Association between prenatal bisphenol A and phthalate exposures and fetal metabolic related biomarkers: The Hokkaido study on Environment and Children's Health.

Bisphenol A and phthalates are widely detected in human urine, blood, breast milk, and amniotic fluid. Both bisphenol A and phthalates have been suggested as playing a role in obesity epidemics. Exposure to these chemicals during fetal development, and its consequences should be concerning because they can cross the placenta. Thus, this study aimed to assess the association between prenatal exposure to bisphenol A and phthalates, and cord blood metabolic-related biomarkers. Maternal serum was used during the first trimester, to determine prenatal exposure to bisphenol A and phthalates. Levels of metabolic-related biomarkers in the cord blood were also determined. Linear regression models were applied to the 365 participants with both, exposure and biomarker assessments, adjusted for maternal age, pre-pregnancy body mass index, parity, education, and sex of the child. The level of bisphenol A was negatively associated with the leptin level (ß = -0.06, 95% confidence interval [CI]: -0.11, -0.01), but was positively associated with the high-molecular-weight adiponectin level, with marginal significance (ß = 0.03, 95%CI: 0.00, 0.06). The mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-(2-ethylhexyl) phthalate (MEHP), and summation of MEHP and MECPP to represent DEHP exposure (∑DEHPm) levels were inversely associated with the leptin levels (ß=-0.14, 95%CI: -0.27, -0.01; ß = -0.12, 95%CI: -0.24, 0.00 with marginal significance; ß=0.08, 95%CI: -0.14, -0.03; and ß = -0.09, 95%CI: -0.16, -0.03, respectively). The present study provided some evidence that prenatal exposure to bisphenol A and certain phthalates may modify fetal adiponectin and leptin levels.

Prenatal exposure to bisphenol A and phthalates and behavioral problems in children at preschool age: the Hokkaido Study on Environment and Children's Health.

BACKGROUND: Studies reported adverse behavioral development including internalizing and externalizing problems in association with prenatal exposure to bisphenol A (BPA) and phthalates; however, findings were not sufficient due to using different assessment tools and child ages among studies. This study aimed to examine associations between maternal serum levels of BPA and phthalate metabolites and behavioral problems at preschool age. METHODS: The Strengths and Difficulties Questionnaire (SDQ) was used to assess behavioral problems at 5 years of age. BPA and phthalate metabolite levels in the first trimester maternal serum was determined by LC-MS/MS for 458 children. Variables used for adjustment were parental ages, maternal cotinine levels, family income during pregnancy, child sex, birth order, and age at SDQ completed. RESULTS: The median concentrations of BPA, MnBP, MiBP, MEHP, and MECPP, primary and secondary metabolites of phthalates, were 0.062, 26.0, 7.0, 1.40, and 0.20 ng/ml, respectively. MECPP level was associated with increase conduct problem risk (OR = 2.78, 95% CI 1.36-5.68) overall and the association remained after child sex stratification, and odds ratios were increased with wider confidence interval (OR = 2.85, 95% CI 1.07-7.57 for boys, OR = 4.04, 95% CI 1.31-12.5 for girls, respectively). BPA, ∑DBPm (MnBP + MiBP), and ∑DEHPm (MEHP+MECPP) levels were not associated with any of the child behavioral problems. CONCLUSIONS: Our analyses found no significant association between BPA or summation of phthalate metabolite levels and any of the behavioral problems at 5 years of age but suggested possible association between MECPP levels and increased risk of conduct problems.

Cord Blood Bisphenol A Levels and Reproductive and Thyroid Hormone Levels of Neonates: The Hokkaido Study on Environment and Children's Health.

BACKGROUND: Bisphenol A (BPA) is widely used and BPA exposure is nearly ubiquitous in developed countries. While animal studies have indicated adverse health effects of prenatal BPA exposure including reproductive dysfunction and thyroid function disruption possibly in a sex-specific manner, findings from epidemiologic studies have not been enough to prove these adverse effects. Given very limited research on human, the aim of this study was to investigate associations between cord blood BPA levels and reproductive and thyroid hormone levels of neonates and whether associations differed by neonate sex. METHODS: The study population included 514 participants of the Hokkaido study recruited from 2002 to 2005 at one hospital in Sapporo, Japan. The BPA level in cord blood was determined by ID-LC/MS/MS, and the limit of quantification was 0.040 ng/ml. We measured nine types of reproductive hormone levels in cord blood, and thyroid hormone levels were obtained from neonate mass screening test data. There were 283 subjects, who had both BPA and hormone levels measurements, included for the final analyses. RESULTS: The geometric mean of cord blood BPA was 0.051 ng/ml. After adjustment, BPA level was negatively associated with prolactin (PRL) (ß = -0.38). There was an interaction between infant sex and BPA levels on PRL; a weak negative association was found in boys (ß = -0.12), whereas a weak positive association was found in girls (ß = 0.14). BPA level showed weak positive association with testosterone, estradiol, and progesterone levels in boys. No association was found between BPA and thyroid hormone levels. CONCLUSIONS: Our findings suggested that fetal BPA levels might be associated with changes in certain reproductive hormone levels of neonates in a sex-specific manner, though further investigations are necessary.

An epigenome-wide analysis of cord blood DNA methylation reveals sex-specific effect of exposure to bisphenol A.

Exposure to bisphenol A (BPA) in utero is associated with adverse health outcome of the offspring. Differential DNA methylation at specific CpG sites may link BPA exposure to health impacts. We examined the association of prenatal BPA exposure with genome-wide DNA methylation changes in cord blood in 277 mother-child pairs in the Hokkaido Study on Environment and Children's Health, using the Illumina HumanMethylation 450 BeadChip. We observed that a large portion of BPA-associated differentially methylated CpGs with p-value < 0.0001 was hypomethylated among all newborns (91%) and female infants (98%), as opposed to being hypermethylated (88%) among males. We found 27 and 16 CpGs with a false discovery rate (FDR) < 0.05 in the analyses for males and females, respectively. Genes annotated to FDR-corrected CpGs clustered into an interconnected genetic network among males, while they rarely exhibited any interactions in females. In contrast, none of the enrichment for gene ontology (GO) terms with FDR < 0.05 was observed for genes annotated to the male-specific CpGs with p < 0.0001, whereas the female-specific genes were significantly enriched for GO terms related to cell adhesion. Our epigenome-wide analysis of cord blood DNA methylation implies potential sex-specific epigenome responses to BPA exposure.

Development of a novel scheme for rapid screening for environmental micropollutants in emergency situations (REPE) and its application for comprehensive analysis of tsunami sediments deposited by the great east Japan earthquake.

The tsunami triggered by the Great East Japan Earthquake of March 2011, the strongest quake ever recorded in Japan, deposited tsunami sediments along the coastline of the affected area. Because the sediments contained a wide variety of hazardous chemicals, including organic micropollutants, a method for rapidly evaluating the environmental and human health risks of such chemicals is necessary. For this purpose, we propose a novel three-step scheme designated "rapid screening for environmental micropollutants in emergency situations (REPE)". In the first step, samples are subjected to target screening analysis using an automated identification and quantification system (TSA-AIQS) involving gas chromatography mass spectrometry (GC-MS). In the second step, the chemicals detected by TSA-AIQS analysis are quantified precisely by conventional target analysis. The third step is risk assessment of the target chemicals. TSA-AIQS analysis of the tsunami sediments detected 63 substances, including polycyclic aromatic hydrocarbons (both native and alkylated PAHs) at high concentrations. These PAHs were precisely quantified by target analysis, and the concentrations were used to assess the health risks posed by oral intake, which were found to be negligible. Our results suggest that the REPE scheme will be useful for rapid, comprehensive screening and risk assessment in emergency situations.

Analysis method for PCBs in reclaimed oil using a fast-GC triple stage quadrupole mass spectrometer with the 13-component quantitation method.

It is necessary for companies supplying reclaimed oil to analyze polychlorinated biphenyls (PCBs), because there is a possibility of the presence of contaminants due to trace-level PCBs in the reclaimed oil. However, common analysis methods of PCBs are time-consuming and complicated. Fast-GC triple stage quadrupole mass spectrometer with the 13-component quantitation method is an official method for analyzing PCBs in insulating oil in Japan. This method is extremely fast and simplified. The purpose of this study involves an investigation of the aforementioned fast and simple method for potential use in the analysis of reclaimed oil. Furthermore, it was attempted to combine the method with sample preparation involving only hexane dilution. The effect of sample dilutions corresponding to 100, 300, and 500 times was evaluated for reducing the matrix effect. The matrix effect was suppressed at a dilution ratio equal to or exceeding 300 times. Calibration curves of four points, namely 0.01, 0.05, 0.1, and 0.5 ng/mL, (ignored origin) by using an internal standard method were prepared for the 13 components. The square of regression coefficient (R2) values of all calibration curves exceeded 0.997. This method was adopted for the analysis of reclaimed oil containing 0.5 µg/mL PCBs, which corresponds to the judgment criteria, and accurate quantitation (accuracy value, 94.0-102%) and good repeatability (%RSD, 3.6%) were obtained. Furthermore, the required sensitivity was maintained even when 800 samples were analyzed without a cleaning ion source and an exchanging analysis column.

Quantifying bisphenol A in maternal and cord whole blood using isotope dilution liquid chromatography/tandem mass spectrometry and maternal characteristics associated with bisphenol A.

Bisphenol A (BPA) is endocrine disrupting chemical that have been detected among general population. Exposure levels among pregnant women and their fetus are yet largely unknown among Japanese. We have developed a new method of measuring total BPA in whole blood samples by using isotopic dilution liquid chromatography-tandem mass spectrometry (ID-LC/MS/MS). For eliminating possible contaminations, we have used glass cartridge instead of polypropylene cartridge and successfully reduced background levels. Additionally gap retention technique was applied to improve sensitivity. We also confirmed no external contamination by measuring free BPA in the samples. The limit of quantification (LOQ) was 0.040 ng/ml. With this developed method, we determined total BPA concentrations of 59 maternal blood at delivery and 285 cord blood samples in prospective birth cohort study and investigated factors possibly related to total BPA levels. Total BPA levels ranged from below LOQ to 0.419 ng/ml and for maternal blood and from below LOQ to 0.217 ng/ml for cord blood, respectively. The geometric mean was 0.051 ng/ml for maternal blood and 0.046 ng/ml for cord blood, respectively. Although no correlation was observed between maternal and fetal blood levels of total BPA, our result suggested fetal exposure to BPA. We have found that younger mothers, frequent beef and pork consumption during pregnancy were positively associated with maternal total BPA levels. We confirmed in utero exposure to BPA, which highlights the importance of further studies of investing the effects of fetus BPA exposure on health outcomes.

Prospective respiratory-triggered multidetector row CT (MDCT) for abdominal examinations: initial experience with a prototype.

PURPOSE: To develop a prototype for prospective respiratory-triggered multidetector row computed tomography (MDCT) for abdominal examinations and to assess its feasibility. MATERIALS AND METHODS: The prototype consisted of the following components: an MDCT unit, personal computer (PC), and a respiratory motion detector in the form of a wearable belt with sensors to measure differences in pressure caused by breathing excursions. The registered signals were processed by the PC. The abdominal MDCT images of 10 healthy volunteers were obtained with an incremental axial technique in the expiration phase during normal breathing. Multiplanar reformations (MPR) were then performed. On the basis of the precision of these reconstructions, two radiologists then assessed the accuracy and applicability of the system. RESULTS: Coronal and sagittal MPR images from these prospective respiratory-gated examinations were found to be accurate. In particular, the continuity of borders and surfaces of scanned organs proved the exactness of the previously acquired respiration-correlated axial source images. CONCLUSION: This prototype is feasible to perform prospective respiratory-triggered abdominal MDCT examinations during normal respiration without breathhold. This system may be useful for patients with reduced compliance in holding their breath.

Congener-specific analysis of polychlorinated naphthalenes (PCNs) in the major Chinese technical PCB formulation from a stored Chinese electrical capacitor.

Impurity of polychlorinated naphthalenes (PCNs) in commercial polychlorinated biphenyl (PCB) formulations has been recognized as a relevant source of PCNs in the environment. Congener-specific analysis of most main PCB formulations has been accomplished previously, excluding the Chinese product. The insulating oil in a stored Chinese electric capacitor containing the major Chinese technical formulation "PCB3" was sampled and tested by isotope dilution technology using high-resolution gas chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). The detected concentration of PCNs in the Chinese PCB oil sample was 1,307.5 µg/g and therefore significantly higher than that reported in PCB formulations from other countries, as well as that in the transformer oil (ASKAREL Nr 1740) additionally tested in the present study for comparison. Based on the measurement, the total amount of PCNs in Chinese PCB3 oil is estimated to be 7.8 t, which would mean only 0.005 % of global production of PCNs of 150,000 t. The homolog profile is similar to those of PCN in Aroclor 1262 and Clophen A40, where the contributions from hexa-CNs and hepta-CNs are predominant and accounted for similar proportions. The Toxic Equivalent Quantity (TEQ) concentration of dioxin-like PCN congeners is 0.47 µg TEQ/g, with the dominant contributors of CN-73 and CN-66/67. This TEQ content from PCN is higher than that in most other PCB formulations with the exemption of the Russian Sovol formulation. The total TEQ in the historic 6,000 t of the Chinese PCB3 formulation is estimated to be 2.8 kg TEQ.

Safety of gadopentetate dimeglumine after 120 million administrations over 25 years of clinical use.

PURPOSE: We evaluated the safety of gadopentetate dimeglumine (Gd-DTPA), the first contrast agent for magnetic resonance imaging, using pharmacovigilance data for spontaneously reported adverse events (AEs) after 120 million cumulative administrations worldwide. METHODS: We analyzed spontaneously reported AEs for Gd-DTPA for pre-specified time periods between 1988 and 2011. RESULTS: Since the market introduction of Gd-DTPA in 1988, its global utilization reached 120 million cumulative administrations in 2011, more than 80% of which was by the USA, countries in the European Union (EU), and Japan. The global AE reporting rate was 21.2 in 100,000 administrations in 1988 and 14.4 in 100,000 administrations by 2011. Regional differences included higher reporting rates in the USA and Japan, and reporting rates lower than global rates in the EU. The reported rate of global serious AEs changed from 1.4 in 100,000 administrations in 1988 to 4.0 in 100,000 administrations in 2011. The highest number of reports of nephrogenic systemic fibrosis (NSF) was received from 2006 to 2008. Since 2009, no report of a current onset of NSF has been received. The reduced report rate of NSF may be due to increased awareness about the use of gadolinium-based contrast agents (GBCAs). CONCLUSION: After more than 120 million cumulative administrations, Gd-DTPA is a widely used GBCA that shows a consistently low and stable incidence of AEs.

Temporal trends of perfluoroalkyl acids in plasma samples of pregnant women in Hokkaido, Japan, 2003-2011.

Perfluoroalkyl acids (PFAAs) are persistent organic pollutants that are used in a wide range of consumer products. Recent epidemiological studies have shown that prenatal exposure to toxic levels of PFAAs in the environment may adversely affect fetal growth and humoral immune response in infants and children. Here we have characterized levels of prenatal exposure to PFAA between 2003 and 2011 in Hokkaido, Japan, by measuring PFAA concentrations in plasma samples from pregnant women. The study population comprised 150 women who enrolled in a prospective birth cohort study conducted in Hokkaido. Eleven PFAAs were measured in maternal plasma samples using simultaneous analysis by ultra-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry. At the end of the study, in 2011, age- and parity-adjusted mean concentrations of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorododecanoic acid (PFDoDA), perfluorotridecanoic acid (PFTrDA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) were 1.35ng/mL, 1.26ng/mL, 0.66ng/mL, 1.29ng/mL, 0.25ng/mL, 0.33ng/mL, 0.28ng/mL, and 3.86ng/mL, respectively. Whereas PFOS and PFOA concentrations declined 8.4%/y and 3.1%/y, respectively, PFNA and PFDA levels increased 4.7%/y and 2.4%/y, respectively, between 2003 and 2011. PFUnDA, PFDoDA, and PFTrDA were detected in the vast majority of maternal samples, but no significant temporal trend was apparent. Future studies must involve a larger population of pregnant women and their children to determine the effects of prenatal exposure to PFAA on health outcomes in infants and children.

Determination of PCBs, PCDDs and PCDFs in insulating oil samples from stored Chinese electrical capacitors by HRGC/HRMS.

Homologue and congener profiles of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in commercial PCBs formulations are key information for the source identification of PCBs contamination as well as for the risk assessment caused by potential exposure. The isotope dilution technology in combination with high resolution gas chromatography-high resolution mass spectrometry (HRGC/HRMS) has made the accurate determination of such profiles possible. So far, various commercial PCB formulations except Chinese products have been successfully determined. Two PCBs containing insulating oil samples from stored Chinese electrical capacitors have been determined with the same methodology for comparability. The total concentration PCBs in two oil samples were 790,000 µg g(-1) and 720,000 µg g(-1), respectively. TriCBs, TetraCBs, and DiCBs were found to be most abundant. Concentration of dioxins contamination in two samples is 650-670 ng TEQ g(-1), of which 69-71ngTEQg(-1) from PCDD/Fs with the predominant congeners of 1,2,7,8-TeCDF; 2,3,7,8-TeCDF; 2,3,4,7,8-PeCDF and 1,2,3,7,8-PeCDF. The contributions of DL-PCBs in total TEQ in both samples were more than 85%. The dioxin-like toxicity in insulating oils contained in electrical capacitors could be considered receive attention as an important dioxins source if such wastes are not managed in an environmentally sound manner.

Retrospectivein utero exposure assessment of PCBs using preserved umbilical cords and its application to case-control comparison.

OBJECTIVES: The aim of this study is to assess preserved umbilical cords as chemical exposure media to investigatein utero chemical exposure. Furthermore, we aim to apply preserved umbilical cords to retrospective studies of the relationship betweenin utero chemical exposure and neurodevelopment disorders. METHODS: Two sets of preserved umbilical cord samples were analyzed for exposure to polychlorinated biphenyls (PCBs): one composed of samples from 20 healthy Japanese subjects and the other set included samples from 17 autistic patients and 7 healthy sibling of theirs. RESULTS: The possibility of external PCBs contamination during storage of preserved umbilical cord samples was found, and due to this problem, the study design should be limited to the comparison between PCBs concentration in preserved cord samples from autistic patients and that in those from their sibling. Total PCBs concentrations in preserved cords from autistic patients and their control siblings were compared and we found no statistically significant difference between them (Wilcoxon signed rank test, p>0.05). CONCLUSIONS: The association between autism andin utero PCBs exposure was not clarified in this study; however, retrospective studies such as a case-control study of siblings using preserved umbilical cords can be a method of choice for examining the possible relationship betweenin utero chemical exposure and child hood disorders.

Polychlorinated biphenyls in preserved human umbilical cords.

Congener-specific PCB analyses were carried out on preserved umbilical cord samples. Total PCB concentrations were higher in the umbilical cords of subjects born in the 1960s and 70s than in those born more recently. Total PCB concentrations in the cords from 3 groups of siblings showed no linear relationships between birth order and total PCB concentration. The congener and homologue compositions of PCBs in the umbilical cords of one group of siblings were similar to those of commercial PCB products.

Fish intake, plasma omega-3 polyunsaturated fatty acids, and polychlorinated dibenzo-p-dioxins/polychlorinated dibenzo-furans and co-planar polychlorinated biphenyls in the blood of the Japanese population.

OBJECTIVES: To evaluate background exposure levels and determinants of the individual variations in the exposure to dioxins in Japan. METHODS: A cross-sectional study was performed on 131 men and 122 women (aged 20-76 years), who resided in five prefectures of Japan and had no occupational exposure to dioxins. Seven polychlorinated dibenzo-p-dioxins (PCDDs), ten polychlorinated dibenzo-furans (PCDFs) and 12 polychlorinated biphenyls (PCBs), which are assigned a toxicity equivalent factor, were determined in fasting blood. Biochemical analysis of plasma and a questionnaire survey on life-style, including dietary habit, were also performed. Factors associated with the levels of dioxin-related compounds in blood were evaluated by multiple linear regression. RESULTS: The median of total toxicity equivalents (TEQs) in men and women was 17 and 16 pg TEQ/g lipid, respectively, with no gender difference. After adjustment for age and other covariates, plasma concentrations of eicosapentaenoic acid, a biomarker of fish intake, were found to be positively associated with blood levels of total dioxin, PCDDs, PCDFs and PCBs, all of which were expressed on a TEQ basis (P<0.01). The frequency of intake of coastal fish, such as horse mackerel, mackerel and sardine, was also associated with TEQ-based concentrations of PCDFs (P=0.03) and PCBs (P=0.08). The intake of raw fish was positively related to total dioxins (P=0.06) and PCBs (P=0.03). CONCLUSIONS: The level of intake of marine fish, especially raw fish and coastal varieties, may be associated with increased blood levels of dioxin-related compounds among the population. Despite high fish consumption in Japan, the body burden of dioxins in the population was not found to be higher than that in western countries.