CoChat
Sign Up
Cited by 164Toxic Organic Pollutants ImpactPharmacogenetics and Drug MetabolismEffects and risks of endocrine disrupting chemicals

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

Open access
Moriguchi, Takashi, Motohashi, Hozumi, Hosoya, Tomonori, Nakajima, Osamu, Takahashi, Satoru, Ohsako, Seiichiroh, Aoki, Yasunobu, Nishimura, Noriko +3 more·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1037886100PMC PMC156256
Open this paper in CoChat — free account

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 h AHR exhibited weaker induction of AHR target genes such as cyp1a1 and cyp1a2 than did C57BL/6J ( Ahr b-1/b-1 ) 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 h AHR 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 h AHR 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 h AHR 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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.1037886100

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The AhrHum allele is less sensitive to TCDD than the Ahrd allele.

    “Interestingly, in early reports, the AhrHum allele was shown to be less sensitive to TCDD than the Ahrd allele (Moriguchi et al., 2003).”

    From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Moriguchi et al., 2003

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 34

  1. [1]Poland A, Knutson C. Annu Rev Pharmacol Toxicol. 1982;22:517–554. doi: 10.1146/annurev.pa.22.040182.002505. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  2. [2]Whitelock J P., Jr Annu Rev Pharmacol Toxicol. 1990;30:251–277. doi: 10.1146/annurev.pa.30.040190.001343. [DOI] [PubMed] [Google Scholar] · DOI
  3. [3]Landers J P, Bunce N J. Biochem J. 1991;276:273–287. doi: 10.1042/bj2760273. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  4. [4]Swanson H J, Bradfield C A. Pharmacogenetics. 1993;3:213–230. doi: 10.1097/00008571-199310000-00001. [DOI] [PubMed] [Google Scholar] · DOI
  5. [5]Hoffman E C, Reyes H, Chu F-F, Sander F, Conly L H, Brooks B A, Hankinsin O. Science. 1991;252:954–958. doi: 10.1126/science.1852076. [DOI] [PubMed] [Google Scholar] · DOI
  6. [6]Okey A B, Riddick D, Harper P A. Toxicol Lett. 1994;70:1–22. doi: 10.1016/0378-4274(94)90139-2. [DOI] [PubMed] [Google Scholar] · DOI
  7. [7]Rowlands J, Gustafsson J A. CRC Crit Rev Toxicol. 1997;27:109–134. doi: 10.3109/10408449709021615. [DOI] [PubMed] [Google Scholar] · DOI
  8. [8]Poellinger L. Food Addit Contam. 2000;17:261–266. doi: 10.1080/026520300283333. [DOI] [PubMed] [Google Scholar] · DOI
  9. [9]Ema M, Ohe N, Suzuki M, Mimura J, Sogawa K, Ikawa S, Fujii-Kuriyama Y. J Biol Chem. 1994;269:27337–27343. [PubMed] [Google Scholar]
  10. [10]Poland A, Glover E. Mol Pharmacol. 1990;38:306–312. [PubMed] [Google Scholar]
  11. [11]Poland A, Palen D, Glover E. Mol Pharmacol. 1994;46:915–921. [PubMed] [Google Scholar]
  12. [12]Ema M, Matsushita N, Sogawa K, Ariyama T, Inazawa J, Nemoto T, Ota M, Oshimura M, Fujii-Kuriyama Y. J Biochem. 1994;116:845–851. doi: 10.1093/oxfordjournals.jbchem.a124605. [DOI] [PubMed] [Google Scholar] · DOI
  13. [13]Dolwick K M, Schmidt J V, Carver L A, Swanson H I, Bradfield C A. Mol Pharmacol. 1993;44:911–917. [PubMed] [Google Scholar]
  14. [14]Okey A B, Vella L M, Harper P A. Mol Pharmacol. 1989;35:823–830. [PubMed] [Google Scholar]
  15. [15]Pohjanvirta R, Unkila M, Tuomisto J. Pharmacol Toxicol. 1993;73:52–56. doi: 10.1111/j.1600-0773.1993.tb01958.x. [DOI] [PubMed] [Google Scholar] · DOI
  16. [16]Pohjanvirta R, Wong J M Y, Li W, Harper P A, Tuomisto J, Okey A B. Mol Pharmacol. 1998;54:86–93. doi: 10.1124/mol.54.1.86. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  17. [17]Tuomisto J T, Viluksela M, Pohjanvirta R, Tuomisto J. Toxicol Appl Pharmacol. 1999;155:71–81. doi: 10.1006/taap.1998.8564. [DOI] [PubMed] [Google Scholar] · DOI
  18. [18]Mocarelli P, Gerthoux P M, Ferrari E, Patterson D G, Jr, Kieszak S M, Brambilla P, Vincoli N, Signorini S, Tramacre P, Carreri V, et al. Lancet. 2000;355:1858–1863. doi: 10.1016/S0140-6736(00)02290-X. [DOI] [PubMed] [Google Scholar] · DOI
  19. [19]Micka J, Milatovich A, Menon A, Grabowski G A, Puga A, Nebert D W. Pharmacogenetics. 1997;7:95–101. doi: 10.1097/00008571-199704000-00002. [DOI] [PubMed] [Google Scholar] · DOI
  20. [20]Kohkalainen M, Tuomisto J, Pohjanvirta R. Biochem Biophys Res Commun. 2001;285:1121–1129. doi: 10.1006/bbrc.2001.5317. [DOI] [PubMed] [Google Scholar] · DOI
  21. [21]Abnet C C, Tanguay R L, Heideman W, Peterson R E. Toxicol Appl Pharmacol. 1999;159:41–51. doi: 10.1006/taap.1999.8719. [DOI] [PubMed] [Google Scholar] · DOI
  22. [22]Mimura J, Yamashita K, Nakamura K, Morita M, Takagi T N, Nakao K, Ema M, Sogawa K, Yasuda M, Katsuki M, et al. Genes Cell. 1997;2:645–654. doi: 10.1046/j.1365-2443.1997.1490345.x. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  23. [23]Hooper M, Hardy K, Handyside A, Hunter S, Monk M. Nature. 1987;326:292–295. doi: 10.1038/326292a0. [DOI] [PubMed] [Google Scholar] · DOI
  24. [24]Ema M, Sogawa K, Watanabe N, Chujoh Y, Matsushita N, Gotoh O, Funae Y, Fujii-Kuriyama Y. Biochem Biophys Res Commun. 1992;184:246–253. doi: 10.1016/0006-291x(92)91185-s. [DOI] [PubMed] [Google Scholar] · DOI
  25. [25]Fernandez-Salguero P, Pineau T, Hilbert D M, McPhail T, Lee S S T, Kimura S, Nebert D W, Rudikoff S, Ward J M, Gonzalez F J. Science. 1995;268:722–726. doi: 10.1126/science.7732381. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  26. [26]Moriguchi T, Sakurai T, Takahashi S, Goto K, Yamamoto M. J Biol Chem. 2002;277:16985–16992. doi: 10.1074/jbc.M107962200. [DOI] [PubMed] [Google Scholar] · DOI
  27. [27]Yasuda M, Igarashi E, Datu A R, Igawa H. Teratology. 1986;34:454–455. [Google Scholar]
  28. [28]Birnbaum L S, Harris M W, Barnhart E R, Morrissey R E. Toxicol Appl Pharmacol. 1987;90:206–216. doi: 10.1016/0041-008x(87)90328-0. [DOI] [PubMed] [Google Scholar] · DOI
  29. [29]Birnbaum L S, Abbott B. In: Methods in Developmental Toxicology and Biology. Klug S, Thiel R, editors. London: Blackwell Science; 1997. pp. 51–63. [Google Scholar]
  30. [30]Tsai F Y, Browne C P B, Orkin S H. Dev Biol. 1998;196:218–227. doi: 10.1006/dbio.1997.8842. [DOI] [PubMed] [Google Scholar] · DOI
  31. [31]Kumar M B, Ramadoss P, Reen R K, Vanden Heuvel J P, Perdew G H. J Biol Chem. 2001;276:42302–42310. doi: 10.1074/jbc.M104798200. [DOI] [PubMed] [Google Scholar] · DOI
  32. [32]Hoffman R E, Stehr-Green P A, Webb K B, Evans R G, Knutson A P, Schramm W F, Staak J L, Gibson B B, Steinberg K K. J Am Med Assoc. 1986;255:2031–2038. [PubMed] [Google Scholar]
  33. [33]Abbott B D, Birnbaum L S, Pratt R M. Teratology. 1987;35:329–334. doi: 10.1002/tera.1420350307. [DOI] [PubMed] [Google Scholar] · DOI
  34. [34]Natsume N, Kawai T, Le H. Cleft Palate Craniofac J. 1998;35:183–185. doi: 10.1597/1545-1569_1998_035_0183_tte_2.3.co_2. [DOI] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Moriguchi, T., Motohashi, H., Hosoya, T., Nakajima, O., Takahashi, S., Ohsako, S., Aoki, Y., Nishimura, N., Tohyama, C., Fujii-Kuriyama, Y., & Yamamoto, M.
Affiliations
  • University of Tsukuba (JP)
  • Institute of Basic Medical Sciences, Center for Tsukuba Advanced Research Alliance, and Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, Tsukuba 305-8575, Japan; Environmental Health Sciences Division, National Institute for Environmental Studies, Onogawa, Tsukuba 305-8506 Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-05
Volume
100
Issue
10
Pages
5652-5657
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1037886100
PMC
PMC156256
OpenAlex
W2044544228
Cited by
164
References
1
Citations by year
2026: 3 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 4 · 2019: 8 · 2018: 5 · 2017: 8 · 2016: 7 · 2015: 6 · 2014: 6 · 2013: 7 · 2012: 8
FWCI
10.16
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
Keywords
aryl hydrocarbon receptor, dioxin toxicity, humanized mice, 2,3,7,8-tetrachlorodibenzo-p-dioxin, 3-methylcholanthrene, CYP1A1, CYP1A2, C57BL/6J mice, hydronephrosis, cleft palate
MeSH terms
Animals, Base Sequence, Dioxins, Female, Humans, Kidney, Methylcholanthrene, Mice, Transgenic, Palate, Pregnancy, Prenatal Exposure Delayed Effects, RNA, Messenger, DNA Primers, Receptors, Aryl Hydrocarbon, Reverse Transcriptase Polymerase Chain Reaction, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review