Evaluation of serum-associated embryotoxicity/mutagenicity in females with reproductive dysfunctions using preimplantation mouse embryos in vitro

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Abstract
Reproductive failures may be caused by chromosomal anomalies, complex interactions of maternal/fetal genotype and environmental factors. Some of them have also been attributed to undefined maternal serum factor(s). We have developed an assay to evaluate maternal-serum associated embryotoxicity/mutagenicity using the preimplantation mouse embryo. It is based on in vitro culture of 8-cell mouse embryos for 48 h in the presence of 10% sera from females with reproductive dysfunction along with suitable controls. The human sera were obtained from three groups of females: (i) with normal reproductive histories (negative controls), (ii) undergoing cancer chemotherapy (positive controls), and (iii) with a history of failing to achieve or maintain pregnancy (test group). The preimplantation mouse embryos were cultured in the three types of human sera and female rat serum (as an internal control for each experiment) and evaluated for toxicity (embryo survival) and mutagenicity (as measured by SCE). Embryos cultured in serum from women with normal reproductive histories and female rats had survival rates of 70.8 ± 4.3 and 78.9 ± 0.9%, respectively. The SCE frequencies for these two sera types were similar: 15.7 ± 0.2 SCEs/cell (rat) and 16.3 ± 0.3 SCEs/cell (human). Mouse embryos cultured in medium supplemented with serum from females undergoing chemotherapy had significantly (P < 0.01) reduced survival (33.7 ± 5.2%) and significantly (P < 0.01) increased SCEs/cell (26.5 ± 0.6). The effect of sera from women with histories of reproductive failures on preimplantation mouse embryos was variable and individual specific. Approximately 40% of the test group female sera yielded survival and SCEs/cell comparable to the sera from patients undergoing chemotherapy. The results suggest that at least some of the females with reproductive failures may possess serum substance(s) that is/are toxic to preimplantation mouse embryos in culture and is/are mutagenic. It is logical to hypothesize that at least in some cases these substance(s) may contribute to or represent the cause of reproductive problems. Furthermore, the preimplantation mouse embryos may be used to evaluate human serum embryotoxicity and mutagenicity before the onset of pregnancy which may provide strategies for appropriate preventative measures.