新型PPAR-δ激动剂对SD大鼠生育力与早期胚胎发育毒性研究

Study on Fertility and Early Embryo Developmental Toxicity of a Noval PPAR-δ Agonist in Rat

目的观察新型PPAR-δ激动剂HS060098对SD大鼠生育力与早期胚胎发育的影响。方法 SD大鼠184只随机分为溶媒对照组(1%HPMC水溶液)和HS060098混悬液10、30、100 mg/(kg·d)剂量组,每组46只,雌雄各半。雄鼠交配前4周至交配期结束后,雌鼠交配前2周至妊娠d7(GD7),分别连续灌喂各组药物。交配结束后处死雄鼠,进行精子数、精子活力及精子形态学等指标检查。受孕雌鼠于妊娠d14(GD14)处死,记录妊娠子宫重、黄体数、着床数等指标,观察胚胎生存死亡情况。结果100 mg/(kg·d)剂量组雌鼠体重增长缓慢(P<0.01),平均动情周期数、平均黄体数、平均着床数、平均活胚胎数显著减少(P<0.01),平均妊娠子宫重减轻(P<0.01),受孕率明显下降(P<0.01);雄鼠体重及睾丸、附睾、前列腺、精囊腺绝对重量明显减轻(P<0.01),精子畸形率上升(P<0.05)。30 mg/(kg·d)剂量组雄鼠体重增长缓慢,附睾、精囊腺绝对重量减少(P<0.01)。结论在本实验条件下,新型PPAR-δ激动剂HS060098对SD大鼠无明显生育力和早期胚胎发育毒性作用剂量在10 mg/(kg·d)以下。

Objective To observe the fertility and early embryo developmental effect of the noval PPAR-δ agonist HS060098 on SD rats. Methods The 184 SD rats were randomly divided into the solvent control group （1% HPMC water solution） and HS060098 suspension 10, 30, 100 mg/（kg-d） dose groups,which included 46 rats per group with half male and half female. The drugs were administered respectively by intragastric gavage to male from 4 weeks before mating to after mating period and to female from 2 weeks before mating to the gestation day 7（GD7）. Male were sacrificed after mating period, and the sperm count, sperm motility, sperm morphology etc. were examined. Female were sacrificed on gestation day 14（GD14）, and the gravid uterus weight, the number of corpora lutea, implantation sites etc. were recorded. The existence and death of embryos were observed. Results In the 100 mg/（kg·d） group, the body weight of female increased slowly （P〈0.01）, meanwhile, the average number of the estrus cycles, COrpora lutea, the implantation sites and the live embryos reduced sharply（P〈0.01）, and the average gravid uterus weight as well as the conception rate declined significantly（P〈0.01）; The body weight of male rats and the absolute weight of testis, epididymis, prostate and seminal vesicle gland were obviously decreased（P〈0.01） while the sperm deformity rate rised （P〈0.05）. In the 30 mg/（kg·d） group, the body weight of male increased slowly while the absolute weight of epididymis and seminal vesicle gland significantly decreased（P〈0.01）. Conclusion Under the experimental conditions, the noval PPAR-6 agonist HS060098 have no obvious fertility and early embryo developmental toxicity on SD rats when the dose below 10mg/（kg·d）.