Hoyt J A, Fisher L F, Hoffman W P, Swisher D K, Seyler D E
Toxicology Research Laboratories, Lilly Research Laboratories, Greenfield, IN 46140.
Reprod Toxicol. 1994 May-Jun;8(3):237-50. doi: 10.1016/0890-6238(94)90008-6.
alpha-Chlorohydrin (ACH) was administered to rats in a short-term male reproductive toxicity study to examine the usefulness of the method and to provide reference data with a substance that is known to elicit adverse effects on both sperm production and sperm quality within or following a 2-week treatment period. Adult male CD rats (10 per group) were administered ACH orally by gavage at doses of 0, 1, 5, or 25 mg/kg/day for 14 days. Males were killed on Test Day (TD) 15 or 29. A 2-week period without treatment was included to distinguish between testicular and posttesticular effects. At each time point, the reproductive system was evaluated by comparing testes weight, DNA ploidy distributions of testicular cell suspensions, testicular and epididymal histopathology, and epididymal sperm concentration, motility, morphology, and breakage. Beginning on TD 14, males to be killed on TD 29 were cohabited with untreated females (1:2). Females were killed on Gestation Day 13 and examined for pregnancy status. During the treatment period, minor depressions in body weight and relative food consumption occurred in rats administered 25 mg/kg ACH. Testicular and epididymal lesions also occurred at this dose level. DNA ploidy distributions determined by flow cytometry were predictive of testicular damage, with effects more pronounced on TD 29 than on TD 15. The preparation methods used selected for the most motile and vigorous population of epididymal sperm. Sperm motion was altered at the 5- and 25-mg/kg dose levels on TD 15. The percentage of motile sperm and the percentage of progressively motile sperm were markedly depressed at both the 5- and 25-mg/kg dose levels where antifertility effects occurred. Sperm velocities and amplitude of lateral head displacement were depressed at the 25-mg/kg dose level on both TD 15 and 29. Additionally, decreased epididymal sperm concentrations and increased breakage were recorded at this dose level. The findings in this study are consistent with the scientific literature for ACH and demonstrate posttesticular effects on epididymal sperm and delayed expression of testicular lesions. They also support the use of this methodology for an initial assessment of male reproductive effects.
在一项短期雄性生殖毒性研究中，给大鼠施用了α-氯醇（ACH），以检验该方法的有效性，并为一种已知在2周治疗期内或之后对精子产生和精子质量均有不良影响的物质提供参考数据。成年雄性CD大鼠（每组10只）以0、1、5或25mg/kg/天的剂量通过灌胃口服ACH，持续14天。在试验日（TD）15或29处死雄性大鼠。设置了一个为期2周的无治疗期，以区分睾丸和睾丸后效应。在每个时间点，通过比较睾丸重量、睾丸细胞悬液的DNA倍性分布、睾丸和附睾组织病理学以及附睾精子浓度、活力、形态和破损情况来评估生殖系统。从TD 14开始，将于TD 29处死的雄性大鼠与未处理的雌性大鼠（1:2）合笼。在妊娠第13天处死雌性大鼠并检查妊娠状态。在治疗期间，给予25mg/kg ACH的大鼠出现体重和相对食物摄入量的轻微下降。在此剂量水平也出现了睾丸和附睾病变。通过流式细胞术测定的DNA倍性分布可预测睾丸损伤，在TD 29时的影响比TD 15时更明显。所采用的制备方法选择了附睾中最具活力和最强壮的精子群体。在TD 15时，5mg/kg和25mg/kg剂量水平的精子运动发生改变。在出现抗生育作用的5mg/kg和25mg/kg剂量水平，活动精子百分比和进行性活动精子百分比均显著降低。在TD 15和TD 29时，25mg/kg剂量水平的精子速度和头部侧向位移幅度均降低。此外，在此剂量水平记录到附睾精子浓度降低和破损增加。本研究的结果与关于ACH的科学文献一致，证明了对附睾精子的睾丸后效应以及睾丸病变的延迟表达。它们还支持使用该方法对雄性生殖效应进行初步评估。
