Neurodevelopmental toxicity of prenatal polychlorinated biphenyls (PCBs) by chemical structure and activity: a birth cohort study

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

Transcriptional profiling and biological pathway analysis of human equivalence PCB exposure in vitro: Indicator of disease and disorder development in humans.

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 PBMC (Primary Blood Mononuclear Cells) 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

Cognitive performance and exposure to organophosphate flame retardants in children : evidence from a cross-sectional analysis of two European mother-child cohorts

Abstract: 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 mu g/g crt (95% CI = 0.49; 0.60), while that of diphenyl phosphate (DPHP) standardized by crt was 1.44 mu g/g crt (95% CI = 1.31; 1.58). The neurodevelopment score showed a small, negative, statistically imprecise trend with BDCIPP standardized by crt (beta = -1.30; 95%CI = -2.72; 0.11; p-value = 0.07) and no clear association with DPHP standardized by crt (beta = -0.98; 95%CI = -2.96; 0.99; p-value = 0.33). The neurodevelopment score showed a negative trend with BDCIPP (beta = -1.42; 95% CI = -2.70; -0.06; p-value = 0.04) and no clear association with DPHP (beta = -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 mu g/g crt (95% CI = 0.16; 0.20), while that of DPHP standardized by crt was 2.24 mu g/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

Cognitive Performance and Exposure to Organophosphate Flame Retardants in Children: Evidence from a Cross-Sectional Analysis of Two European Mother–Child Cohorts

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