2007 Fiscal Year Final Research Report Summary
Species difference s in the functional activation of PPARa and toxicity between mouse and human by plasticizers in relation to the risk assessment
| 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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| Keywords | PPARα / knockin mouse / Plasticizer / DEHP / hepatocellular adenoma / cell cycle / apoptosis / species difference |
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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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[Journal Article] Peroxisome Proliferator-Activated Receptor {alpha} Protects against Glomerulonephritis Induced by Long-Term Exposure to the Plasticizer Di-(2-Ethylhexyl)Phthalate2007
Author(s)
Kamijo, Y, Hora, K, Nakajima, T, Kono, K, Takahashi, K, Ito, Y Higuchi, M, Kiyosawa, K, Shigematsu, H, Gonzalez, FJ, Aoyama, T
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Journal Title
J Am Soc Nephrol 18(1)
Pages: 176-188
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Molecular mechanics and molecular orbital simulations on Specific interactions between peroxisome proliferators-Activated receptor PPAR and plasticizers2007
Author(s)
Iwabuchi, S, Nakagawa, T, Nakamura, H, Yamaguchi, Y, Nasu-, Nakajima, T, Kurita, N
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Journal Title
Journal of Computer Aided Chemistry 8
Pages: 1-11
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Induction of peroxisome proliferator-activated receptor alpha(PPARa)-related enzymes by di(2-ethylhexyl) phthalate (DEHP) treatment in mice and rats, but not marmosets.2007
Author(s)
Ito, Y, Yamanoshita, O, Kurata, Y, Kamijima, M, Aoyama, T, Nakajima, T
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Journal Title
Arch Toxicol 81(3)
Pages: 219-226
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Di-(2-Ethylhexyl)Phthalate induces hepatic tumorigenesis through a peroxisome proliferators-activated receptor a-i ndepndent pathway.2007
Author(s)
Ito, Y, Yamanoshita, O, Asaeda, N, Tagawa, Y, Lee, CH, Aoyama, T, Ichihara, G, Furuhashi, K, Kamijima, M, Gonzalez, DJ, Nakajima, T
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Journal Title
J Occup Health 49(3)
Pages: 172-182
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Species difference in the metabolism of di(2-ethylhexyl) phthalate (DEHP) in several organs from mouse, rat and marmoset.2005
Author(s)
Ito, Y, Yokota, H, Wang, RS, Yamanoshita, O, Ichihara, G, Wang, HL, Kurata, Y, Takagi, K, Nakajima, T
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Journal Title
Aarch Toxicol 79
Pages: 147-154
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Di(2-ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferator-activated receptor a-independent pathway2007
Author(s)
Ito, Y, Yamanoshita, O, Asaeda, N, Tagawa, Y, Lee, CH, Aoyama, T, Ichihara, G, Furuhashi, K, Kamijima, M, Gonzalez, FJ, Nakajima, T
Organizer
I lth International Congress of Toxicology
Place of Presentation
Montreal city
Year and Date
20070715-19
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Mechanism of DEHP-induced hepatocellular adenoma via inflammation.2006
Author(s)
Ito, Y, Yamanoshita, O, Asaeda, N, Tagaea, Y, Lee, CH, Aoyama, T, Ichohara, G, Furuhashi, K, Kamijima, M, Gonzalez, FJ, Nakajima, T
Organizer
6th Annual Meeting of Molecular-Based Environmental and Preventive Medicine
Place of Presentation
Kyoto city
Year and Date
20061201-02
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Effects of plastcizers on lipid metabolism via humen PPARa2006
Author(s)
Nakamura, T, Ito, Y, Yanagiba, Y, Nakagawa, T, Moriya, T, Naito, H, Kamijima, M, Nakajima, T
Organizer
76th Annual Meeting of Japanese Society for Hygene
Place of Presentation
Oosaka city
Year and Date
20060526-28
Description
「研究成果報告書概要(欧文)」より
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[Presentation] DEHP-induced hepatocellular adenoma in mice in relation to Inflammation
Author(s)
Ito, Y, Asaeda, N, Tagawa, Y, Lee, CH, Ichihara, G, Furuhashi, K Kamijima, M, Yamanoshita, O, Nakajima, T
Organizer
3th Annual Meeting of Japanese Society of Endocrine Disruptors Research
Place of Presentation
Tokyo
Year and Date
00000927-29
Description
「研究成果報告書概要(欧文)」より
