Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse
Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse
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DOI：
10.1073/pnas.1037886100
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发表时间：
2003-05-13
影响因子：
11.1
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
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作者：
Moriguchi, T;Motohashi, H;Yamamoto, M
对二恶英毒性的易感性在种间和种内存在很大差异。二恶英及相关化合物风险评估中的一个关键问题是人类对其毒性是否敏感或有抵抗力。哺乳动物对二恶英的不同反应受到芳烃受体（AHR）功能多态性的强烈影响。为了表征人类AHR介导的反应（hAHR），我们产生了具有hAHR而不是小鼠AHR的小鼠。将这些小鼠对2,3,7,8-四氯二苯并-对二恶英（TCDD）和3-甲基胆蒽的反应与自然敏感（C57BL/6J）和耐药（DBA/2）小鼠的反应进行比较。与C57BL/6J （AHR (b-1/b-t)）小鼠相比，hAHR纯合子小鼠对AHR靶基因cyp1a1和cyp1a2的诱导较弱。DBA/2 （Ahr(d/d)）小鼠对cyp基因诱导的反应低于C57BL/6J小鼠。hAHR和DBA/2 AHR表现出相似的配体结合亲和力，纯合的hAHR和AHR （d/d）小鼠被3-甲基胆蒽诱导的AHR靶基因相似。然而，当给予TCDD时，与Ahr（d/d）小鼠相比，纯合子hAHR小鼠的反应大大降低，这表明小鼠中表达的hAHR对TCDD的反应在功能上低于DBA/2 Ahr。母亲暴露于TCDD后，纯合子hAHR胎儿会出现胚胎肾积水，但不会出现腭裂，而拥有Ahr（b-1）或Ahr(d)的胎儿会出现这两种异常。这些结果表明，hAHR可能定义了对各种AHR配体反应的特异性。因此，hAHR敲入小鼠是一种人源化模型小鼠，可以更好地预测TCDD等生物蓄积性环境毒物对人体的生物学效应。
There are large inter- and intraspecies differences in susceptibility to dioxin-induced toxicities. A critical question in risk assessment of dioxin and related compounds is whether humans are sensitive or resistant to their toxicities. The diverse responses of mammals to dioxin are strongly influenced by functional polymorphisms of the arylhydrocarbon receptor (AHR). To characterize responses mediated by the human AHR (hAHR), we generated a mouse possessing hAHR instead of mouse AHR. Responses of these mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene were compared with the responses of naturally sensitive (C57BL/6J) and resistant (DBA/2) mice. Mice homozygous for hAHR exhibited weaker induction of AHR target genes such as cyp1a1 and cyp1a2 than did C57BL/6J (Ahr(b-1/b-t)) mice. DBA/2 (Ahr(d/d)) mice were less responsive to induction of cyp genes than C57BL/6J mice. hAHR and DBA/2 AHR exhibit similar ligand-binding affinities and homozygous hAHR and Ahr(d/d) mice displayed comparable induction of AHR target genes by 3-methylcholanthrene. However, when TCDD was administered, a greatly diminished response was observed in homozygous hAHR mice compared with Ahr(d/d) mice, indicating that hAHR expressed in mice is functionally less responsive to TCDD than DBA/2 AHR. After maternal exposure to TCDD, homozygous hAHR fetuses developed embryonic hydronephrosis, but not cleft palate, whereas fetuses possessing Ahr(b-1) or Ahr(d) developed both anomalies. These results suggest that hAHR may define the specificity of the responses to various AHR ligands. Thus, the hAHR knock-in mouse is a humanized model mouse that may better predict the biological effects of bioaccumulative environmental toxicants like TCDD in humans.