血中の2,3,4,7,8-五塩化ダイベンゾフラン(PeCDF)の個人の半減期：油症患者における臨床症状並びに検診結果との関係

BACKGROUND: In 1968, many people developed dioxin poisoning (Yusho) in Japan. Ingestion of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) was considered to be the cause of this poisoning. Although some patients had high concentrations of 2,3,4,7,8-PeCDF in their blood, individuals' half-lives of 2,3,4,7,8-PeCDF were long. OBJECTIVES: To evaluate the relationship between clinical and laboratory parameters and the individual half-life of 2,3,4,7,8-PeCDF in blood. METHODS: Clinical and laboratory data were collected during annual check-ups from 2001 to 2008. We enrolled 71 patients, who were measured more than 3 times, and who had 2,3,4,7,8-PeCDF concentrations in blood >50pgg(-1) lipid. The half-life of 2,3,4,7,8-PeCDF for each patient was estimated using linear regression. Moreover, relationships between clinical and laboratory parameters and individual half-life were investigated by linear regression. RESULTS: A shortened individual half-life for 2,3,4,7,8-PeCDF was significantly correlated with an increased red blood cell count, increased viscous secretions from the meibomian glands, existing black comedones, and severe cedar pollen allergy. CONCLUSIONS: Symptoms that accelerate excretion of lipids from the body, such as viscous secretions from the meibomian glands, may lead to a shorter half-life of 2,3,4,7,8-PeCDF. Red blood cells are related to the half-life of 2,3,4,7,8-PeCDF. However, further studies are required to investigate the excretory mechanism of 2,3,4,7,8-PeCDF.博士（医学）・乙1325号・平成26年3月17

Prenatal exposure to dioxin-like compounds is associated with decreased cord blood IgE and increased risk of wheezing in children aged up to 7 years : The Hokkaido study

Introduction: In utero exposure to dioxin-like compounds (DLCs) may cause imbalance of immune development in early infancy. However, there are few epidemiological studies into the effects of in utero exposure to DLCs on allergies and infections during childhood. This study evaluates associations between concentrations of maternal DLCs and cord blood immunoglobulin (Ig) E, as well as allergies and infections during childhood. Method: We recruited 514 pregnant women in a maternity hospital in Sapporo, Japan, and measured concentrations of DLCs in 426 maternal blood samples using high-resolution gas chromatography/high-resolution mass spectrometry. We examined the relationship between concentrations of maternal DLCs and cord blood IgE at birth (n = 239), as well as for allergies and infections in children at 3.5 (n = 327) and 7 (n = 264) years, using regression analysis adjusted for confounding variables. Results: We found a positive association between maternal DLC concentrations and frequency of wheezing in children aged up to 7 years [odds ratio (OR); 7.81 (95% confidence interval (CI), 1.42 to 42.9)]. At 3.5 years, boys showed inverse associations between maternal DLC concentrations and cord blood IgE [partial regression coefficient; -0.87 (95% CI), -1.68 to -0.06], and frequency of wheezing [OR; 0.03 (95% CI), 0.00 to 0.94] but girls did not. Discussion: As one reason for the significant association observed at 7 but absent at 3.5 years, we suggest that allergic symptoms are more obvious in older children due to matured immune function. Conclusion: The findings suggest that prenatal exposure to DLCs may modify offspring immune responses and result in increased risk of allergy among children of school age

Effects of prenatal exposure to dioxin-like compounds on allergies and infections during infancy

Dioxin-like compounds are endocrine disruptors. The effects of prenatal exposure to environmental levels of dioxins on immune function during infancy have not been clarified, although dioxins induce immunosuppression in offspring of animals. Moreover, human studies have not assessed the effects of gender- or congener-specific differences. The purpose of this study was to investigate the association between dioxin levels in maternal blood and the risk of infection and allergies in infancy. We examined 364 mothers and their infants enrolled in a Hokkaido Study on Environment and Children's Health between 2002 and 2005 in Sapporo, Japan. Relevant information was collected from a baseline questionnaire during pregnancy, medical records at delivery, and a follow-up questionnaire when the child was 18 months of age that assessed development of allergies and infections in infancy. Dioxin-like compound levels in maternal blood were measured with high-resolution gas chromatography/high-resolution mass spectrometry. Relatively higher levels of polychlorinated dibenzofuran were associated with a significantly increased risk of otitis media, especially among male infants (odds ratio=2.5, 95% confidence interval=1.1-5.9). Relatively higher levels of 2,3,4,7,8-pentachlorodibenzofuran were also associated with a significantly increased risk of otitis media (odds ratio=5.3, 95% confidence interval=1.5-19). However, we observed a weak association between dioxin-like compound levels and allergic symptoms in infancy. At environmental levels, prenatal exposure to dioxin-like compounds may alter immune function and increase the risk of infections in infancy, especially among males. The compound 2,3,4,7,8-pentachlorodibenzofuran may be responsible for this

Dioxin-metabolizing genes in relation to effects of prenatal dioxin levels and reduced birth size : The Hokkaido study

Objectives: We investigated the effects of maternal polymorphisms in 3 genes encoding dioxin metabolizing enzymes in relation to prenatal dioxin levels on infant birth size in Japan. Methods: We examined the relationship between dioxin exposure and birth size in relation to the polymorphisms in the genes encoding aromatic hydrocarbon receptor (AHR [G >A, Arg554Lys]), cytochrome P450 (CYP) 1A1 (T6235C), and glutathione S-transferase mu I (GSTM1; Non-null/null) in 421 participants using multiple linear regression models. Results: In mothers carrying the GSTM1 null genotype, a ten-fold increase in total dioxin toxic equivalency was correlated with a decrease in birth weight of -345g (95% confidence interval: -584, -105). Conclusions: We observed adverse effects of maternal GSTM1 null genotype on birth weight in the presence of dioxins exposure during pregnancy

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 41 weeks 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 20,500 pg/g lipid, respectively. Median total dioxin-TEQ was 13.8 pg/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

Effects of in utero exposure to polychlorinated biphenyls, methylmercury, and polyunsaturated fatty acids on birth size

The adverse effects of in utero exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg), and the beneficial effects of nutrients from maternal fish intake might have opposing influences on fetal growth. In this study, we assessed the effects of in utero exposure to PCBs and MeHg on birth size in the Japanese population, which is known to have a high frequency of fish consumption. The concentrations of PCBs and polyunsaturated fatty acids in maternal blood, and the total mercury in hair (as a biomarker of MeHg exposure) were measured during pregnancy and at delivery. Maternal intakes of fish (subtypes: fatty and lean) and shellfishes were calculated from a food frequency questionnaire administered at delivery. Newborn anthropometric measurement data were obtained from birth records. The associations between chemical exposures and birth size were analyzed by using multiple regression analysis with adjustment for confounding factors among 367 mother–newborn pairs. The birth weight was 3073 ± 37 g (mean ± SD). The incidence of babies small for gestational age (SGA) by weight was 4.9%. The median concentrations of total PCBs and hair mercury were 108 ng/g lipid and 1.41 μg/g, respectively. There was no overall association between mercury concentrations and birth weight, birth length, chest circumference, and head circumference. We observed that the risk of SGA by weight decreased with increasing mercury concentration in regression analyses with adjustment for polyunsaturated fatty acids. Our results suggest that the beneficial effect of essential nutrition may mask the adverse effects of MeHg on birth size. The concentrations of PCBs had no association with birth size

Genetic association of aromatic hydrocarbon receptor (AHR) and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) polymorphisms with dioxin blood concentrations among pregnant Japanese women

Dioxins are metabolized by cytochrome P450, family 1 (CYP1) via the aromatic hydrocarbon receptor (AHR). We determined whether different blood dioxin concentrations are associated with polymorphisms in AHR (dbSNP ID: rs2066853), AHR repressor (AHRR; rs2292596), CYP1 subfamily A polypeptide 1 (CYP1A1; rs4646903 and rs1048963), CYP1 subfamily A polypeptide 2 (CYP1A2; rs762551), and CYP1 subfamily B polypeptide 1 (CYP1B1; rs1056836) in pregnant Japanese women. These six polymorphisms were detected in 421 healthy pregnant Japanese women. Differences in dioxin exposure concentrations in maternal blood among the genotypes were investigated. Comparisons among the GG, GA, and AA genotypes of AHR showed a significant difference (genotype model: P = 0.016 for the mono-ortho polychlorinated biphenyl concentrations and toxicity equivalence quantities [TEQs]). Second, we found a significant association with the dominant genotype model ([TT + TC] vs. CC: P = 0.048 for the polychlorinated dibenzo-p-dioxin TEQs; P = 0.035 for polychlorinated dibenzofuran TEQs) of CYP1A1 (rs4646903). No significant differences were found among blood dioxin concentrations and polymorphisms in AHRR, CYP1A1 (rs1048963), CYP1A2, and CYP1B1. Thus, polymorphisms in AHR and CYP1A1 (rs4646903) were associated with maternal dioxin concentrations. However, differences in blood dioxin concentrations were relatively low