Altered thyroxin and retinoid metabolic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-null mice
Altered thyroxin and retinoid metabolic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-null mice
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DOI：
10.1007/s00204-004-0626-4
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发表时间：
2005-05-01
影响因子：
6.1
通讯作者：
Tohyama, C
中科院分区：
文献类型：
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作者：
Nishimura, N;Yonemoto, J;Tohyama, C
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通过芳香烃受体（AhR）介导，在妊娠第12.5天，对AhR杂合子（AhR+/-）妊娠小鼠单次口服10 μ g/kg（-1）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。而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，TCDD对AhR-/-小鼠没有影响。在AhR+/-小鼠中，TCDD可显著诱导肝脏中UDP-葡萄糖醛酸基转移酶（UGT）1A 6、细胞色素P450（CYP）1A 1和CYP 1A 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，从而证实了对TCDD的CYP 1A 1诱导反应。棕榈酸视黄酯的水平大大降低，在TCDD暴露的AhR+/-小鼠的肝脏，但不是在溶剂处理的AhR+/-小鼠。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的诱导被认为至少是TCDD暴露小鼠血清甲状腺激素水平降低的部分原因。
To determine whether the disruption of thyroid hormone and retinoid homeostasis that occurs after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can be mediated by the arylhydrocarbon receptor (AhR), pregnant AhR-heterozygous (AhR+/-) mice were administered a single oral dose of 10 mu g kg(-1) TCDD at gestation day 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. Whereas TCDD exposure resulted in a marked reduction of total thyroxin (TT4) and free T4 (FT4) levels in the serum of AhR+/- mice, TCDD had no effects on AhR-/- mice. Gene expression of UDP-glucuronosyltransferase (UGT)1A6, cytochrome P450 (CYP)1A1, and CYP1A2 in the liver was induced markedly by TCDD in AhR+/- but not AhR-/- mice. Induction of CYP1A1 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. 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 reduced serum thyroid hormone levels in TCDD-exposed mice.