棉籽粉及棉酚的抗生育作用研究

棉籽粉对雄性大鼠有抗生育作用,其有效成份为棉酚。棉酚对雄性大鼠的抗生育作用最低有效剂量为10～12mg/kg,连续给药4～5周。停药后4～5周生育力能可逆恢复。棉酚对大鼠的交配行为及副性腺的功能均无明显的影响;亦不改变大鼠及猴血浆中睾丸酮的含量。棉酚对子代生长及生育力均无不良影响。大鼠长期服用棉酚后,心电图未见有异常变化。部分大鼠的血清谷丙转氨酶及γ球蛋白值稍有升高,停药后恢复正常。个别大鼠肝组织切片显于肝细胞有病理性改变。右旋棉酚既无明显的抗生育作用,亦无显著的毒性反应,提示棉酚的抗生育作用及毒性反应与左旋体有关。棉酚结构上的CHO基与OH基,一旦用其它基团取代,即失去抗生育作用。     

醋酸棉酚与米索前列醇对大鼠和小鼠的抗早孕研究

用抗早孕实验和大鼠子宫离体实验,研究了醋酸棉酚与米索前列醇抗早孕的协同作用。结果表明,早孕小鼠单服米索,其终止早孕作用微弱;当与棉酚合用时,对小鼠的抗早孕作用增强。对离体大鼠子宫,米索有明显的增强宫缩作用,而棉酚则无影响,但早孕大鼠po棉酚80mg·kg^-1·d^-1,3d后其子宫对米索的敏感性较对照组有显著提高。大鼠于妊娠d 6～8 po棉酚或米索,或两药剂量的一半合并用药,可使子宫蜕膜组织损伤,而以两药合用组最为严重,但子宫孕酮受体含量和分布与对照组相似。结果提示,两药合用有协同抗早孕作用。     

醋酸棉酚对雄性木鼠睾酮、黄体生成素(LH)和卵泡刺激素(FSH)的影响

给大鼠口服醋酸棉酚30mg/kg/d每周6次,给药2,4或8周,用放射免疫法测血清睾酮、LH和FSH水平。结果表明,给药2周(生精上皮破坏不明显)和6,8周(曲精细管严重破坏)血清睾酮水平显著下降,而血清LH无变化。给药8周时血清FSH显著升高,为对照组的4倍。实验结果提示棉酚可能影响间质细胞的功能。     

碳酸二乙酯对大鼠生育力与早期胚胎发育的毒性作用

目的观察碳酸二乙酯(DEC)对雌雄大鼠生育力与早期胚胎发育的影响。方法雌雄SD大鼠分别经口给予DEC 80、200和500 mg/kg·bw·d及阴性对照(大豆油,10 ml/kg·d),雄鼠连续给药4周、雌鼠连续给药2周后按1∶1合笼,交配成功后雄鼠继续给药至剖解,雌鼠继续给药至妊娠第6天(GD6)。试验期间观察各组雌雄SD大鼠的一般毒性反应、体重及摄食量影响,合笼期间雌鼠动情周期,记录交配情况;交配成功雌鼠于GD15剖检,进行终末检查,评价雌性生殖机能、生育力,以及子代的胚胎形成和早期发育影响;雄鼠于交配成功后剖检,并分析精子浓度及活力,评价雄性生殖机能、生育力影响。结果各剂量组DEC对雌雄大鼠亲代均未出现明显的亲代一般毒副反应;对雌雄大鼠体重未见明显异常,仅高剂量GD0和低剂量GD0、GD6雌鼠体重略低于阴性对照组(P0.05);对雌雄大鼠的摄食量、生殖系统脏器重量和脏器系数、交配成功天数、交配率、妊娠率、雌鼠动情周期、雄鼠精子浓度及活力均未见明显影响;对孕鼠子代胚胎形成和早期发育未见明显影响。结论在本试验条件下,雌雄SD大鼠的生育力以及早期胚胎发育均未见明显毒性影响,未观察到明显毒性反应剂量(NOEAL)为500 mg/kg·bw·d。     

醋酸棉酚在大鼠的抗甾体激素和抗促性腺激素作用

给去卵巢后一周的大鼠皮下注射雌二醇,同时喂以醋酸棉酚40mg/kg,连续8天,可抑制雌二醇的促子宫作用。此外,醋酸棉酚40mg/kg能抑制黄体酮致蜕膜瘤的增长。醋酸棉酚尚能抑制hCG引起的未成熟雄大鼠血清睾丸酮水平的升高。醋酸棉酚能直接抑制体外培养的间质细胞分泌睾丸酮;又能对抗hCG对间质细胞的刺激作用。     

赤苷脉通注射液对大鼠生育力和早期胚胎发育的毒性研究

目的 研究赤苷脉通注射液(CGMT)对大鼠生育力与早期胚胎发育的毒性.方法 160只SD大鼠随机均分为对照组和CGMT 75、150、300 mg· kg-剂量组;雄鼠交配前9周至交配成功,雌鼠交配前2周至妊娠7d分别连续于尾静脉给药,交配结束处死雄鼠,进行精子数、精子活力和精子形态学等指标检查,孕鼠于妊娠14 d时处死,记录妊娠子宫重量、黄体数和着床数等指标,观察胚胎死亡情况.结果 CGMT各剂量组各项检测指标与对照组相比无显著性差异(P＞0.05).结论 试验条件下,CGMT在300 mg· kg-剂量下对SD大鼠的生育力和早期胚胎发育无明显毒性作用.     

棉酚合并卡前列甲酯(PG05)抗早孕作用研究

观察棉酚合并 PG0 5对小鼠的抗早孕作用。结果显示 :单用棉酚 75mg/( kg·d) ,3d无抗早孕作用 ,而同样剂量棉酚与 PG0 50 .2 mg/( kg·d) ,合用 2 d可显著增强抗早孕作用 ,使小鼠活胎数进一步减少 ;棉酚 30 μg/ml和 ( - )棉酚 1 5μg/ml对大鼠黄体细胞 3β- HSD活性均有显著抑制作用 ,( + )棉酚 1 5μg/ml和PG0 51 0 μg/ml对此酶活性无影响 ;( - )棉酚 1 5μg/ml还能抑制大鼠颗粒细胞雌二醇的分泌 ,提示棉酚增强 PG0 5抗早孕作用可能是从多环节影响胚胎正常发育。     

棉酚对雄性大鼠睾酮生成的影响

给大鼠喂服醋酸棉酚每日30mg/kg,6或8wk后用放射免疫法测定血清、睾丸间质细胞液和曲精细管液中睾酮的浓度;用放射配体结合法测定睾丸中黄体生成素(LH)和卵泡刺激素(FSH)受体的含量。结果表明在上述剂量和给药时间的条件下,棉酚对垂体-睾丸轴系无影响。     

醋酸棉酚对雌性大鼠的抗早孕作用

大鼠于妊娠第6～9天,喂以醋酸棉酚80 mg/kg/d, 有明显的抗早孕作用。皮下注射孕酮5 mg/d或hCG 25 IU/d可拮抗醋酸棉酚的抗早孕作用。醋酸棉酚80 mg/kg/d对去卵巢后给以外源性雌酮和孕酮以维持妊娠的大鼠无抗早孕作用。正常妊娠大鼠,给醋酸棉酚后,血清孕酮水平下降,妊娠中止,若同时注射hCG,孕酮水平回升接近对照动物的水平,药物抗早孕作用消失,但仍低于单给hCG组大鼠血清孕酮水平,说明醋酸棉酚可阻断hCG促黄体分泌孕酮的作用,这可能是醋酸棉酚抗早孕作用的主要机理之一。     

(-)和(+)棉酚对雄大鼠生育力的影响

棉酚有明显的抗雄性生育作用,但在理论上尚不清楚消旋棉酚的抗生育作用和毒性来自那一种光学异构体。已有报告指出(+)棉酚无毒无效。但对(-)棉酚的研究迄今尚未有报道。本文应用本所合成室制备之(+)和(-)棉酚,观察了他们的抗生育作用。实验用Wistar雄大鼠(190～220g)25只,分为对照,(+)棉酚30mg/kg,(-)棉酚15和30 mg/kg以及消旋棉酚30 mg/kg等5组。每天喂药1次,(+)棉酚和(-)棉酚     

睾丸酮、雌二醇和棉酚合并用药的雄性抗生育作用及其安全性的研究

睾丸酮、雌二醇和棉酚合并用药的雄性抗生育作用及其安全性的研究叶惟三，但凌，郭燕，钱晓菁，应骏，薛社普（中国医学科学院，中国协和医科大学基础医学研究所，北京１００００５）减轻有抗男性生育活性棉酚的副作用是发展棉酚成为男性避孕药急待解决的问题［１，２］。...     

双-三氯甲基砜对雄大鼠抗生育作用及其可逆性的研究

用略加改进的MB 50程序,进一步对双 三氯甲基砜(BTS)进行药效鉴定。结果表明,BTS10mg·kg^-1po,每周6次连服8周或30mg·kg^-1连服4周,可使SD雄鼠丧失生育力,附睾尾部精子密度,特别是精子活率,与对照比较下降非常显著(P<0.001)。给药鼠的体重、性行为、血睾酮水平以及主要内脏组织学观察均与对照无明显差异。30mg·kg^-1用药4周大鼠即不育,继续用药4周动物保持不育状态,停药4周生育力开始恢复,第6周后生育力全部恢复至正常水平。结果提示BTS有雄性抗生育作用。     

雷公藤单体雷醇内酯对雄鼠的抗生育作用

从雷公藤多甙中分离出的单体T_9(雷醇内酯)有明显抗精子发生作用。T_9喂服雄鼠剂量为0.1mg/kg·d~(-1),喂服7周后处死观察,睾丸组织结构损伤轻微,而附睾精子有明显损伤,表现为精子尾部中段鞘膜崩解,特别是精子头尾大量分离,其分离率高达90%以上;但T_9并不引起精子头部明显畸变,没有明显免疫抑制作用,对主要脏器没有损伤,其抗生育效果是雷公藤多甙的100倍。     

The effect of ornidazole on fertility and epididymal sperm function in rats

A comprehensive study of male fertility and sperm production and function was performed in 20 control and 20 rats treated with ornidazole, a compound with trichomonacidal activity. Rats were treated for 4 weeks at dosages of 0 (control) and 400 mg/kg/day of ornidazole during which fertility was assessed by weekly matings. Testicular sperm production and epididymal sperm function were assessed in one-half of the rats while the reversibility of effects after a 2-week recovery period was assessed in the remaining half. Male rats treated with ornidazole were infertile during the second week of treatment. After 4 weeks of treatment, testicular and epididymal weights, testicular spermatid counts, epididymal sperm reserves, sperm morphology, and sperm viability were similar in treated and control rats. A quantitative assessment of epididymal sperm motility using a dark-field photomicroscope with a stroboscopic light source revealed that ornidazole markedly inhibited sperm motility. Although the percentage of nonmotile sperm was not substantially increased in treated rats, the vigor of tail movement was markedly decreased which resulted in decreased sperm velocity. Restoration of fertility and normal sperm motility and velocity were observed in the group of recovery rats assessed 2 weeks after the cessation of ornidazole treatment. It is concluded that ornidazole, at a high dosage of 400 mg/kg/day, produces infertility in male rats by inhibiting epididymal sperm motility in terms of decreased sperm velocity. These effects are rapidly reversible after the cessation of treatment.     

(-)和(+)棉酚对雄大鼠生育力的影响

Racemic, (-) and (+) gossypol, provided by the Department of Organic Chemistry of our institute, was suspended in 2.5% tween 80 solution. Adult male Wistar rats 190～220 g in weight were allotted to 5 groups. Animals in group 1 received 2.5% tween 80 solution as control. Rats in group 2 were treated with racemic gossypol at the dosage of 30 mg/kg for 2 weeks. Animals in group 3 and 4 were given 15 mg/kg of (-) gossypol for 2 weeks and 30 mg/kg of (-) gossypol for 1 week respectively. Rats in group 5 were treated with (+) gossypol at the dosage of 30 mg/kg for 2 weeks.Four weeks from the beginning of gossypol treatment the rats were cohabited with adult females for 7 days. Then the motility of the sperms in the cauda epididymides was estimated The female rats were examined for pregnancy 7 days later.Treatment with (-) gossypol at 30 mg/kg caused significant decreases in body weight of the rats (P<0.05). One of the five rats died 7 days after the last administration, while (+) gossypol and racemic gossypol at the dosage employed had no effect on the body weight. (+) Gossypol at 30 mg/kg for 2 weeks had no effect on the motility of the sperms in the cauda epididymides and no effect on the fertility of the animals: nor was there any effect on the weights of the testis, epididymis, prostate and seminal vesicle. The sperms of the cauda epididymides were found to be dead in the groups treated with 15 and 30 mg/kg of (-)gossypol. Raccmic gossypol given for 2 weeks at 30 mg/kg caused loss of fertility of the male rats which confirmed our previous findings.(?)t may be postulated that (+) gossypol has no antifertility effect nor toxicity at the dosage employed. (-) Gossypol is the active stereoisomer of racemic gossypol.     

Effect of gossypol on liver metabolic enzymes in male rats

The effects of gossypol on liver metabolism were examined in male rats. Gossypol acetic acid was administered to Sprague-Dawley rats intraperitoneally (i.p.) at 5 mg/kg daily, 5 days/week for 2 weeks. The rats were killed 24 h after the last injection. The liver/body weight ratio (-42%), concentration of liver glutathione (-34%), activities of liver alpha-naphthtylacetate esterase (-30%) and DNase (-39%) were significantly decreased when compared to controls. Hepatic beta-glucuronidase (+37%), RNase (+35%) and serum alkaline RNase (+23%) activities were significantly increased. No changes were found in serum transaminases (SGPT, SGOT) or in hepatic RNA and DNA concentration. Elevation of liver and serum RNase activities suggest that gossypol treatment produces some catabolic effects. The depletion of hepatic glutathione and the elevation of beta-glucuronidase activity indicate that gossypol is hepatotoxic when given at this dose for 2 weeks.     

Effect of Metronidazole on Fertility and Testicular Function in Male Rats

Effect of Metronidazole on Fertility and Testicular Functionin Male Rats. MCCLAIN. R. M., DOWNING, J. C., AND EDGCOMB, J.E. (1989). Fundam. Appl. Toxicol 12,386–396. The reproductivetoxicology of metronidazole was studied in rats. Male CharlesRiver Crl:CD(SD)BR rats (10/group) were treated with metronidazoleas a dietary admixture at doses of 0 (control), 25, 100, and400 mg/kg/day for 8 weeks. The reversibility of effects aftera 3?-month recovery period was determined in separate groupsof 10 control and 10 rats treated with 400 mg/kg/day of metronidazole.After 2 and 4 weeks of metronidazole treatment, mating performanceand fertility in treated and control animals were comparable.After 6 weeks of treatment, all high-dose rats were infertile;however, fertility in low- and middose rats was not affected.High-dose male rats killed after 8 weeks of treatment showedmarkedly decreased testicular and epididymal weights, and markedlydecreased testicular spermatid counts and epididymal sperm counts.Most of the few epididymal sperm present in high-dose rats wereviable, but morphologically abnormal. Histologically, severedegeneration of the seminiferous epithelium was observed inthe testes of high-dose rats; the tubules were generally devoidof primary or secondary spermatocytes and spermatids. Rats treatedwith the low and middle doses of metronidazole exhibited normaltesticular and epididymal weights, and normal testicular spermatidcounts and epididymal sperm reserves. Epididymal sperm viabilityand morphology of treated and control animals were comparable.Minimal histologic changes were observed in the testes of middoserats, including degenerative fragmentation of spermatozoa andspermatids. In high-dose recovery rats, fertility was restoredin most rats by 8 weeks after the cessation of treatment; however,the testicular and epididymal weights and sperm counts of ratskilled after 3? months of recovery had increased but were stillsignificantly decreased in treated rats as compared with controls.Histologically, spermatogenesis was observed in most tubules;however, a portion of atrophic tubules persisted. It is concludedthat high doses of metronidazole produce infertility in themale rat through inhibition of spermatogenesis as early as thestage of the primary spermatocyte. This effect is partiallyreversible.     

Application of computer-assisted sperm analysis system to elucidate lack of effects of cyclophosphamide on rat epididymal sperm motion.

A computer-assisted sperm analysis (CASA) system was used to examine the motion of epididymal spermatozoa derived from cyclophosphamide (CP)-treated male rats. Male rats were orally dosed daily for 1 week with 20 mg/kg of CP. Males were euthanized or were mated 3 times with untreated females at 1 day, 3 weeks, and 8 weeks after the final treatment. Significant decreases in testicular and epididymal weights and epididymal sperm counts of the treated animals were noted after 8-week recovery. Histopathological morphometry of the testis revealed minimal damage to spermatogonia at 1 day after the final treatment and to spermatocytes after 3-week recovery in the CP-treated group. On Caesarian section, increased post-implantation losses were found in females mated with CP-treated males in matings starting 1 day and 3 weeks after the final treatment. On the other hand, none of the sperm motion parameters of treated males derived from the CASA system exhibited significant changes at any time points, although the spermatozoa of treated males at 1 day and 3 weeks after the final treatment were damaged at the DNA level, and the spermatozoa of males after 8-week recovery had been the target cells of CP when they were spermatogonia in the testis. It was thus found that damaged spermatozoa could exhibit no changes on their motion when the damage was confined to the nuclei, and that the effect of CP on sperm nuclei was reversible.