Differential Response to Abiraterone Acetate and Di-n-butyl Phthalate in an Androgen-Sensitive Human Fetal Testis Xenograft Bioassay
Differential Response to Abiraterone Acetate and Di-n-butyl Phthalate in an Androgen-Sensitive Human Fetal Testis Xenograft Bioassay
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DOI：
10.1093/toxsci/kft266
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发表时间：
2014-03-01
影响因子：
3.8
通讯作者：
Boekelheide, Kim
中科院分区：
文献类型：
--
作者：
Spade, Daniel J.;Hall, Susan J.;Boekelheide, Kim
子宫内暴露于抗雄激素外源性物质（如邻苯二甲酸二丁酯（DBP））与男性生殖道的先天性缺陷（包括隐睾症和尿道下裂）以及晚年影响（如睾丸癌和精子计数减少）有关。实验证据表明，DBP在大鼠子宫内具有抗雄激素作用。然而，目前还不清楚DBP是否对人胎儿睾丸中雄激素的生物合成有类似的影响。为了解决这个问题，我们开发了一种具有多个雄激素敏感性生理终点的异种移植物生物测定法，类似于啮齿动物Hershberger测定法。将成年雄性无胸腺裸鼠去势，将人胎儿睾丸异种移植到肾包膜下间隙。用人绒毛膜促性腺激素治疗4周以刺激睾酮的产生。在第3周和第4周期间，宿主暴露于DBP或醋酸阿比特龙（一种CYP 17 A1抑制剂）。醋酸阿比特龙（14 d，75 mg/kg/d po）显著降低睾酮水平和雄激素敏感性器官重量，而DBP（14 d，500 mg/kg/d po）对雄激素指标无影响。DBP确实产生了异种移植物中多核生殖细胞增加的接近显著的趋势。基因表达分析显示，阿比特龙降低了与转录和细胞分化相关的基因的表达，同时增加了参与基因表达的表观遗传控制的基因的表达。DBP诱导氧化应激反应基因的表达和肌动蛋白细胞骨架基因的表达改变。
In utero exposure to antiandrogenic xenobiotics such as di-n-butyl phthalate (DBP) has been linked to congenital defects of the male reproductive tract, including cryptorchidism and hypospadias, as well as later life effects such as testicular cancer and decreased sperm counts. Experimental evidence indicates that DBP has in utero antiandrogenic effects in the rat. However, it is unclear whether DBP has similar effects on androgen biosynthesis in human fetal testis. To address this issue, we developed a xenograft bioassay with multiple androgen-sensitive physiological endpoints, similar to the rodent Hershberger assay. Adult male athymic nude mice were castrated, and human fetal testis was xenografted into the renal subcapsular space. Hosts were treated with human chorionic gonadotropin for 4 weeks to stimulate testosterone production. During weeks 3 and 4, hosts were exposed to DBP or abiraterone acetate, a CYP17A1 inhibitor. Although abiraterone acetate (14 d, 75mg/kg/d po) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500mg/kg/d po) had no effect on androgenic endpoints. DBP did produce a near-significant trend toward increased multinucleated germ cells in the xenografts. Gene expression analysis showed that abiraterone decreased expression of genes related to transcription and cell differentiation while increasing expression of genes involved in epigenetic control of gene expression. DBP induced expression of oxidative stress response genes and altered expression of actin cytoskeleton genes.