联苯菊酯的抗雄激素作用及其机制

The antiandrogenic effect and mechanism of bifenthrin

目的探讨联苯菊酯的抗雄激素作用及其可能机制。方法体外雄激素受体(AR)依赖转录活化试验中,在96孔板上接种稳定表达荧光素酶报告基因的MDA-kb2细胞,加入联苯菊酯或已知抗雄激素,同时加一定剂量的双氢睾酮(DHT)以诱导荧光素酶基因的表达,裂解细胞后测定荧光素酶活力值,以溶剂对照组的倍数比值作为标化荧光强度单位,此值高低表示抗雄激素作用的大小。体内Hershberger试验中,将去势的30只雄性大鼠随机分为联苯菊酯低、中、高剂量,阳性对照、溶剂对照和睾酮缺乏共6组,每组5只。除睾酮缺乏组外每天皮下注射丙酸睾酮(TP)100μg,连续7 d;给药组、阳性对照组、溶剂对照和睾酮缺乏组分别同时灌胃给予联苯菊酯1.5、4.5和13.5 mg/kg、氟他胺50 mg/kg、以及同体积花生油。7 d后处死大鼠并称重雄激素依赖组织。结果Hershberger试验中联苯菊酯13.5 mg/kg剂量组大鼠的精囊腺、腹侧前列腺等主要雄激素依赖组织重量与溶剂对照组比较,差异有统计学意义(P<0.05),但未出现明显的一般毒性反应。报告基因试验中,联苯菊酯1.0×10-8、1.0×10-7、1.0×10-6、1.0×10-5mol/L能拮抗DHT的荧光素酶诱导作用(P<0.05),呈剂量-效应关系。结论证实联苯菊酯是一种环境抗雄激素,其作用可发生在一般毒性之前,AR拮抗可能是其作用机制之一。

Objective Herein we conducted in vivo and in vitro assays to investigate the antiandrogenic actitivity and mechanism of bifenthrin, Method Hershberger assay was used to determine the antiandrogenic potential of bifenthrin in vivo, Six-weekold castrated male SD rats were randomly divided into six groups, each of which consisted of five rats. Each group of rats were administrated once daily for 7 days with testosterone propionate （rip） （ 100 μg, SC）, excluding an additional group without rip, plus gavage dosage of bifenthrin （1.5,4.5 and 13.5 mg/kg）, flutamide （50 mg/kg）, while hormone deficient control and vehicle control groups of rats were gavaged with same volumes of corn oil. After 7-day treatments, all rats were euthanized and the liver, kidney, spleen, ventral prostate, seminal vesicle were excised and weighed respectively. Transcriptional activation assay was used to determine the mechanism. Cells stably expressing an androgen-responsive reporter （AR） gene, MDA-kb2, were treated with various concentrations of bifenthrin or known antiandrogen hydroxyflutamide with adding dihydrotestosterone （DHT） at the same time. Cells were lysed after incubation, and then luciferase activity was measured. Finally the fold inductions over vehicle control were calculated as standard luciferase activity value, which represents antiandrogenic potency, Results In in vivo assay, compared with vehicle control, bifenthrin at dose of 13.5 mg/kg caused significant decrease in some major androgen-responsive tissues;while in in vitro assay, it could block DHT-induced AR activity in MAD-kb2 cells in a dose-dependent manner, Conclusion Bifenthrin is an environmental antiandrogen, and AR antagonism may contribute to its antiandregenic activity, which may occur before significant general toxicity presents,