ALTERED- RETINOID AND THYROXIN METABOLIC RESPONSE TO 2,3,7,8-TETRACHLORODIBENSO-p-DIOXIN

对 2,3,7,8-四氯二苯-对-二恶英的类维生素A和甲状腺素代谢反应的改变

• 批准号: 16510049
• 负责人: NISHIMURA Noriko
• 金额: $ 2.5万
• 依托单位: NATIONAL INSTITUTE FOR ENVIRONMENTAL STUDIES (NIES)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16510049/
• 关键词: TCDD; RETINOIDS; THYROXIN; AHR-NULL MICE; TTR-NULL MICE; CROSS-FOSTERING; TTR-欠損マウス; ダイオキシン; レチノイド代謝

To determine whether the disruption of thyroid hormone and retinoid homeostasis that occurs following exposure to 2,3,7,8-tetrachlodibenzo-p-dioxin (TCDD) can be mediated by the arylhydrocarbon receptor (AhR), pregnant AhR-heterozygous (AhR+/-) mice were administered a single oral dose of 10 μg/kg TCDD,at gestation dray 12.5. Serum and liver were collected on postnatal day 21 from vehicle-treated control or TCDD-treated AhR+/- and AhR-null (AhR-/-) mouse pups. While TCDD exposure resulted in a marked reduction of total thyroxin (TT4) and free T4 (FT4) levels in the serum from AhR+/- mice, TCDD had no effects on AhR-/- mice. Gene expressions of UDP-glucuronosyltransferase (UGT)1A6, cytochrome P450 (CYP) 1A1 and CYPIA2 in the liver were induced markedly by TCDD in AhR+/- but not in AhR-/- mice. Induction of OYP1A1 in response to TCDD was confirmed by immunohistochemical evidence in that CYP1A1 protein was conspicuously localized in the cytoplasm of hepatocytes in the centrilobular region … More . The levels of retinyl palmitate were greatly reduced in the liver of TCDD-exposed AhR+/- mice, but not in vehicle-treated AhR+/- mice. No effects of TCDD on retinoid levels in the liver were found in AhR-/- mice. We conclude that disruption of thyroid hormone and retinoid homeostasis is mediated entirely via AhR. Induction of UGT1A6 is thought to be responsible at least partly for the decreased serum thyroid hormone levels in TCDD-exposed mice.We also studied to clarify whether lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is entirely responsible for the perturbation in thyroid hormone homeostasis during the neonatal period. Pregnant Holtzman rats were given a single oral dose of 1.0 μg TCDD/kg body weight on gestational day 15. Half of the litters were cross-fostered with the half of the dams treated with vehicle on postnatal day (PND) 1 to make four groups of rats, control (C/C), prenatal TCDD exposure only (T/C), postnatal TCDD exposure only (C/T), and both prenatal and postnatal TCDD exposure (T/T). On PND 21, the C/T and T/T groups, but not the T/C and C/C groups, showed a significant decrease in serum total thyroxin (TT4) and free thyroxin (FT4) concentrations in both sexes and a significant increase in serum thyroid-stimulating hormone (TSH) levels, particularly male pups. These two groups of male and female pups had significantly higher concentrations of TCDD in the liver, with marked induction of CYP1A1 mRNA And intense immunostaining of CYP1A1 in the liver. UGT1A6 and UGT1A7 mRNAs were induced in their livers, with marked immunostaining of UGT1A6. The transfer of TCDD from dams to the pups was confirmed by the detection of TCDD in mother's milk remaining in the stomachs of lactationally exposed pups on PND 1. The present results demonstrate that lactational, but not in utero, exposure to TCDD was responsible for the disruption of thyroid hormone homeostasis. Less

为了确定暴露于2，3，7，8-四氯二苯并对二恶英（TCDD）后甲状腺激素和类维生素A体内平衡的破坏是否可以由芳烃受体（AhR）介导，在妊娠dray 12.5时，对怀孕的AhR杂合子（AhR+/-）小鼠单次口服10 μg/kg TCDD。在出生后第21天从溶剂处理的对照或TCDD处理的AhR+/-和AhR-无效（AhR-/-）小鼠幼仔中收集血清和肝脏。虽然TCDD暴露导致AhR+/-小鼠血清中总甲状腺素（TT 4）和游离T4（FT 4）水平显著降低，但TCDD对AhR-/-小鼠没有影响。TCDD可显著诱导AhR+/-小鼠肝内UDP-葡萄糖醛酸基转移酶（UGT）1A 6、细胞色素P450（CYP）1A 1和CYPIA 2的基因表达，但对AhR-/-小鼠无明显影响。通过免疫组织化学证据证实，CYP 1A 1蛋白明显定位于小叶中心区肝细胞的细胞质中，从而证实了TCDD诱导OYP 1A 1应答 ...更多信息 .棕榈酸视黄酯的水平在TCDD暴露的AhR+/-小鼠的肝脏中大大降低，但在溶剂处理的AhR+/-小鼠中没有降低。在AhR-/-小鼠中没有发现TCDD对肝脏中类维生素A水平的影响。我们的结论是甲状腺激素和类维生素A稳态的破坏完全通过AhR介导。UGT 1A 6的诱导被认为是TCDD暴露小鼠血清甲状腺激素水平下降的部分原因，我们还研究了哺乳期暴露于2，3，7，8-四氯二苯并对二恶英（TCDD）是否完全是导致新生儿期甲状腺激素稳态紊乱的原因。在妊娠第15天，对妊娠Holtzman大鼠单次口服1.0 μg TCDD/kg体重。将出生后第1天（PND）用溶剂处理的一半母鼠与一半母鼠交叉培养，形成4组大鼠：对照组（C/C）、仅产前TCDD暴露组（T/C）、仅产后TCDD暴露组（C/T）和产前和产后TCDD暴露组（T/T）。在PND 21，C/T和T/T组，但不是T/C和C/C组，显示血清总甲状腺素（TT 4）和游离甲状腺素（FT 4）浓度显着降低，在两种性别和显着增加血清促甲状腺激素（TSH）水平，特别是雄性幼崽。这两组雄性和雌性幼仔的肝脏中TCDD浓度显著较高，肝脏中CYP 1A 1 mRNA和CYP 1A 1免疫染色强烈。在其肝脏中诱导UGT 1A 6和UGT 1A 7 mRNA，具有显著的UGT 1A 6免疫染色。在PND 1哺乳期暴露的幼鼠胃中残留的母乳中检测到TCDD，证实了TCDD从母鼠转移到幼鼠。目前的结果表明，哺乳期，但不是在子宫内，接触TCDD是负责甲状腺激素稳态的破坏。少

项目成果

化学物質と健康-胎仔期および授乳期ダイオキシン曝露によるラット甲状腺過形成とその毒性メカニズム

化学品与健康 - 胎儿和哺乳期二恶英暴露引起的大鼠甲状腺增生及其毒性机制

• 发表时间: 2006
• 期刊: 生物物理化学 (印刷中)
• 作者: Nakajima;A.;Tsuruta;T.;西村典子
• 通讯作者: 西村典子

Effects on thyroid hormone and retinoid metabolism in transthyretin-null mice by polychlorinated biphenyl isomers 118 and 114.

多氯联苯异构体 118 和 114 对转甲状​​腺素蛋白缺失小鼠的甲状腺激素和类视黄醇代谢的影响。

• 发表时间: 2005
• 期刊: Organohalogen Compounds 66
• 作者: 丸山禮子;王冰;山内正剛;Miyabara Y;Nishimura N;Miyabara Y;Nishimura N
• 通讯作者: Nishimura N

Altered thyroxin and retinoid metabolic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-null mice

• DOI: 10.1007/s00204-004-0626-4
• 发表时间: 2005-05-01
• 期刊: ARCHIVES OF TOXICOLOGY
• 影响因子: 6.1
• 作者: Nishimura, N;Yonemoto, J;Tohyama, C
• 通讯作者: Tohyama, C

Disruption of Thyroid Hormone Homeostasis at Weaning of Holtzman Rats by Lactational But Not in Utero Exposure to 2,3,7,8-Tetrachlorodibenzo-p

哺乳期而非子宫内暴露于 2,3,7,8-四氯二苯并-p 的 Holtzman 大鼠断奶时甲状腺激素稳态的破坏

• 发表时间: 2005
• 期刊: Toxicological Sciences Vol.84
• 作者: Nishimura N;Yonemoto J;Nishimura H;Ikushiro SI;Tohyama C.
• 通讯作者: Tohyama C.

Disruption of thyroid hormone homeostasis at weaning in Holtzman rats by lactational but not in uteroe exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin.

哺乳期而非子宫内暴露于 2,3,7,8-四氯二苯并-对二恶英会破坏 Holtzman 大鼠断奶时的甲状腺激素稳态。

• 发表时间: 2005
• 期刊: Toxicol Sci 85
• 作者: 丸山禮子;王冰;山内正剛;Miyabara Y;Nishimura N;Miyabara Y;Nishimura N;Nishimura N
• 通讯作者: Nishimura N