2005 Fiscal Year Final Research Report Summary
Endocrinological analysis of genetically modified mice with abnormal estrogen metablism
| Project/Area Number |
16590916
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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 |
Endocrinology
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| Research Institution | Fujita Health University |
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Principal Investigator |
HARADA Nobuhiro Fujita Health University, School of Medicine, Professor, 医学部, 教授 (00189705)
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| Co-Investigator(Kenkyū-buntansha) |
HONDA Shin-ichiro Fujita Health University, School of Medicine, Lecturer, 医学部, 講師 (40257639)
SASAKI Emi Fujita Health University, School of Medicine, Assistant, 医学部, 助手 (20178635)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Transgenic mouse / Knockout mouse / Estrogen / Aromatase / Steroid sulfatase / Estrogen sulfotransferase / Cyp1B1 |
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| Research Abstract |
In the present study, we successfully prepared transgenic (TG) mice stationarily overexpressing estrogen-related enzymes consisting of aromatase (AR), steroid sulfatase (STS), estrogen sulfotransferase (EST), and 17b-hydroxysteroid dehdrogenase types I and II. We analyzed the histopathological aberration, interstitial and intracellular dynamics of estrogen metabolism, morphological and functional disorders in the organ and tissue levels, and changes of signal transduction systems and expression levels of the genes in these TG mice.
Estrogen-dependent cancers were often observed in the TG mice of AR and STS. On the other hand, cyp1B1 was reported to participate in the introduction of mutations into genomic DNA by metabolic activation of estrogens. In fact, TG mice overexpressing cyp1B1 often caused estrogen-dependent cancers. Then, we are now preparing double TG mice of AR and cyp1B1, and planning to observe susceptibility to carcinogenesis of the mice.
TG mice overexpressing EST as well
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as AR knockout mice exhibited obesity concomitant with an increased appetite probably due to decrease of intracellular levels of activated estrogens. We have previously observed abnormalities of sexual, parental, and aggressive behaviors, appearance of infanticide, decrease of locomotive (exploring) behavior, and increase of appetite in AR knockout mice. Then we introduced a human AR trangene controlled with 6.5 kb brain-specific promoter region of aromatase gene into AR knockout mice, and observed the behaviors in those mice. Although elevated levels of androgens and undetectable levels of estrogens were still observed in those mice as well as AR knockout mice, abnormal behaviors observed in the AR knockout mice were almost recovered in those mice. These results indicate that brain-specific expression (neuron-specific, hypothalamus-, preoptic area- and amygdala-specific, and perinatal period-specific expression) of aromatase and consequent brain-localized estrogens may play important roles in the organization of neuronal networks controlling these behaviors. Less
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