Vogel R, Spielmann H
Max von Pettenkofer-Institute, Federal Health Office, Berlin, Federal Republic of Germany.
Teratog Carcinog Mutagen. 1989;9(1):51-9. doi: 10.1002/tcm.1770090107.
To study mechanisms of embryotoxicity in early pregnancy, we have evaluated the genotoxic and embryolethal effects of ascorbic acid (AA) alone or in combination with cyclophosphamide (CPA). Female mice were exposed on day 3 of pregnancy. Embryotoxicity was investigated at term and genotoxicity shortly after treatment using the chromosomal aberration test and the sister chromatid exchange (SCE) assay as sensitive end points. Additionally, cytotoxic effects were determined by a proliferation test. AA was not found to be embryotoxic, cytotoxic, or genotoxic when given alone. In combination with 10 mg/kg CPA, however, which induced 50% aberrant metaphases, 100% increase SCE frequency, and a strong inhibition of cell proliferation, AA in a dose range of 25-1,600 mg/kg did not change SCE and proliferation, but reduced the rate of aberrant metaphases significantly. This anticlastogenic effect was clearly correlated to a beneficial effect on embryolethality at term when 200 mg/kg ascorbic acid was given in combination with 40 mg/kg CPA. The results suggest that during early pregnancy AA is not genotoxic even at so-called megadoses doses, but it seems to protect early embryos against damage induced by genotoxic agents like CPA.
为研究妊娠早期胚胎毒性的机制，我们评估了单独使用抗坏血酸（AA）或其与环磷酰胺（CPA）联合使用时的遗传毒性和胚胎致死效应。雌性小鼠在妊娠第3天接受处理。在足月时研究胚胎毒性，并在处理后不久使用染色体畸变试验和姐妹染色单体交换（SCE）试验作为敏感终点来研究遗传毒性。此外，通过增殖试验确定细胞毒性作用。单独给予AA时，未发现其具有胚胎毒性、细胞毒性或遗传毒性。然而，与10 mg/kg CPA联合使用时（CPA可诱导50%的中期相畸变、SCE频率增加100%以及强烈抑制细胞增殖），25 - 1600 mg/kg剂量范围内的AA并未改变SCE和增殖情况，但显著降低了中期相畸变率。当200 mg/kg抗坏血酸与40 mg/kg CPA联合使用时，这种抗致断裂效应与足月时对胚胎致死性的有益作用明显相关。结果表明，在妊娠早期，即使是所谓的大剂量AA也没有遗传毒性，但它似乎能保护早期胚胎免受CPA等遗传毒性剂诱导的损伤。
