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[Experimental studies on the etiological mechanism of congenital microcephaly]
Abstract:
Pregnant mice were injected intraperitoneally on different gestational day with either one or three successive doses of 30 mg/kg of cytosine arabinoside (ara-C), which has been known to interfere with DNA synthesis. Some of them were injected intraperitoneally with tritiated thymidine (3H-TdR) consecutively. The fetuses and the youngs were sacrificed at various hours and days after treatment. Pyknotic nuclei or nuclear debris were observed at the matrix layer three hours after the injection of single dose of ara-C. Nuclear debris were increased as time elapse and they were most prominent 12 hours after treatment. However, 24 hours later, new matrix layer was regenerating. Twenty-four hours after treatment with two successive doses of ara-C, labeling index in the matrix layer was about one third of that of control. Cerebral hemispheres of the treated youngs were reduced in size. The youngs, treated with three successive doses of ara-C on day 13, 14 and 15 of gestation, showed most severe microcephalus. Cytoarchitecture in the cortices of these microcephalic mice was characterized by irregular arrangement of the pyramidal neurons and their dendritic branches. Autoradiographic study revealed that cortical neurons which were produced at the regenerated matrix layer after ara-C treatment migrated to the surface of the cortex.
Insights
Cytosine arabinoside (ara-C) exposure during pregnancy causes severe microcephaly and disrupts cortical neuron development in mice. This DNA synthesis inhibitor leads to abnormal brain development and neuron migration patterns.
Area of Science:
- Developmental neuroscience
- Neurotoxicology
- Teratology
Context:
- Cytosine arabinoside (ara-C) is a chemotherapy agent known to inhibit DNA synthesis.
- Prenatal exposure to teratogens can lead to significant developmental abnormalities.
- Understanding the impact of ara-C on developing neural tissue is crucial for assessing risks.
Purpose:
- To investigate the effects of prenatal cytosine arabinoside (ara-C) exposure on fetal brain development in mice.
- To examine the impact of varying doses and timings of ara-C administration on neurogenesis and cortical cytoarchitecture.
- To analyze the migration patterns of cortical neurons following ara-C-induced damage and regeneration.
Summary:
- Pregnant mice received single or multiple doses of cytosine arabinoside (ara-C) during gestation.
- Ara-C treatment resulted in pyknotic nuclei and nuclear debris in the matrix layer, indicating cell death.
- Severe microcephaly, reduced cerebral hemispheres, and disorganized cortical cytoarchitecture were observed in offspring, particularly after multiple doses.
- Autoradiography showed aberrant migration of neurons produced in the regenerated matrix layer.
Impact:
- This study highlights the significant neuroteratogenic potential of cytosine arabinoside (ara-C).
- Findings underscore the vulnerability of the developing brain to DNA synthesis inhibitors during critical gestational periods.
- Results provide insights into the mechanisms of developmental neurotoxicity and potential long-term consequences of prenatal drug exposure.