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A Study on Polychlorinated Biphenyls Specifically--Accumulated in Blood of Yusho Patients Collected from Medical Check-Ups in 2012. 2012年玉树患者体检血液中多氯联苯特异性积累的研究
Takashi Miyawaki, Shusaku Hirakawa, Takashi Todaka, Hironori Hirakawa, Tsuguhide Hori, Junboku Kajiwara, Teruaki Hirata, Hiroshi Uchi, Masutaka Furue

In this study, we analyzed polychlorinated biphenyls (PCBs) in the blood of Yusho patients collected from medical check-ups, which were conducted in 2012. The results show that 65 PCB isomers, not including non-ortho PCBs, were detected in the blood samples, and the total concentration was 620 ng g(-1) lipid. This value was comparable to the concentration in blood samples collected in 2005, and indicated that PCB concentrations in Yusho patients remained unchanged from 2005 to 2012. Here, we focused on major and specific PCB isomers in the blood samples of Yusho patients and normal controls. Examples of the former include hexaCB-153, hexaCB-138, and heptaCB-180, which are detected in human blood, while the latter include hexaCB-156, hexaCB-157, and heptaCB-189, and are highly detected in the blood of Yusho patients. Additionally, we tried to determine why the specific isomers were highly accumulated in the blood of Yusho patients as compared to the normal controls. We therefore analyzed these isomers in the contaminated rice oil, and found that the concentrations of hexaCB-156, hexaCB-157, and heptaCB-189 were 1800, 450, and 190 ng g(-1), respectively. Notably, previous studies indicated that these isomers might not be easily metabolized in humans. Therefore, these findings demonstrated that these isomers were highly accumulated in the blood of Yusho patients.

在本研究中,我们分析了2012年进行体检的玉树患者血液中的多氯联苯(PCBs)。结果表明,血样中检出65种多氯联苯异构体,总浓度为620 ng g(-1)脂质。该值与2005年采集的血液样本中的浓度相当,表明2005年至2012年玉树患者的多氯联苯浓度保持不变。在这里,我们重点研究了玉树患者和正常人血液样本中的主要和特定的多氯联苯异构体。前者包括hexaCB-153、hexaCB-138和heptaCB-180,在人类血液中检测到,后者包括hexaCB-156、hexaCB-157和heptaCB-189,在禹州患者血液中检测到的量很高。此外,我们试图确定为什么与正常对照相比,特定的异构体在玉树患者的血液中高度积累。因此,我们在污染的米油中分析了这些异构体,发现hexaCB-156、hexaCB-157和heptaCB-189的浓度分别为1800、450和190 ng g(-1)。值得注意的是,先前的研究表明,这些异构体可能不容易在人体内代谢。因此,这些发现表明这些异构体在玉树患者的血液中高度积累。
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引用次数: 0
Foreword. The Twenty-five Reports of the Study on Yusho--PCBs and Dioxin-Related Compounds. 前言。鱼松-多氯联苯及二恶英相关化合物25份研究报告
Masutaka Furue
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引用次数: 0
[Comparison of the prevalence of symptoms and medical histories between Yusho patients and healthy controls]. [玉树患者与健康对照者症状及病史的比较]。
Manabu Akahane, Shinya Matsumoto, Yoshiyuki Kanagawa, Chikage Mitoma, Hiroshi Uchi, Takesumi Yoshimura, Masutaka Furue, Tomoaki Imamura

Yusho disease was first reported in October 1968 in western Japan. Although a previous survey revealed that Yusho patients have suffered from various symptoms for 40 years after the outbreak of Yusho, some symptoms could be caused by aging. Therefore, we compared the prevalence of symptoms and medical histories (symptoms or patient-reported diseases) between Yusho patients and healthy controls to demonstrate the effects of Yusho on health conditions. We conducted a survey of healthy controls who had already registered to a survey company and created a dataset of symptoms and medical histories. We then merged the healthy control data with the Yusho survey data obtained from The Ministry of Health, Labour, and Welfare of Japan. Statistical analyses were performed using a chi-square analysis for the incidence of symptoms. Symptoms included in the major diagnostic criteria for Yusho, such as pigmentation and acneform eruption, were expectedly higher in the Yusho patients than in the healthy individuals. Symptoms that could be caused by aging, such as general fatigue, arthralgia, and numbness in the extremities, were also significantly higher in the Yusho patients after adjustment for age, indicating the possibility that Yusho may cause various systemic symptoms and diseases.

鱼松病于1968年10月在日本西部首次报道。虽然之前的调查显示,在“玉树”爆发后的40年里,玉树患者一直患有各种症状,但有些症状可能是由衰老引起的。因此,我们比较了“玉树”患者和健康对照者之间的症状患病率和病史(症状或患者报告的疾病),以证明“玉树”对健康状况的影响。我们对已经在一家调查公司注册的健康对照者进行了调查,并创建了症状和病史数据集。然后,我们将健康对照数据与从日本厚生劳动省获得的Yusho调查数据合并。采用卡方分析对症状发生率进行统计分析。包括在主要诊断标准中的症状,如色素沉着和针状疹,在玉树病患者中预期高于健康个体。年龄调整后,可能由衰老引起的全身疲劳、关节痛、四肢麻木等症状在玉树患者中也明显增加,这表明玉树可能引起各种全身症状和疾病。
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引用次数: 0
[Serum Levels of Regulatory T Cell in the Yusho Patients]. [玉树病患者血清调节性T细胞水平]。
Yoshiko Mine, Yutaka Kuwatsuka, Atsushi Utani

Dioxin and dioxin-like compounds receptor (Ahr) mainly expressed on the surface of regulatory T (Treg) cell and Th17 cell could regulate immunological functions in the Yusho patients. We prospectively analyzed data obtained in a total of 56 cases of Yusho, which include patients identified ('Nintei' ) or non-identified ( 'Minintei') or identified as a family member, at the annual health check in 2014. The number of Treg cell showed lower among identified patients compared with non-identified group or family identified group (p = 0.4184 and p = 0.291, respectively). There was also a strong correlation between serum levels of neutral fat and the number of Treg cells (p = 0.0313). These results suggest that Treg cell plays a principal role in the immune response among Yusho patients.

二恶英及二恶英样化合物受体(Ahr)主要表达于调节性T细胞(Treg)和Th17细胞表面,可调节郁松患者的免疫功能。我们前瞻性地分析了在2014年年度健康检查中获得的56例Yusho病例的数据,其中包括确定('Nintei')或未确定(' Minintei')或确定为家庭成员的患者。识别组Treg细胞数量低于未识别组和家族识别组(p = 0.4184和p = 0.291)。血清中性脂肪水平与Treg细胞数量之间也有很强的相关性(p = 0.0313)。这些结果表明Treg细胞在玉树患者的免疫应答中起主要作用。
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引用次数: 0
[Latest Findings of Yusho and Its Therapeutic Development]. [玉树的最新发现及其治疗进展]。
Chikage Mitoma, Hiroshi Uchi, Gaku Tsuji, Saori Koga, Masutaka Furue

Yusho incident is an unprecedented mass food poisoning that occurred in the western area of Japan in 1968. It was caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls (PCBs) and various dioxins and dioxin-like compounds, such as polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). The victims of Yusho have suffered from characteristic skin manifestations in company with systemic, ophthalmological, and mucosal symptoms for a long period. Since the outbreak of Yusho, the Study Group of Yusho has been conducting annual medical check-ups on Yusho victims. We describe here the latest research findings of chronic dioxin-induced toxicity to Yusho patients and the mechanisms of toxicities of dioxins through the aryl hydrocarbon receptor (AhR) pathway. High amounts of PCBs and PCDFs are still present in a number of patients with Yusho. The patients have persistent various symptoms, some of which were significantly associated with blood levels of PCBs, dioxins, or dioxin-like compounds. The adverse effects on the next generation are also found. According to the findings of recent basic studies, the biological and toxicological effects mediated by the AhR system have been becoming clear; therefore, the therapeutic interventions may be found in the near future.

鱼松事件是1968年发生在日本西部地区的一起史无前例的大规模食物中毒事件。这是由于摄入了被多氯联苯(PCBs)和各种二恶英和二恶英类化合物(如多氯二苯并对二恶英(pcdd)和多氯二苯并呋喃(pcdf))污染的米糠油而引起的。在很长一段时间内,玉树病的受害者都有特征性的皮肤表现,并伴有全身、眼科和粘膜症状。自玉树病爆发以来,玉树病研究小组每年对玉树病患者进行体检。本文介绍了二恶英对玉树患者慢性毒性的最新研究成果,以及二恶英通过芳烃受体(aryl hydrocarbon receptor, AhR)通路的毒性机制。大量的多氯联苯和多氯联苯仍存在于许多玉松患者体内。患者持续出现各种症状,其中一些症状与多氯联苯、二恶英或二恶英样化合物的血液水平显著相关。对下一代的不利影响也被发现。根据最近的基础研究结果,AhR系统介导的生物学和毒理学效应已逐渐明确;因此,治疗干预可能在不久的将来被发现。
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引用次数: 0
[Anti- SSA/Ro and Anti-SSB/ La Antibodies in Patients with Yusho]. [抗SSA/Ro和抗ssb / La抗体在玉露患者中的应用]。
Hiroshi Tsuji

To investigate chronic immune effects of polychlorinated biphenyl (PCB) and polychlorinated dibenzofuran (PCDF), anti-SSA/Ro and anti-SSB/La antibodies were studied in serum of 213 patients with Yusho and 63 control subjects in 2013. Anti-SSA/Ro antibodies were found in 4.2% (9/213) of patients with Yusho and 1.6% (1/63) of control subjects. The prevalence rates of anti-SSA/Ro antibodies in Yusho patients were not associated with blood PCB concentration or blood 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) concentration. Anti-SSB/La antibodies were found in 1.4% (3/213) of patients of Yusho, but none of controls. Furthermore, high concentrations of PCB and 2,3,4,7,8-PeCDF were present in Yusho patients with anti-SSB/La antibodies. We conclude that anti-SSB/La antibody is present in patients with Yusho, and it may be associated with PCB and 2,3,4,7,8-PeCDF in the blood.

为探讨多氯联苯(PCB)和多氯二苯并呋郎(PCDF)的慢性免疫作用,2013年对213例玉松患者和63例对照者进行血清抗ssa /Ro和抗ssb /La抗体检测。有4.2%(9/213)的患者和1.6%(1/63)的对照组检测到抗ssa /Ro抗体。玉树患者抗ssa /Ro抗体阳性率与血中PCB浓度或血中2,3,4,7,8-五氯二苯并呋喃(PeCDF)浓度无关。1.4%(3/213)患者检测到抗ssb /La抗体,对照组无。此外,在玉树患者的抗ssb /La抗体中存在高浓度的PCB和2,3,4,7,8- pecdf。我们认为,玉松患者体内存在抗ssb /La抗体,该抗体可能与血中PCB和2,3,4,7,8- pecdf有关。
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引用次数: 0
[The Distribution of Dioxin Concentrations in the Blood of Yusho Patients]. [玉树患者血液中二恶英浓度的分布]。
Jumboku Kajiwara, Takashi Todaka, Hironori Hirakawa, Tsuguhide Hori, Teruaki Hirata, Takao Iida, Hiroshi Uchi, Masutaka Furue

In 1968, the contamination of cooking oil by heat-degraded polychlorinated biphenyls (PCBs) caused a case of mass poisoning, the so-called Yusho incident. The cause of Yusho disease is thought to be ingested toxic substances, including not only PCBs but also polychlorinated dibenzofuran (PCDFs) in Kanemi rice oil. We previously measured dioxins concentrations in the blood of 854 Yusho patients by annual medical examination from 2001 to 2013. We determined the concentrations of 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, 1,2,3,6,7,8-HxCDF and 3,3',4,4',5,5'-HxCB (#169) in the blood of Yusho patients were more than double those of normal controls. In 2012, a new Yusho criteria was established. Family members living with a Yusho patient were also certified as Yusho patients and called Yusho family cohabitant patients. In this study, we compared the distribution of 2,3,4,7,8-PeCDF concentration in the blood of Yusho patients and Yusho family cohabitant patients. It was suspected that the distribution of 2,3,4,7,8-PeCDF concentration in Yusho family cohabitant patients would be lower than that of Yusho patients.

1968年,食用油被热降解的多氯联苯(PCBs)污染,导致了一起大规模中毒事件,即所谓的玉树事件。鱼松病的病因被认为是摄入有毒物质,不仅包括多氯联苯,还包括Kanemi米油中的多氯联苯。我们之前通过2001年至2013年的年度体检测量了854名玉树患者血液中的二恶英浓度。我们测定了玉树患者血液中2,3,4,7,8- pecdf, 1,2,3,3,4,7,8 - hxcdf, 1,2,3,6,7,8- hxcdf和3,3',4,4',5,5'-HxCB(#169)的浓度是正常对照的两倍以上。2012年,制定了新的玉树标准。与“玉树”患者一起生活的家庭成员也被认定为“玉树”患者,并被称为“玉树家庭同居患者”。在本研究中,我们比较了2、3、4、7、8-PeCDF在玉树患者和玉树家族常住患者血液中的分布。推测2、3、4、7、8-PeCDF浓度在玉树家族常住患者中的分布可能低于玉树患者。
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引用次数: 0
[Blood PCB Concentrations and their Tendencies Examined in Fukuoka 2011-2014 Annual Inspections for Yusho]. [福冈市2011-2014年检中血液多氯联苯浓度及其趋势分析]。
Daisuke Yasutake, Toshitaka Kogiso, Tsuguhide Hori, Takashi Miyawaki, Takamitsu Yamamoto, Jumboku Kajiwara, Teruaki Hirata, Hiroshi Uchi, Masutaka Furue

We measured PCBs of blood of 154 people in the Yusho medical check-up from January 2011 through December 2014 and analyzed their PCB blood patterns. Eleven examinees were newly certified as Yusho patients during these 4 years. Of these 11, we identified three Yusho patients with the A pattern, five with the B pattern, and three with the BC pattern. We found no Yusho patients with the C pattern. The B pattern was found in 27 of the 154 examinees, such that the probability that an examinee with the B pattern would be certified as a Yusho patient was about 20%. Since 2012, any family members living with a Yusho patient have also been certified as Yusho patients. The number of such family cohabitants was 16, among whom the PCB pattern was uniformly the C pattern. There were 20 examinees born after 1989, and all those examinees were Yusho-suspected persons. The total PCB concentrations of this younger-age group was less than 0.5 ng/g on average and was low compared with the normal controls.

从2011年1月至2014年12月,我们在玉树医院体检中测量了154人的多氯联苯血液,并分析了他们的多氯联苯血液模式。在这4年中,有11名考生被新认证为玉树患者。在这11例患者中,我们鉴定出3例A型,5例B型,3例BC型。我们没有发现有C型的玉穗患者。在154名考生中,有27人出现了B型,因此,B型考生被认定为“柳松患者”的可能性约为20%。自2012年以来,任何与玉树患者生活在一起的家庭成员也被认证为玉树患者。该家庭同居者共16人,其中PCB型均为C型。1989年以后出生的考生有20人,这些考生都是“柳生”嫌疑人。该年龄组的总PCB浓度平均小于0.5 ng/g,与正常对照相比较低。
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引用次数: 0
[The Effect of Maternal Exposure to Dioxins on the Level of Thyroid Hormone in Developing Pups]. [母体接触二恶英对幼鼠甲状腺激素水平的影响]。
Yukiko Hattori, Tomoki Takeda, Junki Taura, Hiroaki Kuroki, Yuji Ishii, Hideyuki Yamada

Maternal exposure to dioxins causes a number of developmental disorders in the offspring. Previous studies have suggested that lactational exposure to 2,3,7,8-tetrachlorodizenzo-p-dioxin (TCDD) reduces the pup level of thyroid hormone after weaning, leading to the damage to their development including neural maturation. However, the specificity for age and dioxin congeners as well as dose dependency in terms of a reduction in pup thyroid hormone remains to be clarified. To address this issue, we investigated whether TCDD or 2,3,4,7,8-pentachlorodibenzofuran (PenCDF), one of the dioxins which caused 'Yusho' incident, affects the status of thyroid hormone during the fetal and neonatal periods. Treating pregnant rats at gestational day (GD)15 with 1 μg/kg TCDD scarcely affected the serum concentration of thyroxine, although a significant reduction by TCDD was detected at limited endpoints [GD21 and postnatal day (PND)21]. In addition, maternal exposure to TCDD (0.05-30 μg/kg) or PenCDF (1-1,000 μg/kg) did not have any change in the serum level of thyroxine in GD20 fetuses even at the maximum dose. Neither the expression of pituitary thyroid-stimulating hormone β (TSHβ) nor hypothalamic thyrotropin-releasing hormone was sensitive to TCDD treatment. In pregnant dams, TCDD decreased the serum level of thyroxine at GD20 and 21, while the pituitary expression of TSHβ was induced. These results suggest that a single administration of dioxins to pregnant rats at GD15 have little effect on the level of thyroxine in the fetuses and infants, while a reduced level of this hormone observed in the offspring at GD21 and PND21 and pregnant dams at GD20 and 21.

母亲接触二恶英会导致后代出现一些发育障碍。先前的研究表明,哺乳期暴露于2,3,7,8-四氯二氮杂-对二恶英(TCDD)会降低断奶后幼犬的甲状腺激素水平,导致其发育受损,包括神经成熟。然而,在幼犬甲状腺激素减少方面,年龄和二恶英同系物的特异性以及剂量依赖性仍有待澄清。为了解决这一问题,我们调查了TCDD或引起“玉松”事件的二恶英之一2,3,4,7,8-五氯二苯并呋喃(PenCDF)是否会影响胎儿和新生儿时期甲状腺激素的状态。妊娠第15天(GD)用1 μg/kg TCDD治疗妊娠大鼠几乎不影响血清甲状腺素浓度,尽管在有限的终点[GD第21天和出生后第21天]检测到TCDD显著降低血清甲状腺素浓度。此外,即使在最大剂量下,母体暴露于TCDD (0.05 ~ 30 μg/kg)或PenCDF (1 ~ 1000 μg/kg)对GD20胎儿血清甲状腺素水平也没有任何影响。垂体促甲状腺激素β (TSHβ)和下丘脑促甲状腺素释放激素的表达对TCDD治疗均不敏感。TCDD可降低孕鼠GD20和gd21时血清甲状腺素水平,并可诱导垂体TSHβ的表达。这些结果表明,在GD15时对怀孕大鼠单次给予二恶英对胎儿和婴儿甲状腺素水平的影响很小,而在GD21和PND21时的后代以及GD20和21时的怀孕大鼠中观察到该激素水平降低。
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引用次数: 0
[Metabolism of 2,2',3,4,4',5,5'-Heptachlorobiphenyl (CB180) by Animal Liver Microsomes]. [动物肝微粒体对2,2',3,4,4',5,5'-七氯联苯(CB180)的代谢]。
Chiho Ohta, Koichi Haraguchi, Yoshihisa Kato, Tetsuya Endo, Osamu Kimura, Nobuyuki Koga

The in vitro metabolism of 2,2',3,4,4', 5,5'-heptachlorobiphenyl (CB180) was examined using liver microsomes of rats, guinea pigs and hamsters. Of liver microsomes from untreated animals, rats and guinea pigs produced one metabolite (M-1) with the activity of 1.2 and 18.1 pmol/hr/mg protein, respectively, but hamsters did not at all. Pretreatment of phenobarbital (PB) resulted in about 32-fold increase in rats, 4-fold increase in guinea pigs and an appearance of M-1 in hamsters (15 pmol/hr/mg protein). In addition, another metabolite (M-2) was formed only by liver microsomes of PB-treated guinea pigs. In contrast, pretreatment of 3-methylcholanthrene showed no metabolite in three animals. By comparison of the GC-MS data of the metabolites with synthesized authentic samples, M-1 and M-2 was determined to be 3'-hydroxy (OH)-CB180 and 4'-OH-2,2',3,4,5,5'-hexachlorobiphenyl (CB141), respectively. These results suggest that 3'-OH-CB180 is a major metabolite and is formed by PB-inducible cytochrome P450 (CYP2B enzymes) in animals and also guinea pigs possess much higher activity to metabolize CB180 than rats and hamsters.

采用大鼠、豚鼠和仓鼠肝微粒体研究了2,2′,3,4,4′,5,5′-七氯苯(CB180)的体外代谢。在未处理的动物肝微粒体中,大鼠和豚鼠分别产生一种代谢产物(M-1),其活性分别为1.2和18.1 pmol/hr/mg蛋白,而仓鼠则完全没有。苯巴比妥(PB)预处理导致大鼠的M-1增加约32倍,豚鼠增加4倍,仓鼠出现M-1 (15 pmol/hr/mg蛋白)。此外,另一种代谢物(M-2)仅由pb处理的豚鼠的肝微粒体形成。相比之下,预处理3-甲基胆蒽在3只动物中没有代谢产物。将代谢产物的GC-MS数据与合成的真实样品进行比较,确定M-1和M-2分别为3'-羟基(OH)-CB180和4'-OH-2,2',3,4,5,5'-六氯联苯(CB141)。这些结果表明,3′-OH-CB180是铅诱导的细胞色素P450 (CYP2B酶)在动物体内形成的主要代谢物,并且豚鼠对CB180的代谢活性远高于大鼠和仓鼠。
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引用次数: 0
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Fukuoka igaku zasshi = Hukuoka acta medica
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