Arsenic trioxide impairs spermatogenesis via reducing gene expression levels in testosterone synthesis pathway
Arsenic trioxide impairs spermatogenesis via reducing gene expression levels in testosterone synthesis pathway
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DOI：
10.1021/tx700366x
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发表时间：
2008-08-01
影响因子：
4.1
通讯作者：
Liao, Chi-Jr
中科院分区：
文献类型：
--
作者：
Chiou, Tzeon-Jye;Chu, Sin-Tak;Liao, Chi-Jr
三氧化二砷（As 2 O3）最近受到了广泛关注，因为它能够使急性早幼粒细胞白血病（APL）完全缓解。为了评估砷治疗期间对雄性生殖系统的可能毒性，使用雄性小鼠作为模型。远交系小鼠（ICR/CD 1和S-W，6周龄）皮下注射As 2 O3连续5天，间隔2天，为期3周。As 2 O3剂量分别为0、0.15、0.3、1.5和3.0 mg/kg体重。所有剂量组均无小鼠死亡。我们的数据显示，AS-203给药后，摄食量或体重、肝脏、睾丸或附睾重量无显著变化。用组织学观察来确定曲细精管的阶段，我们表明，As_2O_3处理C导致精子发生的抑制。As 2 O3处理后，成熟曲细精管（第七和第八阶段）的频率显着下降。计算机辅助精子分析（CASA）和SYBR 14/PI染色试验也发现精子活力和存活率显著降低。使用酶联免疫吸附试验（ELISA），我们发现在3.0毫克/公斤体重的剂量血浆促黄体生成素（LH）的水平显着下降。血浆促卵泡激素（FSH）在各剂量组间无显著差异。在所有剂量下，血浆睾酮均显著降低，但睾丸内睾酮无差异，3.0 mg/kg体重剂量的As 2 O3除外。此外，参与睾丸睾酮合成、细胞色素P450侧链裂解（P450 SCC）、3 β-羟基类固醇脱氢酶（3 β-HSD）和细胞色素P450 17-α羟化酶/C17-20裂解酶（Cyp 17）的mRNA水平显著降低。免疫组织化学观察表明，0.3和1.5mg/kg剂量的As，03处理的小鼠睾丸间质细胞睾酮水平无明显差异。我们的结论是，As 2 O3治疗造成损害精子的活动性和活力。As 2 O3处理通过降低睾酮合成关键酶的基因表达而干扰精子发生。
Arsenic trioxide (As2O3) has recently received a great deal of attention because of its capacity to cause complete remission of acute promyelocytic leukemia (APL). To evaluate possible toxicity on the male reproductive system during arsenic therapy, male mice were used as a model. Outbred mice (ICR/CD1 and S-W, 6 weeks old) were subcutaneously administered As2O3 continuously for 5 days, with a 2-day interval, for a period of 3 weeks. As2O3 doses were 0, 0.15, 0.3, 1.5, and 3.0 mg/kg of body weight, respectively. No mice died in any dosage group. Our data showed no significant changes in food consumption or in the weight of the body, liver, testis, or epididymis after AS-203 treatment. Using histological observation to identify the stages of seminiferous tubules, we showed that As2O3 treatment C resulted in the inhibition of spermatogenesis. The frequency of mature seminiferous tubules (stages VII and VIII) was markedly decreased after As2O3 treatment. A significant decrease in sperm motility and viability also was found with computer-assisted sperm analysis (CASA) and a SYBR14/PI staining assay. Using an enzyme-linked immunosorbent assay (ELISA), we found a significant decrease in levels of plasma luteinizing hormone (LH) at a dose of 3.0 mg/kg body weight. No significant difference was found in plasma follicle-stimulating hormone (FSH) in all dosages. A significant decrease was found in plasma testosterone in all dosages, but no difference in intratesticular testosterone, with the exception of As2O3 at a dose of 3.0 mg/kg body weight. Moreover, there was a significant decrease in the levels of mRNA involved in testicular testosterone synthesis, cytochrome P450 side chain cleavage (P450scc), 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), and cytochrome P450 17-alpha hydroxylase/C17-20 lyase (Cyp17). The use of immunohistological observation showed no obvious difference in the testosterone level of Leydig cells of mice treated with As,03 at doses of 0.3 and 1.5 mg/kg body weight. We concluded that As2O3 treatment caused damage to sperm mobility and viability. As2O3 treatment disturbed spermatogenesis via reducing gene expression of the key enzymes in testosterone synthesis.