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Neurodevelopmental toxicity of prenatal polychlorinated biphenyls (PCBs) by chemical structure and activity: a birth cohort study Park HY, Hertz-Picciotto I, Sovcikova E, et al. Environ Health 2010;9:51. BACKGROUND: Polychlorinated biphenyls [...]

Abstract Background Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxins. Although there is growing evidence to support an association between PCBs and deficits of neurodevelopment, the specific mechanisms are not well understood. The potentially different roles of specific PCB groups defined by chemical structures or hormonal activities e.g., dioxin-like, non-dioxin like, or anti-estrogenic PCBs, remain unclear. Our objective was to examine the association between prenatal exposure to defined subsets of PCBs and neurodevelopment in a cohort of infants in eastern Slovakia enrolled at birth in 2002-2004. Methods Maternal and cord serum samples were collected at delivery, and analyzed for PCBs using high-resolution gas chromatography. The Bayley Scales of Infant Development -II (BSID) were administered at 16 months of age to over 750 children who also had prenatal PCB measurements. Results Based on final multivariate-adjusted linear regression model, maternal mono-ortho-substituted PCBs were significantly associated with lower scores on both the psychomotor (PDI) and mental development indices (MDI). Also a significant association between cord mono-ortho-substituted PCBs and reduced PDI was observed, but the association with MDI was marginal (p = 0.05). Anti-estrogenic and di-ortho-substituted PCBs did not show any statistically significant association with cognitive scores, but a suggestive association between di-ortho-substituted PCBs measured in cord serum and poorer PDI was observed. Conclusion Children with higher prenatal mono-ortho-substituted PCB exposures performed more poorly on the Bayley Scales. Evidence from this and other studies suggests that prenatal dioxin-like PCB exposure, including mono-ortho congeners, may interfere with brain development in utero. Non-dioxin-like di-ortho-substituted PCBs require further investigation.

Anthropometry provides a non-invasive technique for evaluating growth and obesity and serves as an indicator of health status. This cross-sectional study aims to investigate the association of internal arsenic (As), cadmium (Cd), total mercury (THg), methylmercury (MeHg), and lead (Pb) exposure with anthropometric parameters, including obesity, in adolescents. Participants (N = 320) were children aged 10-14 years (mean 11.8 years) from eastern Slovakia, at an early stage of adolescence characterized by growth acceleration. Metal concentrations in blood and urine were measured by ICP-MS (for As, Cd, and Pb), GC/ICP-MS (for MeHg) and amalgamation technique AAS (for THg). Median concentrations of the studied elements in whole blood (Cd: 0.16, Pb: 10.6, THg: 0.25, MeHg: 0.11 µg/L) and urine (Cd: 0.25, Pb: 0.73, As: 3.38 µg/g creatinine) were relatively low in our study group. The results showed that blood Cd and Pb concentrations were inversely associated with several anthropometric parameters (body weight, BMI, body fat percentage, chest circumference, and waist circumference) in both boys and girls. Conversely, blood THg concentration was positively associated with these parameters in boys. A positive relationship was also observed between blood MeHg concentration and height in boys, while negative associations between blood Cd and Pb concentrations and height were significant only in girls. No associations were found between metal concentrations (As, Cd, Pb) in urine and parameters of physical growth or obesity. This study demonstrates that even low-level exposure to Cd, Pb, and Hg can influence growth and obesity indicators in adolescents, with distinct sex-specific patterns, highlighting the need for ongoing monitoring and protection against environmental metal exposure., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The knowledge of the effects of organophosphate flame retardants on children's neurodevelopment is limited. The purpose of the present research is to evaluate the association between exposure to organophosphate flame retardants and children's neurodevelopment in two European cohorts involved in the Human Biomonitoring Initiative Aligned Studies. The participants were school-aged children belonging to the Odense Child Cohort (Denmark) and the PCB cohort (Slovakia). In each cohort, the children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score of the Wechsler Intelligence Scale for Children, using two different editions. The children's urine samples, collected at one point in time, were analyzed for several metabolites of organophosphate flame retardants. The association between neurodevelopment and each organophosphate flame retardant metabolite was explored by applying separate multiple linear regressions based on the approach of MM-estimation in each cohort. In the Danish cohort, the mean ± standard deviation for the neurodevelopment score was 98 ± 12; the geometric mean (95% confidence interval (95% CI)) of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) standardized by creatinine (crt) was 0.52 µg/g crt (95% CI = 0.49; 0.60), while that of diphenyl phosphate (DPHP) standardized by crt was 1.44 µg/g crt (95% CI = 1.31; 1.58). The neurodevelopment score showed a small, negative, statistically imprecise trend with BDCIPP standardized by crt ( β = -1.30; 95%CI = -2.72; 0.11; p -value = 0.07) and no clear association with DPHP standardized by crt ( β = -0.98; 95%CI = -2.96; 0.99; p -value = 0.33). The neurodevelopment score showed a negative trend with BDCIPP ( β = -1.42; 95% CI = -2.70; -0.06; p -value = 0.04) and no clear association with DPHP ( β = -1.09; 95% CI = -2.87; 0.68; p -value = 0.23). In the Slovakian cohort, the mean ± standard deviation for the neurodevelopment score was 81 ± 15; the geometric mean of BDCIPP standardized by crt was 0.18 µg/g crt (95% CI = 0.16; 0.20), while that of DPHP standardized by crt was 2.24 µg/g crt (95% CI = 2.00; 3.52). The association of the neurodevelopment score with BDCIPP standardized by crt was -0.49 (95%CI = -1.85; 0.87; p -value = 0.48), and with DPHP standardized by crt it was -0.35 (95%CI = -1.90; 1.20; p -value = 0.66). No clear associations were observed between the neurodevelopment score and BDCIPP/DPHP concentrations that were not standardized by crt. No clear associations were observed with bis(1-chloro-2-propyl) phosphate (BCIPP) in either cohort, due to the low detection frequency of this compound. In conclusion, this study provides only limited evidence of an inverse association between neurodevelopment and exposure to BDCIPP and DPHP. The timing of exposure and effect modification of other organophosphate flame retardant metabolites and other substances should be the subject of further investigations that address this scientific hypothesis.

Information about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL ® DINCH) on children's neurodevelopment is limited. The aim of the present research is to evaluate the association between phthalate/HEXAMOLL ® DINCH exposure and child neurodevelopment in three European cohorts involved in HBM4EU Aligned Studies. Participating subjects were school-aged children belonging to the Northern Adriatic cohort II (NAC-II), Italy, Odense Child Cohort (OCC), Denmark, and PCB cohort, Slovakia. In each cohort, children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score (FSIQ) of the Wechsler Intelligence Scale of Children test using three different editions. The children's urine samples, collected for one point in time concurrently with the neurodevelopmental evaluation, were analyzed for several phthalates/HEXAMOLL ® DINCH biomarkers. The relation between phthalates/HEXAMOLL ® DINCH and FSIQ was explored by applying separate multiple linear regressions in each cohort. The means and standard deviations of FSIQ were 109 ± 11 (NAC-II), 98 ± 12 (OCC), and 81 ± 15 (PCB cohort). In NAC-II, direct associations between FSIQ and DEHP's biomarkers were found: 5OH-MEHP+5oxo-MEHP (β = 2.56; 95% CI 0.58-4.55; N = 270), 5OH-MEHP+5cx-MEPP (β = 2.48; 95% CI 0.47-4.49; N = 270) and 5OH-MEHP (β = 2.58; 95% CI 0.65-4.51; N = 270). On the contrary, in the OCC the relation between DEHP's biomarkers and FSIQ tended to be inverse but imprecise ( p -value ≥ 0.10). No associations were found in the PCB cohort. FSIQ was not associated with HEXAMOLL ® DINCH in any cohort. In conclusion, these results do not provide evidence of an association between concurrent phthalate/DINCHHEXAMOLLR DINCH exposure and IQ in children.

Introduction: To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive., Objective: We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs., Methods: Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis., Results: A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education., Conclusion: We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444.

Background: Attention-deficit/hyperactivity disorder (ADHD) is increasing worldwide for reasons largely unknown and environmental chemicals with neurotoxic properties, such as persistent organic pollutants (POPs), have been proposed to play a role. We investigated the association between prenatal and postnatal exposure to polychlorinated biphenyl-153 (PCB-153), p-p´-dichlorodiphenyldichloroethylene (p-p'-DDE) and hexachlorobenzene (HCB) and ADHD in childhood., Methods: We pooled seven European birth cohort studies encompassing 4437 mother-child pairs from the general population with concentrations of PCB-153, p-p´-DDE and HCB measured in cord blood, maternal blood or milk. We then calculated prenatal (birth) and postnatal (3, 6, 12 and 24 months) POP concentrations using a pharmacokinetic model. The operational definition of ADHD varied across cohorts and ranged from doctor diagnosis obtained from patient registries to maternal or teachers reports. We used multilevel (mixed) logistic regression models to estimate the associations between exposure to POPs at birth, 3, 6, 12 and 24 months and ADHD., Results: The global prevalence of ADHD in our study was 6%. The mean age at assessment of ADHD was 5.8 years (range: 3.8-9.5 years). We found no association between exposure to PCB-153, p-p´-DDE and HCB at any age point between birth and 24 months and ADHD, in the pooled analyses (pooled odds ratios ranging from 1.00 to 1.01). A number of sensitivity analyses gave basically the same results., Conclusions: In the largest study to date of 4437 children in seven European birth cohorts, we did not observe any association between either pre- or postnatal exposure (up to 24 months) to PCB-153, p-p´-DDE and HCB and the risk of ADHD before the age of 10 years.

The risk of cancer due to PCB exposure in humans is highly debated. In eastern Slovakia, high exposure of the population to organochlorines (especially PCBs) was associated with various disease and disorder pathways, viz., endocrine disruption, metabolic disorder & diabetes, and cancer, thereby disturbing several cellular processes, including protein synthesis, stress response, and apoptosis. We have evaluated a Slovak cohort (45-month children, at lower and higher levels of PCB exposure from the environment) for disease and disorder development to develop early disease cancer biomarkers that could shed new light on possible mechanisms for the genesis of cancers under such chemical exposures, and identify potential avenues for prevention.Microarray studies of global gene expression were conducted from the 45-month-old children on the Affymetrix platform followed by Ingenuity Pathway Analysis (IPA®) to associate the affected genes with their mechanistic pathways. High-throughput qRT-PCR TaqMan low-density array (TLDA) was performed to further validate the selected genes on the whole blood cells of the most highly exposed children from the study cohort (n = 71). TP53, MYC, BCL2, and LRP12 differential gene expressions suggested strong relationships between potential future tumor promotion and PCB exposure in Slovak children. The IPA analysis further detected the most important signaling pathways, including molecular mechanism of cancers, prostate cancer signaling, ovarian cancer signaling, P53 signaling, oncostatin M signaling, and their respective functions (viz., prostate cancer, breast cancer, progression of tumor, growth of tumor, and non-Hodgkin's disease). The results suggest that PCB exposures, even at the early age of these children, may have lifelong consequences for the future development of chronic diseases.

Background and Aims: Our earlier gene-expression studies with a Slovak PCBs-exposed population have revealed possible disease and disorder development in accordance with epidemiological studies. The present investigation aimed to develop an in vitro model system that can provide an indication of disrupted biological pathways associated with developing future diseases, well in advance of the clinical manifestations that may take years to appear in the actual human exposure scenario., Methods: We used human Primary Blood Mononuclear Cells (PBMC) and exposed them to a mixture of human equivalence levels of PCBs (PCB-118, -138, -153, -170, -180) as found in the PCBs-exposed Slovak population. The microarray studies of global gene expression were conducted on the Affymetrix platform using Human Genome U133 Plus 2.0 Array along with Ingenuity Pathway Analysis (IPA) to associate the affected genes with their mechanistic pathways. High-throughput qRT-PCR Taqman Low Density Array (TLDA) was done to further validate the selected 6 differentially expressed genes of our interest, viz., ARNT, CYP2D6, LEPR, LRP12, RRAD, TP53, with a small population validation sample (n=71)., Results: Overall, we revealed a discreet gene expression profile in the experimental model that resembled the diseases and disorders observed in PCBs-exposed population studies. The disease pathways included endocrine system disorders, genetic disorders, metabolic diseases, developmental disorders, and cancers, strongly consistent with the evidence from epidemiological studies., Interpretation: These gene finger prints could lead to the identification of populations and subgroups at high risk for disease, and can pose as early disease biomarkers well ahead of time, before the actual disease becomes visible., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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 46.1 months) 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±0.03 ng/mg of serum lipid, for the two groups, respectively (18.1±4.4 and 0.3±0.1 ng/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 © 2011 Elsevier Ltd. All rights reserved.)

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±1.4 months) 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 © 2011 Elsevier Ltd. All rights reserved.)

Background: Hydroxylated polychlorinated biphenyls (OH-PCBs), unlike PCBs, are in general readily excreted yet are still detected in humans and animals. Active transport of OH-PCBs across the placenta and hydroxylation of PCBs by the fetus suggest the potential for greater impact on the fetus compared with the parent PCB compounds, but little is known about their health effects, particularly in humans., Objectives: The objective of this study was to evaluate the associations between prenatal OH-PCB exposure and neurodevelopment in children at 16 months of age in eastern Slovakia., Methods: A birth cohort (n = 1,134) was enrolled during 2002-2004. We analyzed six OH-PCB metabolites (4-OH-CB-107, 3-OH-CB-153, 4-OH-CB-146, 3'-OH-CB-138, 4-OH-CB-187, and 4'-OH-CB-172) in a subset of the cohort. The Bayley Scales of Infant Development were administered to the children at the 16-month follow-up visit. We developed multiple linear regression models predicting standardized scores for the Mental Development Index (MDI) and Psychomotor Development Index (PDI) from maternal (n = 147) and cord (n = 80) serum OH-PCB concentrations, adjusting for sex of child, district, HOME (Home Observation for Measurement of the Environment) score, and maternal score on Raven's Progressive Matrices., Results: Cord 4-OH-CB-107 was significantly associated with lower MDI (beta = -2.27; p = 0.01) and PDI (beta = -4.50; p = 0.004). Also, maternal 4-OH-CB-107 was significantly associated with lower MDI (beta = -1.76; p = 0.03) but not PDI. No other OH-PCB metabolites were associated with decreased PDI or MDI., Conclusions: Our findings showed a significant association of 4-OH-CB-107 with decreased MDI, which can possibly be mediated by endocrine disruption, altered neurotransmitter functions, or reduced thyroid hormone concentrations in brain.

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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 (chi(2)=8.35; p=0.03) according to their serum PCB concentration (group 0: <200; group 1: 200-600; group 2: >600 ng PCBs g(-1) serum lipids). The proportion of permanent teeth affected with any enamel defect was significantly higher in higher exposed children (chi2=7.237; p=0.027). Furthermore, the extent of the enamel defects was also greater (chi2=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.