1998 Fiscal Year Final Research Report Summary
Molecular Mechanism of Developmental Toxicity Caused by Dioxin in Mice.
| Project/Area Number |
09670015
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General anatomy (including Histology/Embryology)
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
YAMASHITA Keisuke Hiroshima University Faculty of Medicine, Associate Professor, 医学部, 助教授 (40166666)
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| Project Period (FY) |
1997 – 1998
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| Keywords | Teratogenesis / Dioxins / Homologous recombination / Gene targeting / Cleft palate / Mice / Pathogenesis / Development |
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| Research Abstract |
The aryl hydrocarbon receptor (AhR or dioxin receptor) is a ligand-activated transcription factor that is considered to mediate developmental toxicity caused by dioxins, environmental contaminants. There was no direct proof that the AhR is involved in the teratogenic effects of dioxins. In order to reveal the involvement of the AhR in teratogenesis caused by dioxins, mice were generated whose AhR gene was disrupted by homologous recombination. AhR-null mice were viable and fertile. When pregnant dams were administered with 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) by gavage at a dose of 40 mug/kg body weight at gestation day 12.5 (vaginal plug=DG 0), and killed at GD 18.5. None of the AhR-null mutant fetuses were sensitive to the teratogenic effects of TODD, although almost all wild-type (WT) fetuses suffered from cleft palate and dilated renal pelvis. Heterozygotes (AhR+/-) exhibited a lower incidence (24%) to TODD in cleft palate induction. These results clearly showed that the AhR is involved in the malformation of the secondary palate and renal pelvis in mouse fetuses by TCDD.
In the next study we examined dose-response relationship for induction of cleft palate and enlarged renal pelvis in heterozygotes. Heterozygous embryos (Ahr+/-) were produced by mating Ahr-null males with WI females. Pregnant mice were given TCDD at 0.6-80 mug/kg at GD 12.5. The fetuses were harvested at GD 18.5 and examined for cleft palate and enlarged renal pelvis. Comparison of dose-response curves between WT and Ahr+/- fetuses indicated haploinsufficiency for cleft palate induction at high dose levels (10-80 mug/kg) and for enlarged renal pelvis at low dose levels (0.6-2.5 mug/kg) . These results suggested that the mechanism(s) of AhR involvement may differ between cleft palate and enlarged renal pelvis.
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[Publications] Junsei Mimura, Keisuke Yamashita, Kenji Nakamura, Masanobu Morita, Toshio N.Takagi, Kazuki Nakao, Masatsugu Ema, Kazuhiro Sogawa, Mineo Yasuda, Motoya Katsuki, and Yoshiaki Fujii-Kuriyama: "Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)in mice lacking the Ah(dioxin)receptor." Genes to Cells. Vol.2, No.10. 645-654 (1997)
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