吡哆素L-2-吡咯烷酮-5-羧酸酯雄性生殖毒性及机制研究

Study on reproductive toxicity and mechanism of metadoxine in male rats

目的:研究吡哆素L-2-吡咯烷酮-5-羧酸酯(Metadoxine,MTDX)对雄性大鼠的生殖毒性及机制。方法:灌胃染毒雄性成年SD大鼠0,250,500和1000 mg/kgMTDX,每天1次,连续4周。染毒结束后观察性腺和附属性腺脏器系数、精子质量、组织形态学和血清睾酮等指标的变化。Hershberger方法检测MTDX抗雄激素活性作用:40只4周龄雄性SD大鼠行双侧睾丸切除手术,2周后,除1组皮下注射花生油并灌胃给予蒸馏水外,其余3组去势大鼠每天皮下注射丙酸睾酮(TP,1 mg/kg),并同时灌胃给予蒸馏水或MTDX(500,1000 mg/kg),连续7 d,观察雄激素依赖组织重量的变化。对体外培养睾丸碎块合成睾酮的影响:利用离体组织培养和放射免疫技术,观察不同浓度MTDX对体外培养睾丸碎块合成睾酮的影响。结果:1000 mg/kg剂量组大鼠睾丸、附睾、前列腺和精囊腺脏器系数明显降低;精子数量和精子存活率减少,精子活力降低,精子畸形率增高,血清T无变化;500 mg/kg剂量组在睾丸相对重量、精子数量和精子活力方面与对照组比较有显著性差异。在Hershberger实验中,1000 mg/kg组大鼠的精囊腺、前列腺以及球海绵体肌的脏器系数值均显著低于对照组。MTDX各剂量组睾丸培养液中睾酮的含量与对照组相比均没有显著性差异。结论:MTDX能引起雄性大鼠生殖毒性,这种毒性作用可能与其具有抗雄激素样作用有关。

Objective：To syudy reproductive damage and mechanism induced by metadoxine in the male rats. Methods：Male Sprague-Dawley rats were administered daily by oral gavage of 0, 250, 500, 1000 mg/kg of MTDX, respectively for 4 weeks. The organ coefficients, sperm quality histopathological changes of sexual glands and the level of serum testosterone were determined. In Hershberger assay, forty male Sprague- Dawley rats of 4 weeks were castrated. After 2 weeks, the rats in other groups were dosed once a day for 7 days with testosterone propionate （ 1 mg/kg, sc） plus gavage dosed of either distilled water vehicle or MTDX （500, 1000mg/kg）, but one group castrated rats underwent subcutaneous injection with peanut oil and gavage dosed with distilled water as control. Then, the adrenals, prostate, glans penis, seminal vesicle, levator ani and bulbocavernosus muscles were removed and weighed. Observing the effect on T produced by miced-testis of MTDX at different concentrations（0, 0. 1,1, 10 and 20 mg/ml） in vitro, by the approachs of tissue culture and radioactivity. Results：After 4 -week administration, the relative weights of testes, epididymis, prostate gland and seminal vesicle decreased dramadically compared with the control. The 4 weeks treatments also caused decreased spermatid count in the epididymis canda, sperm motility and sperm viability, and increased sperm malformation rate, but serum testosterone concentration did not significantly altered in the 1000 mg/kg MTDX group. In addition, in the 500 mg/kg MTDX group, the variety of the above parameters including the testes relative weight, spermatid count and sperm motility had significant differences compared with those in the control. In Hershberger assay, relative weight of prostate, seminal vesicle and bulbocavernous muscle was respectively, in the 1000 mg/kg group, sign ificandy decreased as compared with those in the control group. Compared with control group, there were not significant difference of T generated by miced-testis in vitro in any MTDX group. Conclusion：MTDX administered by oral gavage can result in serious damage in the sexual glands of male rats,indicating that its antidrogenic effect may be involved in its male reproductive toxicity.