the differentially altered gene set in high PCB-exposed children. The differential gene expressions appeared to play a pivotal role in the development of probable diseases and disorders, including cardiovascular disease and cancer, in the PCB-exposed population. The analyses also pointed out possible organ-specific effects, e.g., cardiotoxicity, hepatotoxicity and nephrotoxicity, in high PCB-exposed subjects. A few notable genes, such as BCL2, PON1, and ITGB1, were significantly altered in our study, and the related pathway analysis explained their plausible involvement in the respective disease processes, as mentioned. Our results provided insight into understanding the associated molecular mechanisms of complex gene–environment interactions in a PCB-exposed population. Future endeavors of supervised genotyping of pathway-specific molecular epidemiological studies and population biomarker validations are already underway to reveal individual risk factors in these PCB-exposed populations. [Copyright &y& Elsevier]

Abstract: The chemical composition of persistent organic pollutants (POPs) in the environment is not uniform throughout the world, and these contaminants contain many structurally different lipophilic compounds. In a well-defined study cohort in the Slovak Republic, the POP chemicals present in the peripheral blood of exposed children were chemically analyzed. The chemical analysis data revealed that the relative concentration and profile of structurally different organic pollutants, including polychlorinated biphenyls (PCBs), 2,2′-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p′-DDE), 2,2′-bis(4-chlorophenyl)-1,1,1-trichloro-ethane (p,p′-DDT), hexachlorobenzene (HCB) and β-hexachlorocyclohexane (β-HCH), may vary from individual to individual, even within the same exposure area. These chemicals can be broadly classified into two groups. The first group, the PCB congeners, primarily originated from industrial compounds and their byproducts. The second group of compounds originated from or was commonly used in the agricultural sector (e.g., DDT, HCB). The objective of this study was to examine the effects of the two POP exposure profiles on gene expression. For the study population, we selected pre-pubertal girls (mean age of 46.2±1.4months) with high POP concentrations in their blood (>75% tile of total POP) and classified them in the high ‘PCB’ group when the total PCB concentration was significantly higher than the total concentration of other POP components and in the ‘Other Than PCB’ (OTP) group, when the total PCB concentration was significantly lower than the concentration of the other major POP constituents. A matched control group of girls (<25% tile of total POP) was selected for comparison purpose (n=5 per group). Our aims were to determine whether there were any common effects of high POP exposure at a toxicogenomic level and to investigate how exposure may affect physiological functions of the children in two different exposure scenarios. Global gene expression analysis using a microarray (Affymetrix Gene Chip Human genome U133 Plus 2.0 Array) platform was conducted on the total RNA of peripheral blood mononuclear cells from the girls. The results were analyzed by Partek GS, Louis, MI, which identified twelve genes (ATAD2B, BIVM, CD96, CXorf39, CYTH1 ETNK1, FAM13A, HIRA, INO80B, ODG1, RAD23B, and TSGA14) and two unidentified probe sets, as regulated differentially in both the PCB and OTP groups against the control group. The qRT-PCR method was used to validate the microarray results. The Ingenuity Pathway Analysis (IPA) software package identified the possible molecular impairments and disease risks associated with each gene set. Connective tissue disorders, genetic disorders, skeletal muscular disorders and neurological diseases were associated with the 12 common genes. The data therefore identified the potential molecular effects of POP exposure on a genomic level. This report underscores the importance of further study to validate the results in a random population and to evaluate the use of the identified genes as biomarkers for POP exposure. [Copyright &y& Elsevier]

The aim of the present study was to understand the placental transfer of polychlorinated biphenyls (PCBs), specific hydroxylated PCB metabolites (OH-PCBs), and pentachlorophenol (PCP) in blood serum, in a birth cohort from eastern Slovakia. During the period 2002–2004, cord blood specimens were collected in parallel with maternal specimens from women delivering in the two eastern Slovak districts of Michalovce and Svidnik/Stropkov. A total of 92 pairs of mother-cord specimens at delivery were selected for this study. 4-OH-CB107, 3-OH-CB153, 4-OH-CB146, 3′-OH-CB138, 4-OH-CB187, and 4′-OH-CB172 were quantified. The median concentrations of Σ17PCBs, Σ6OH-PCBs, and PCP in cord serum were 0.92, 0.33, and 0.69ng/g wet wt., respectively and highly correlated with the corresponding maternal serum levels (correlations were R 2 =0.61, 0.78, and 0.82, respectively). The median cord to mother ratios of the Σ17PCBs, Σ6OH-PCBs, and PCP were 0.18, 0.75, and 1.10, respectively. The median ratio of the Σ6OH-PCBs to the Σ17 PCBs in the cord serum was 0.38 from wet weight based concentrations, which was about four times higher than the ratio of these compounds in maternal serum (0.09). PCP was more abundant than any PCB or OH-PCB congener measured in cord serum. The higher cord to maternal ratios of OH-PCB metabolites as compared with the parent compounds suggests either a higher placental transfer rate or greater metabolism in the fetus as compared with the maternal compartment. These findings are consistent with their preferential binding to TTR that can cross the placenta. The cord to maternal ratio varies by congener (e.g., 4-OH-CB107=0.58, 4-OH-CB146=0.74, 3′-OH-CB138=1.01). [Copyright &y& Elsevier]

Abstract: Polychlorinated biphenyls (PCBs) were commercially produced between 1959 and 1984 in eastern Slovakia. Improper handling led to a highly contaminated local environment and high levels of PCBs in humans and wildlife in the Michalovce area. The aim of this study was to analyse serum for methylsulfonyl metabolites of PCB (MeSO2-PCBs) and DDE (3-MeSO2-DDE) in serum samples from pregnant women and in a selected number of paired cord blood samples to assess maternal sulfone levels and patterns, and transplacental transfer of these metabolites. The donating women were from two districts in eastern Slovakia. A liquid–liquid extraction method together with separation of substance groups and further clean-up on silica gel columns were applied prior to analysis by gas chromatography/mass spectrometry. 3-MeSO2-DDE was the major methyl sulfone in most of the samples followed by a yet not identified MeSO2-hexaCB, 4′-MeSO2-CB101, 4′-MeSO2-CB87 and 4-MeSO2-CB149. The women from the contaminated area had three times higher concentrations of the MeSO2-PCBs than women from the reference area. This is the first report on methyl sulfone metabolites of PCB and DDE in human cord serum. It is shown that these metabolites are transported through the placenta. The levels of MeSO2-PCBs in the maternal serum were about 1.5 times higher than in the corresponding cord serum on a lipid weight basis. For 3-MeSO2-DDE, the levels were about the same in maternal and cord serum. The difference in the maternal:cord ratio, comparing MeSO2-PCBs with 3-MeSO2-DDE might be due to differences in transport through the placenta caused by their different affinities for lipoproteins and plasma proteins. [Copyright &y& Elsevier]

Abstract: Human breast milk represents the best choice for the nutrition of infants. It is often used for monitoring human exposures to environmental chemicals. Uniquely suited to meet human biological needs, breast milk composition, especially fat content, changes significantly with time from delivery. With the aim to compare the concentration of organochlorine compounds (OCs) in colostrum versus mature milk, we obtained samples of fourth–fifth day postpartum milk (colostrum) and day-14 postpartum milk (mature milk) from 12 women enrolled in the project “Early Childhood Development and PCB Exposure in Slovakia”. The concentrations of selected organochlorine pesticides and congeners of polychlorinated biphenyls (PCBs) were measured using gas chromatography with electron capture detection and reported on lipid adjusted basis. No significant differences were found between organochlorine levels in colostrum and those in mature milk samples. A very close correlation was found between the concentrations of organochlorine compounds in colostrum and mature milk (Spearman correlation coefficient r =0.94–0.98 for PCBs, and r =0.85–0.99 for organochlorine pesticides, p <0.001 for all compounds). The present study concludes that the use of colostrum samples provides a close estimate of the child’s exposure to OCs in the early neonatal period and demonstrates that, despite the lower fat content, colostrum specimens are adequate to conduct OC analyses. [Copyright &y& Elsevier]

The effects of long-term exposure to polychlorinated biphenyls (PCBs) on developmental dental defects of deciduous and permanent teeth in children in eastern Slovakia, where PCBs from a chemical plant manufacturing Delors contaminated the surrounding district were evaluated. Four hundred and thirtytwo children, lifelong residents, aged 8–9 years were examined. Children’s caries susceptibility and gingival health was assessed by standard dental indices, and developmental enamel defects by the FDI index. Data from the PCBRISK project data set and questionnaires completed by the parents provided information on exposure and various confounding factors. The proportion of teeth with different types and extensions of developmental enamel defects correlated with serum PCB concentration. The proportion of deciduous teeth affected with enamel defects was significantly higher in higher exposed children (χ 2 =8.35; p =0.03) according to their serum PCB concentration (group 0: <200; group 1: 200–600; group 2: >600ng PCBsg−1 serum lipids). The proportion of permanent teeth affected with any enamel defect was significantly higher in higher exposed children (χ 2 =7.237; p =0.027). Furthermore, the extent of the enamel defects was also greater (χ 2 =10.714; p =0.005). In multivariate linear regression analysis PCB exposure was significantly related to developmental enamel defects of permanent teeth only. No associations between PCB exposure and caries susceptibility, gingival health or number of teeth were observed. This study demonstrated a dose–response relationship between PCB exposure and developmental enamel defects of permanent teeth in children, the evidence for deciduous teeth was not conclusive. [Copyright &y& Elsevier]