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Developmental anomalies derived from exposure of zygotes and first-cleavage embryos to mutagens
J C Rutledge1, W M Generoso, A Shourbaji
1Department of Laboratory Medicine, Children's Hospital and Medical Center, Seattle, WA 98105.
Abstract:
Results of continuing studies indicate that the mouse zygote and two-cell embryo stages are a window of susceptibility in the experimental induction of congenital anomalies with certain mutagenic agents. The mechanisms by which the mutagens initiate the pathogenesis of these developmental defects are not known. However, in certain cases there is evidence that a nonconventional, perhaps epigenetic, mechanism is involved. Detailed characterization of the spectrum of anomalies induced and comparison of responses at the various stages exposed allowed classification of the mutagens generally into two groups. One group is characterized by being effective only in the early stages of zygote development and capable of producing a relatively high incidence of fetal death and hydrops. The other group affects all of the zygote stages studied as well as the two cell-embryo, but does not increase the incidence of fetal death and hydrops. Except for hydrops, chemicals in the two groups do not differ in terms of the types of anomalies present among malformed live fetuses, which bear a resemblance to a subset of common, sporadic human developmental anomalies that are of unknown etiology. This similarity raises the possibility that certain human developmental defects may have their origins in events that happen in the zygote and early pre-implantation stages.
Insights
Early mouse embryo stages are susceptible to mutagen-induced congenital anomalies. Some mutagens cause fetal death and hydrops, while others induce different anomalies, potentially mirroring human developmental defects.
Area of Science:
- Developmental Biology
- Toxicology
- Genetics
Background:
- Congenital anomalies are a significant concern in human health, with many cases of unknown etiology.
- The early stages of embryonic development, particularly the zygote and two-cell stages, are critical periods for development.
- Understanding the impact of environmental factors, such as mutagens, on early development is crucial for preventing birth defects.
Purpose of the Study:
- To investigate the susceptibility of mouse zygote and two-cell embryo stages to experimentally induced congenital anomalies.
- To characterize the spectrum of anomalies induced by different mutagenic agents.
- To explore potential mechanisms, including epigenetic factors, underlying mutagen-induced developmental defects.
Main Methods:
- Exposure of mouse zygotes and early embryos to various mutagenic agents at different developmental stages.
- Detailed characterization of induced congenital anomalies, including fetal death, hydrops, and specific malformations.
- Classification of mutagens based on their effects on different embryonic stages and outcomes.
Main Results:
- Mouse zygote and two-cell embryo stages are identified as windows of susceptibility for mutagen-induced congenital anomalies.
- Mutagens were classified into two groups: one primarily affecting early zygote stages and causing fetal death/hydrops, and another affecting all stages without increasing fetal death/hydrops.
- Induced anomalies in live fetuses, excluding hydrops, resembled a subset of common human developmental defects of unknown cause.
Conclusions:
- Early pre-implantation stages, including the zygote, are critical periods for susceptibility to mutagenic agents causing developmental defects.
- The findings suggest that some human congenital anomalies of unknown etiology may originate from events occurring during zygote and early pre-implantation development.
- Further research into nonconventional, possibly epigenetic, mechanisms is warranted to understand the pathogenesis of these defects.