Flutamide 拮抗貝芬替在雄大鼠所誘發之雄性素受體表現   全文下載

Carbendazim-Induced Androgen Receptor Expression Antagonized by Flutamide in Male Rats

貝芬替為一廣泛使用之殺菌劑，已知其在大鼠具生殖與發育毒性。本研究目的在探討貝芬替誘發雄性素受體表現及flutamide之拮抗作用。大鼠投予貝芬替、flutamide或混合處理，評估其對大鼠睪丸組織中雄性素受體mRNA 、免疫活性及蛋白等之影響情形。結果顯示，貝芬替單處理雄大鼠，雄性素受體mRNA表現顯著以劑量－－反應關係增加，flutamide則顯著以劑量－－反應關係減少，當貝芬替與flutamide混合處理時，雄性素受體mRNA表現隨著flutamide劑量增加而減少；另一種混合處理，則隨貝芬替劑量增加而增加。免疫組織染色與西方墨點分析結果顯示，貝芬替顯著以劑量－－反應關係增加大鼠睪丸組織雄性素受體免疫活性與蛋白表現；而flutamide則抑制其表現。此外，貝芬替與flutamide處理7天均以劑量反應關係增加血清中睪固酮及激濾泡素濃度，其原因可能雄性素受體受到前述兩藥劑干擾作用所致。儘管仍需再進一步探討雄性素受體涉及貝芬替與其前驅物免賴得誘發大鼠生殖毒與荷爾蒙干擾作用機制，但吾人應討論如何利用flutamide拮抗貝芬替誘發生殖毒與荷爾蒙干擾作用對人體之影響。總言之，貝芬替誘發大鼠睪丸組織雄性素受體mRNA及蛋白表現，而flutamide拮抗此作用。本研究為首次探討有關flutamide拮抗貝芬替誘發雄性素受體mRNA及蛋白表現之報告，將有助於釐清貝芬替及其他化學物質誘發大鼠發育毒與荷爾蒙干擾作用之機制。

Carbendazim, a widely used fungicide, exhibits reproductive and developmental toxicity. The objective of this study was to investi-gate the expression of androgen receptor induced by carbendazim and the antagonistic effect of flutamide. Rats were treated with carben-dazim, flutamide or a combination of both to measure androgen receptor mRNA, immune activity and protein expression. Carbendazim treatment increased androgen receptor mRNA in a dose-dependent manner, while flutamide, an androgen receptor antagonist, blocked the androgen receptor mRNA. Co-treatment with carbendazim and various flutamide doses decreased the androgen receptor mRNA in a dose-dependent manner. Conversely, co-treatment with flutamide and various carbendazim doses increased the androgen receptor mRNA in a dose-dependent manner. Immunohistochemistry and Western blot analyses showed that carbendazim increased androgen receptor activity (especially in rat testes) in a dose-dependent manner, while flutamide decreased it. Furthermore, carbendazim or flutamide treatment for 7 days increased testosterone and follicular stimulating hormone concentrations in the serum of male rats in a dose-dependent manner, which might involve the disruption of the androgen receptor. Although we need to examine the exact mechanism of androgen receptor involved in the reproductive toxicity and endocrine-disrupting activity induced by carbendazim and its parent, benomyl, we should first discuss how to take advantage of flutamide antagonism on carbendazim-induced reproductive and endocrine-disrupting activity possibly in human. In summary, carbendazim induced androgen receptor expression in mRNA and protein levels, while flutamide antagonized this effect. This is the first report on the antagonistic effect of flutamide on the carbendazim-androgenic effect on mRNA and protein levels. The results would help to clarify the mechanism of carbendazim- and chemical-induced develop-mental toxicity and endocrine-disrupting activity.