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Cited by 626Toxic Organic Pollutants ImpactEffects and risks of endocrine disrupting chemicalsPharmacological Effects and Toxicity Studies

Loss of teratogenic response to 2,3,7,8‐tetrachlorodibenzo‐ p ‐dioxin (TCDD) in mice lacking the Ah (dioxin) receptor

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Mimura, Junsei, Yamashita, Keisuke, Nakamura, Kenji, Morita, Masanobu, Takagi, Toshio N., Nakao, Kazuki, Ema, Masatsugu, Sogawa, Kazuhiro +3 more·1997·Genes to Cells
DOI 10.1046/j.1365-2443.1997.1490345.x
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Abstract

Background: The aryl hydrocarbon receptor (AhR or dioxin receptor) is a ligand‐activated transcription factor that is considered to mediate pleiotropic biological responses such as teratogenesis, tumour promotion, epithelial hyperplasia and the induction of drug‐metabolizing enzymes to environmental contaminants usually represented by 2,3,7,8‐tetrachlorodibenzo‐ p ‐dioxin (TCDD). In contrast to the role of AhR in the regulatory mechanism of xenobiotic‐metabolizing enzymes, there is no direct proof that the AhR is involved in the teratogenic effects of TCDD. Results: To gain insight into the physiological and teratogenic role of the AhR, we have used gene targeting in mice to disrupt the murine Ahr gene by homologous recombination. Ahr ‐null mice were viable and fertile and were apparently normal at birth, but displayed a slightly slower growth rate than wild‐type mice for the first few weeks of life. When pregnant dams were administered with TCDD by gavage, at a dose of 40 μg/kg body weight at gestation day 12.5, none of the Ahr ‐null mutant foetuses were sensitive to the teratogenic effects of TCDD, although almost all wild‐type foetuses suffered from cleft palate and hydronephrosis. In heterozygous Ahr +/− genotypes, nearly all foetuses suffered from hydronephrosis in response to TCDD treatment, while haplo‐insufficiency was observed in the incidence of cleft palate. Conclusion: These results clearly show that the AhR is involved in the malformation of the palate and kidney in mouse embryos caused by TCDD and suggests that the mechanism of its involvement differs between the cleft palate and hydronephrosis.

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  • Genetic tools such as the Ahr null mouse model have revealed an essential role of AHR in normal physiology.

    “Genetic tools such as the Ahr null mouse model have revealed an essential role of AHR in normal physiology (Fernandez-Salguero et al., 1995; Mimura et al., 1997; J. V. Schmidt et al., 1996).”

    From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Mimura et al., 1997

    The Abstract (page unavailable) identifies this as an Ahr-null mouse study and reports slightly slower early growth, supporting a role for AHR in normal physiology. But it also says the null mice were viable, fertile, and apparently normal at birth; the paper's main finding concerns TCDD-induced malformations. These findings do not establish the broad claim that AHR is essential to normal physiology. (LLM, conf=0.84)

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  • The generation of three independent Ahr null mouse models (AhrΔ1, AhrΔ2, and AhrLacZ) has revealed a significant role for the AHR in hepatic and vascular development as well as for the maintenance of barrier tissues and the immune system.

    “The generation of three independent Ahr null mouse models (AhrΔ1, AhrΔ2, and AhrLacZ) described in more detail below, has revealed a significant role for the AHR in hepatic and vascular development as well as for the maintenance of barrier tissues (e.g., intestine, skin, and lung) and the immune system (Fernandez-Salguero et al., 1995; Mimura et al., 1997; J. V. Schmidt et al., 1996).”

    From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Mimura et al., 1997

    The ‘Targeting of the AhR gene by homologous recombination’ section describes generating an Ahr-null mouse by replacing part of the gene with LacZ, supporting this paper’s identification as one of the cited mouse models. It mentions hepatic portal fibrosis, and the expression section detects AhR mRNA in the epidermis, but neither establishes the claimed roles in hepatic and vascular development or in maintaining barrier tissues and the immune system. The paper chiefly tests the mutants’ response to TCDD. (LLM, conf=0.87)

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Cites

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Research works printed but not linked: 5

  1. ᭧ Blackwell Science Limited 13652443, 1997, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2443.1997.1490345.x, Wiley Online Library on [23/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License palate and enhancing the incidence of clefts after coadminis- tration of retinoic acid and TCDD. Toxicol. Appl. Pharmacol. 106, 418-432.
  2. Birnbaum, L.S. & Abbott, B. (1997) Effect of dioxin on growth factor and receptor expression in developing palate. In: Methods in Developmental Toxicology and Biology (eds S. Klug & R. Thiel), pp. 51-63. London: Blackwell Science.
  3. Matsui, K.A., Takagi, T., Sato, T.J., Yamashita, K. & Yasuda, M. (1997) Reinvestigation of mechanism for induction of cleft palate in mice by tetrachlorodibenzo-p-dioxin (TCDD): epithelial cell death revealed by supravital staining and TUNEL method. In: Methods in Developmental Toxicology and Biology (eds S. Klug & R. Thiel), pp. 65-73. London: Blackwell Science.
  4. Schmidt, J.V., Su, G.H.T., Reddy, J.K., Simon, M.C. & Bradfield, C.A. (1996) Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic Response to TCDD and dioxin receptor ᭧ Blackwell Science Limited Genes to Cells (1997) 2, 645-654 653 13652443, 1997, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2443.1997.1490345.x, Wiley Online Library on [23/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License growth and development. Proc. Natl. Acad. Sci. USA 93, 6731-6736.
  5. Wilkinson, D.G. (1992) In Situ Hybridization: a Practical Approach. London: Oxford University Press.

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Authors
Mimura, J., Yamashita, K., Nakamura, K., Morita, M., Takagi, T. N., Nakao, K., Ema, M., Sogawa, K., Yasuda, M., Katsuki, M., & Fujii‐Kuriyama, Y.
Affiliations
  • Tohoku University (JP)
  • Hiroshima University (JP)
  • Institute of Medical Science, The University of Tokyo (JP)
Corresponding author
Fujii‐Kuriyama, Yoshiaki
ORCID
Venue
Genes to Cells
Publisher
Wiley
Published
1997-10
Volume
2
Issue
10
Pages
645-654
ISSN
  • 1356-9597 (ISSN-L)
  • 1365-2443
DOI
10.1046/j.1365-2443.1997.1490345.x
OpenAlex
W2059565720
Cited by
626
References
2
Citations by year
2026: 3 · 2025: 8 · 2024: 10 · 2023: 6 · 2022: 11 · 2021: 21 · 2020: 19 · 2019: 21 · 2018: 14 · 2017: 22 · 2016: 26 · 2015: 20 · 2014: 25 · 2013: 25 · 2012: 23
FWCI
9.92
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 2235 d)
Locations
  • Genes to Cells (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
Keywords
aryl hydrocarbon receptor, 2,3,7,8-tetrachlorodibenzo-p-dioxin, teratogenesis, cleft palate, hydronephrosis, haploinsufficiency, embryonic malformations, gene targeting, mouse embryo development
MeSH terms
Polychlorinated Dibenzodioxins, Animals, Female, Kidney, Mice, Mutant Strains, Palate, Pregnancy, RNA, Messenger, Teratogens, Mutagenesis, Receptors, Aryl Hydrocarbon, Gene Targeting, Maternal Exposure, Mice

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