What summarized in this paper is the progress in recent years' in the causdive mechanism on study of developmental toxicants as chemical teratogenesis in three aspects.(1) It is about the phenomena and the possibl...
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What summarized in this paper is the progress in recent years' in the causdive mechanism on study of developmental toxicants as chemical teratogenesis in three aspects.(1) It is about the phenomena and the possible reason of chemical teratogenesis in the preimplantation period. These research results are contrary to the past traditional concepts. (2) Due to using much more molecular biology methods, it can be observed more dead foetus phenomena before birth, which cannot be done previously and are of great value for reference. (3) When analyzing the genetic reason of chemical abnormal, a new research idea may be showed, i.e. the developmental abnormal due to chemical teratogenesis is induced with association of more relative genes and their expression abnormal. 13 references are involved in.
目的检测连翘酯苷冻干粉的遗传毒性,为临床前安全性评价提供依据。方法分别应用 Ames 试验、小鼠骨髓微核试验、体外培养 CHO 细胞染色体畸变试验、CHO 细胞和正常人肝细胞 Chang liver 两个细胞株单细胞凝胶电泳法。结果 Ames 试验选用组氨酸营养缺陷型鼠伤寒沙门氏菌 (***)TA97、TA98、TA100、TA102及 TA1535为指示菌株,加和不加代谢活化系统(S9)时对鼠伤寒沙门氏菌均无致突变性。小鼠骨髓微核试验采用 ICR 小鼠,尾静脉注射给药,剂量分别为0．2、0．4和0．8 g/kg,结果显示：雌性小鼠微核诱发率分别为1．50、2．67和6．75％,雄性小鼠微核诱发率分别为1．87、 5．79和6．57％;其中雌性小鼠在0．8g/kg 剂量下、雄性小鼠在 0．4、0．8g/kg 剂量下的微核诱发率与阴性对照组比较差异有统计学意义(P＜0．05)。表明受试物连翘酯苷冻干粉在0．4、0．8 g/kg 剂量下对 ICR 小鼠有诱发骨髓嗜多染红细胞微核的效应。 CHO 细胞染色体畸变试验结果显示：受试物连翘酯苷冻干粉在受试剂量下作用24 h,-S9的染色体畸变率分别为3％、7％和 9％,与阴性对照组比较164．0和328．0μg/ml 2个剂量组均显示差异有统计学意义(P＜0．05);-S9作用48h 的染色体畸变率分别为3％、5％和8％,与阴性对照组比较164．0和328．0μg/ml 剂量组差异有统计学意义(P＜0．05);+S9的染色体畸变率分别为1％、1％和6％,各剂量组与阴性对照组比较差异均无统计学意义(P＞0．05)。重复试验结果一致。以上结果说明连翘酯苷冻干粉在无代谢活化系统时,作用24 h 328μg/ml 以上剂量对 CHO 细胞有致染色体畸变作用,作用48 h 164μg/ml 以上剂量对 CHO 细胞具有致染色体畸变作用,在有 S9代谢活化系统时,在受试剂量下对 CHO 细胞均无致染色体畸变作用。细胞彗星试验结果显示,在各试剂量的拖尾率和尾长与溶剂对照组相比较差异无统计学上意义,表明酯苷冻干粉在受试剂量下无损伤 CHO 细胞和人肝细胞 Chang liverDNA 的能力。结论连翘酯苷在体外培养 CHO 细胞染色体畸变试验和微核试验中,在较高剂量时呈阳性,无损伤 CHO 细胞和人肝细胞 Chang liver DNA 的能力。连翘酯苷冻干粉有一定的遗传毒性,分析连翘酯苷所致染色体畸变和微核的机制,可能不是通过损伤 DNA 机制诱导的, 而是通过抑制 DNA 合成的、抑制拓扑异构酶、细胞毒性等非 DNA 损伤所致。
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