Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse

Takashi Moriguchi, Hozumi Motohashi, Tomonori Hosoya, Osamu Nakajima, Satoru Takahashi, Seiichiroh Ohsako, Yasunobu Aoki, Noriko Nishimura, Chiharu Tohyama, Yoshiaki Fujii-Kuriyama, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

133 Citations (Scopus)

Abstract

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 (Ahrb-1/b-1) mice. DBA/2 (Ahrd/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 Ahrd/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 Ahrd/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 Ahrb-1 or Ahrd 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.

Original languageEnglish
Pages (from-to)5652-5657
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number10
DOIs
Publication statusPublished - 2003 May 13

Keywords

  • C57BL6/J
  • CYP1A1
  • DBA/2
  • Human

ASJC Scopus subject areas

  • General

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