| Project/Area Number |
17390169
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hygiene
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| Research Institution | Nagoya University |
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Principal Investigator |
NASU Tamie Nagoya University, Graduate School of Medicine, Professor (10020794)
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| Co-Investigator(Kenkyū-buntansha) |
KAMIJIMA Michihiro Nagoya University, Graduate School of Medicine, Associate Professor (80281070)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥14,240,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥840,000)
Fiscal Year 2007: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2006: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥7,600,000 (Direct Cost: ¥7,600,000)
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| Keywords | PPARα / knockin mouse / Plasticizer / DEHP / hepatocellular adenoma / cell cycle / apoptosis / species difference / フタル酸ジー(2-エチルヘキシル) / PPARa / ノックアウトマウス / 炎症 / 酸化ストレス / hPPARα-マウス / mPPARα-マウス / PPARα-nullマウス / DBP / 標的遺伝子発現 / DEHA / リスク評価 / 肝発がん性 / 混餌 |
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| Research Abstract |
We directly compared the species differences in the function of PPARα between mice and human by three kinds of plasticizers, using wild-type (mPPARα) and humanized PPARα. (hPPARα) mice. In general, mouse PPARα was activated stronger than human PPARα when the several kinds of target genes. The result was also reflected in the liver triglyceride levels. When compared the functional activation of PPARα among three plasticizers, that of DBP was smaller than that of DEHP or DEHA. Thus, these plasticizers activated both mouse and human PPARα, but the magnitude was stronger in the former than the latter
Wild-type and PPARα-null mice were treated for 22 months with diets containing DEHP. The incidence of liver tumor was higher in PPARα-null than the wild-type mice. The levels of 8-OHdG increased in both mice, but the degree was higher in PPARα-null than in wild-type mice ; NFκB levels also significantly increased only in the former. c-jun-mRNA was induced, and c-fos-mRNA tended to be induced only in PPARa-null mice fed DEHP diet. These results suggest that the increases in oxidative stress induced by DEHP may lead to the induction of inflammation and/or the expression of protooncogenes, which may result in the high incidence of tumorigenesis in PPARa-null mice.
The gene expressions of Apafl and Gadd45a were increased in the hepatocellular adenoma of wild-type mice exposed to DEHP, whereas they were not changed in corresponding tissues of Pparα-null mice. The expressions of cyclinB2 and Mcll were increased only in the hepatocellular adenoma of Ppara-null mice. No difference was senn in the expression of Bc12-like 1 between wild-type and Ppara-null mice. Thus, DEHP may induce hepatocellular adenomas, in part, via suppression of 02/M arrest regulated by Gadd45a and Casp3-dependent apoptosis in Ppara-null mice, but these genes may not be involved in the tumorigenesis of the wild-type mice.
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