Tsuguhide Hori

Effects of Prenatal Exposure to Polychlorinated Biphenyls and Dioxins on Mental and Motor Development in Japanese Children at 6 Months of Age

Several studies have shown that prenatal and/or postnatal background-level exposure to environmental chemicals, such as polychlorinated biphenyls (PCBs) and dioxins, induces adverse effects on the neurodevelopment of children. However, other studies have not detected any harmful influences on neurodevelopment. Furthermore, except in western countries, no developmental tests have been carried out in relation to detailed assessment of exposure to PCBs and dioxins. In this study (the Hokkaido Study on Environment and Children’s Health), the effect of prenatal exposure to background levels of PCBs and dioxins on infant neurodevelopment in Japan/Sapporo was elucidated. The associations between the total or individual isomer level of PCBs and dioxins in 134 Japanese pregnant women’s peripheral blood and the mental or motor development of their 6-month-old infants were evaluated using the second edition of the Bayley Scales of Infant Development. The mean level of total toxicity equivalency quantity (TEQ) was 18.8 (4.0–51.2) pg/g lipid in blood of 134 mothers. After adjustment for potential confounding variables, the total TEQ value was shown not to be significantly associated with mental developmental index (MDI) or psychomotor developmental index (PDI). However, the levels of one polychlorinated dibenzo-p-dioxin (PCDD) isomer, total PCDDs, and total PCDDs/polychlorinated dibenzofurans (PCDFs) were significantly negatively associated with MDI, and the levels of two PCDD isomers and three PCDF isomers were significantly negatively associated with the PDI. In conclusion, the background-level exposure of several isomers of dioxins during the prenatal period probably affects the motor development of 6-month-old infants more than it does their mental development.

Prenatal exposure to PCDDs/PCDFs and dioxin-like PCBs in relation to birth weight

Several human studies have shown that low-level exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs) and organochlorine pesticides, negatively influences birth outcomes. However, the effects of low-level exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs (DL-PCBs) on birth outcomes have not been clarified in human studies. A prospective cohort study was established to investigate the possible adverse effects of PCDDs/PCDFs and DL-PCBs on fetal growth and neurodevelopment. We recruited 514 pregnant women between July 2002 and October 2005 in Sapporo, Japan. We measured 29 congener levels of PCDDs/PCDFs and DL-PCBs in maternal blood. Using multiple liner regression analysis of the association between birth weight and the levels of PCDDs/PCDFs and DL-PCBs with full adjustments for potential confounders, a significant adverse effect was observed regarding total PCDDs toxic equivalents (TEQ) levels (adjusted beta=-231.5g, 95% CI: -417.4 to -45.6) and total PCDFs TEQ levels (adjusted beta=-258.8g, 95% CI: -445.7 to -71.8). Among male infants, significant adverse associations with birth weight were found for total PCDDs TEQ level, total PCDDs/PCDFs TEQ level, and total TEQ level. However, among female infants, these significant adverse associations were not found. With regard to individual congeners of PCDDs/PCDFs and DL-PCBs, we found significantly negative association with the levels of 2,3,4,7,8-PeCDF (adjusted beta=-24.5g, 95% CI: -387.4 to -61.5). Our findings suggest that prenatal low-level exposure to PCDDs and PCDFs, especially 2,3,4,7,8-PeCDF, may accumulate in the placenta and retard important placental functions, which result in lower birth weight.

Hexabromocyclododecane determination in seafood samples collected from Japanese coastal areas

The levels of three hexabromocyclododecane (HBCD) isomers and ΣHBCDs in 54 wild and 11 farmed seafood samples collected from four regions of Japan were determined by LC/MS/MS. For the fish classified as Anguilliformes, Perciformes, Clupeiformes and farmed Salmoniformes, the medians (ranges) of ΣHBCDs are 2.09 (0.05-36.9), 0.75 (ND-26.2), 0.12 (0.09-77.3) and 1.29 (1.09-1.34) ng g(-1)ww, respectively. However, HBCDs were not detected in samples classified as Crustacea, Mollusca, Pleuronectiformes and Scorpaeniformes, or if detected, the levels were very low. The rank correlation between ΣHBCDs (or α-HBCD) and fat content could not be found except for the Japanese sea bass of the Tohoku region. In HBCD isomer profiles, for fish samples above 20 ng g(-1)ww, the trend was found that γ-HBCD was predominant, which suggests the influence of discharge from a nearby industrial plant. In the other wild fish and the farmed fish samples, on the other hand, α-HBCD was mostly predominant, which suggests biomagnification via the food chain. Additionally, to assess the risk to human health, based on the determined HBCD median concentrations for Anguilliformes, farmed Salmoniformes and Perciformes, the daily intake of HBCDs from fish by an average Japanese adult was tentatively calculated to be 3.7, 2.3 and 1.3 ng (kg body weight)(-1) d(-1), respectively.

Characterization of placental transfer of polychlorinated dibenzo-p-dioxins, dibenzofurans and polychlorinated biphenyls in normal pregnancy

Aim:  Prenatal exposure to dioxins may result in many adverse health effects. However, the mechanisms by which dioxins are transferred from mother to fetus through the placenta are not well understood. The aim of this study was to investigate the differences in dioxin concentrations between maternal blood, the placenta, and cord blood in normal pregnant women, and to identify which individual congeners of these compounds are transferred from mother to fetus through the placenta.

Congener-specific analysis of non-dioxin-like polychlorinated biphenyls in blood collected from 195 pregnant women in Sapporo City, Japan.

We conducted a congener-specific analysis of non-dioxin-like polychlorinated biphenyls (non-dioxin-like PCBs) in blood collected between July 2002 and July 2004 from 195 pregnant women living in Sapporo City of Hokkaido Prefecture, Japan. The present study is one of the few studies in which full congener concentrations of non-dioxin-like PCBs have been measured in the blood of pregnant women. Of the 195 pregnant women, 101 were primipara (mean: 28.8 years, median: 28.0 years) and 94 were multipara (mean: 32.3 years, median: 33.0 years). Among the 197 non-dioxin-like PCB congeners, 58 congeners were identified in the blood of pregnant women. The arithmetic mean total concentrations of 58 non-dioxin-like PCB congeners in the blood of primiparous and multiparous mothers in Sapporo City were 42.2-329.3 (mean: 114.5, median: 98.6) and 31.5-258.0 (mean: 100.3, median: 91.4)ngg(-1)lipid, respectively. The results show that the contamination of non-dioxin-like PCBs in the blood of women has decreased compared to past levels in other domestic areas, in which the subject age was similar to that in this study. The results of the present study indicate that current levels of non-dioxin-like PCBs in the blood of Japanese women and can be used as baseline data for future temporal trends. The sums of the ratios of the concentrations of hexaCBs and heptaCBs to the total concentrations of 58 non-dioxin-like PCB congeners in the blood of primiparous and multiparous mothers were 78.5% and 77.7%, respectively. The hexaCBs ratios in the blood of primiparous and multiparous mothers were 45.4% and 44.7%, respectively. HexaCB-153 among hexaCBs congeners, the most abundant congener in the blood of primiparous and multiparous mothers, contributed approximately 22.0% and 21.8% to the total concentrations of 58 non-dioxin-like PCBs congeners that were measured in the blood, respectively. Among the non-dioxin-like PCB congeners measured in the present study, hexaCB-138, heptaCB-170, heptaCB-180, and heptaCB-182/heptaCB-187 also showed high ratios to total concentrations of 58 non-dioxin-like PCB congeners detected in the blood of primiparous and multiparous mothers. With regard to the relationship between the total concentrations of 58 non-dioxin-like PCB congeners in maternal blood and the number of deliveries or the age of primiparous and multifarious mothers, the total levels of these PCB congeners tended to decreases with increases in the number of deliveries and significantly increased with increasing maternal age in both groups. Furthermore, significant correlations were observed between the total concentrations of these PCB congeners in blood and the age of primiparae and multiparae. The concentrations of hexaCB-153 in the blood of primiparous and multiparous mothers showed a close correlation to the total concentrations of these PCBs, suggesting that hexaCB-153 could be an indicator of total concentrations of non-dioxin-like PCB congeners in the blood of pregnant women.

Concentrations of polychlorinated biphenyls in blood of Yusho patients over 35 years after the incident

We conducted a congener-specific analysis of polychlorinated biphenyls (PCBs) in blood collected from 242 Yusho patients (mean: 65.5 years, median: 67.0 years) and 74 Yusho-suspected persons (mean: 54.7 years, median: 55.0 years) in 2004, and compared each congener concentrations of PCBs among the groups of Yusho patients, Yusho-suspected persons, and normal controls (mean: 68.1 years, median: 67.0 years) with the concentrations previously reported. Among the 209 PCB congeners, 8 congeners of mono-ortho PCBs and 56 congeners of non-dioxin-like PCBs were identified in the blood of Yusho patients and Yusho-suspected persons. Among the PCB congeners measured in the present study, hexaCB-153, hexaCB-138, heptaCB-180, and heptaCB-182/heptaCB-187 showed high ratios to total concentrations of 64 PCB congeners detected in the blood of Yusho patients and Yusho-suspected persons, and the congener profiles were the same as those obtained in normal controls. The sums of the concentrations of 64 PCB congeners in the blood of Yusho patients and Yusho-suspected persons were 40-3032 (mean: 645, median: 536) and 20-1418 (mean: 355, median: 317) ng g(-1) lipid, respectively, and the concentrations were 50% higher and 20% lower than those of normal controls, respectively. The relative contribution ratios of the concentrations of the triCBs, tetraCBs, and pentaCBs to the total concentrations of 64 PCB congeners in the blood of Yusho patients were slightly lower than those of Yusho-suspected persons and normal controls, and the ratios of nonaCBs and decaCB-209 concentrations were nearly the same among the Yusho patients, Yusho-suspected persons, and normal controls. However, the ratios of the concentrations of hexaCBs, heptaCBs, and octaCBs to the total concentrations of 64 PCB congeners in the blood of Yusho patients tended to be slightly higher compared to those of the Yusho-suspected persons and normal controls. From the results comparing the concentrations of 64 PCB congeners in the blood between Yusho patients and normal controls, the concentrations of hexaCB-156, hexaCB-157, heptaCB-181, and heptaCB-189 of the Yusho patients were 3.4, 3.8, 3.9, and 3.8 times higher than those of the normal controls, respectively, indicating that even now, 35 years after exposure, Yusho patients still have a higher concentration of hexaCB-156, hexaCB-157, heptaCB-181, and heptaCB-189 in their blood than do unaffected people. These four congeners may be considered the most important congeners for evaluating the PCBs toxicity of Yusho patients.

Concentrations of Polychlorinated Biphenyls in Blood Collected from Yusho Patients during Medical Check- ups Performed from 2004 to 2007

To elucidate the exposure levels of polychlorinated biphenyls (PCBs) for Yusho patients, we conducted a congener-specific analysis of polychlorinated biphenyls (PCBs) in blood collected from 242, 237, 300, and 96 Yusho patients during medical check-ups performed from 2004 to 2007, respectively, and in samples from 74, 113, 125, and 148 Yusho-suspected persons during those same years, respectively, and compared the individual congener concentrations of PCBs among the groups of Yusho patients, Yusho-suspected persons, and normal controls with the concentrations previously reported. Among the 209 PCB congeners, 8 congeners of mono-ortho PCBs and 56 congeners of non-dioxin-like PCBs were identified in the blood of Yusho patients and Yusho-suspected persons. Among the PCB congeners measured in the present study, hexaCB-153, hexaCB-138, heptaCB-180, and heptaCB-182/heptaCB-187 showed high ratios to total concentrations of 64 PCB congeners detected in the blood of Yusho patients and Yusho-suspected persons from 2004 to 2007, and the profiles of the major congeners were the same as those obtained in normal controls. With respect to the minor congeners of PCBs, several differences were observed among the three groups. The sums of the concentrations of 64 PCB congeners in the blood of Yusho patients from 2004 to 2007 were 645, 760, 667, and 510 ng g(-1) lipid for each year, respectively, and the concentrations were 1.5, 1.8, 1.5, and 1.2 times higher than those of normal controls for each year, respectively. Those of the Yusho-suspected persons were approximately 0.8, 1.1, 0.9, and 1.0 times higher than those of normal controls for each year, respectively. The ratios of heptachlorinated biphenyls (heptaCBs) to the total concentrations of 64 PCB congeners in the blood of Yusho patients and Yusho-suspected persons from 2004 to 2007 tended to be slightly higher than those in the normal controls. From the results comparing the concentrations of 64 PCB congeners in the blood between Yusho patients and normal controls, the concentrations of hexaCB-156, hexaCB-157, heptaCB-181, and heptaCB-189 for Yusho patients were 3.4, 3.8, 3.9, and 3.8 times, respectively, 3.9, 4.1, 3.9, and 4.4 times, respectively, 3.6, 3.9, 5.0, and 4.1 times, respectively, and 2.3, 2.5, 2.7, and 2.9 times higher than those of the normal controls for each year from 2004 to 2007, respectively. These results indicated that Yusho patients still have higher concentrations of hexaCB-156, hexaCB-157, heptaCB-181, and heptaCB-189 in their blood than do unaffected people, even though over 35 years have passed since the outbreak of Yusho. These four congeners can therefore be considered to be the most important congeners for evaluating the PCBs exposure of Yusho patients.

Follow-up Survey of Dioxins Concentrations in the Blood of Yusho Patients in 2002-2003

We measured the concentrations of polychlorinated dizenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and non-ortho-coplanar polychlorinated biphenyls (Co-PCBs) in blood collected from 279 Yusho patients and 92 Yusho-suspected persons living in Japan in 2002, 269 Yusho patients and 74 Yusho-suspected persons living in Japan in 2003 and 128 normal controls living in Fukuoka Prefecture, and compared with the concentrations of these compounds among the groups. The total TEQ concentrations of PCDDs, PCDFs, and Co-PCBs in the blood of Yusho patients were 3.6 times and 3.3 times higher than those in the normal controls in 2002 and 2003, respectively. In the case of Yusho-suspected persons, the concentrations were 1.1 times and 1.0 times higher in 2002 and 2003, respectively. Among the TEQ concentrations of PCDDs, PCDFs, and Co-PCBs, the concentrations of PCDFs in the blood of Yusho patients were 10.3 times and 9.4 times higher than those of the normal controls in 2002 and 2003, respectively, whereas the concentrations of PCDDs and Co-PCBs in blood were identical in Yusho patients, Yusho-suspected persons and normal controls. Yusho patients indicated the highest concentrations ratio of PCDFs to the total TEQ concentrations. Moreover, of the PCDFs congeners for Yusho patients, the concentrations of 2,3,4,7,8-PeCDF were about 11.0 times and 10.1 times higher in 2002 and 2003 than those in normal controls. These results indicated that Yusho patients have a much higher concentration of 2,3,4,7,8-PeCDF in their blood than do unaffected persons even though over 34 years have passed since the outbreak of Yusho.

Association of prenatal exposure to PCDD/Fs and PCBs with maternal and infant thyroid hormones: The Hokkaido Study on Environment and Children's Health☆

Polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) are persistent organic pollutants that are universally detected. Some congeners of PCDDs, PCDFs or PCBs have dioxin-like toxicity, whereas non-dioxin-like PCBs are considered to have different toxicity. Reports of the relationships between prenatal exposure to PCDDs, PCDFs or PCBs and thyroid homeostasis in pregnant women and infants have been inconsistent. The aim of this study was to investigate the effect of maternal serum PCDD/F or PCB levels on maternal and neonatal thyroid hormone (TH) levels in a prospective cohort. Of the 514 subjects in the prospective cohort, 386 mothers and 410 infants were included for analysis. Fifteen dioxins and seventy PCBs in maternal blood collected between 23 and 41weeks of gestation were measured using high-resolution gas chromatography and high-resolution mass spectrometry. Blood samples to measure thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from mothers at an early gestational stage (median ten weeks), and from infants between four and seven days of age, respectively. Multiple linear regression analysis was conducted. Median concentration of total PCBs, PCB 153 were 104,700, and 20,500pg/g lipid, respectively. Median total dioxin-TEQ was 13.8pg/g lipid. Total dioxin-TEQ, coplanar PCBs were positively associated with neonatal FT4 (beta=0.224, 0.206, respectively). The association was stronger in boys (beta=0.299, 0.282, respectively). Several PCDD/F and PCB isomers were also positively associated with neonatal FT4. Total PCBs or non-dioxin-like PCBs were not associated with any maternal or neonatal THs. No DLC grouping or congeners were associated with neonatal TSH. Non-ortho PCBs were positively associated with maternal FT4. Three PCB congeners had significant positive association(s) with maternal THs. In conclusion, the results of our study suggest that perinatal exposure to background-level DLCs increases neonatal FT4, especially in boys.

Gender-specific association of exposure to non-dioxin-like polychlorinated biphenyls during pregnancy with methylation levels of H19 and long interspersed nuclear element-1 in cord blood in the Hokkaido study

BACKGROUND Associations between prenatal exposure to polychlorinated biphenyls (PCBs) and reduced birth-size, and between DNA methylation of insulin-like growth factor-2 (IGF-2), H19 locus, and long interspersed nuclear element-1 (LINE-1) and reduced birth-size are well established. To date, however, studies on the associations between prenatal exposure to PCBs and alterations in methylation of IGF-2, H19, and LINE-1 are lacking. Thus, in this study, we examined these associations with infant-gender stratification. METHODS We performed a prospective birth cohort study using the Sapporo cohort from the previously described Hokkaido Birth Cohort Study on Environment and Childrens Health conducted between 2002 and 2005 in Japan. In the final 169 study participants included in this study, we measured the concentrations of various non-dioxin-like PCBs in maternal blood during pregnancy using high-resolution gas chromatography/high-resolution mass spectrometry. IGF-2, H19 and LINE-1 methylation levels in cord blood were measured using the bisulfite pyrosequencing methods Finally, we assessed the associations between prenatal exposure to various PCBs and the gene methylation levels using multiple regression models stratified by infant gender. RESULTS We observed a 0.017 (95% confidence interval [CI]: 0.003-0.031) increase in the log10-transformed H19 methylation levels (%) in cord blood for each ten-fold increase in the levels of decachlorinated biphenyls (decaCBs) in maternal blood among all infants. Similarly, a 0.005 (95% CI: 0.000-0.010) increase in the log10-transformed LINE-1 methylation levels (%) in cord blood was associated with each ten-fold increase in heptachlorinated biphenyls (heptaCBs) in maternal blood among all infants. In particular, we observed a dose-dependent association of the decaCB levels in maternal blood with the H19 methylation levels among female infants (P value for trend=0.040); likewise a dose-dependent association of heptaCB levels was observed with LINE-1 methylation levels among female infants (P value for trend=0.015). Moreover, these associations were only observed among infants of primiparous women. CONCLUSION Our results suggest that the dose-dependent association between prenatal exposure to specific non-dioxin-like PCBs and increases in the H19 and LINE-1 methylation levels in cord blood might be more predominant in females than in males.