| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a prototype halogenated aromatic hydrocarbon, and it is considered to be one of the most potent toxicants ever studied. The adverse biological effects of TCDD seen in experimental animals include immune, reproductive, and developmental toxicity, carcinogenicity, wasting syndrome, chlorancne, and lethality. In order to clarify the mechanism of dioxin toxicity, we determined the activity of signal transduction systems and CYP1 A1 induction level as a target gene.
1) The activation of ERK1/2 was determined using basic myelin protein as a substrate. After 30 min of the treatment of HepG2 cells with TCDD, the activation of ERK1/2 was observed. Using anti-phospho-ERK antibody, the increase of phosphorylated form of ERK was observed at 30min after the treatment of TCDD.
2) MEK inhibitor, PD98059 inhibited the induction of CYP1A1 inHepG2 cells by TCDD treatment, but not that by omeprazole. However PD98059 was reported to inhibit the CYP1A1 induction by antagonizing Ah receptor. Thus, ERK activation does not correlate directly to the induction of CYP1A1, but it has some other target genes.
3) To identify the target genes, which is induced by TCDD, we applied the differential display method to mouse B cell line, CH12. We are getting many genes which are induced by TCDD in B cell line.
From these observations, there must be Ah receptor mediated pathway and signal transduction mediated pathway in the mechanisms of dioxin toxicity.
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