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2'-Deoxyadenosine causes cell death in embryonic chicken sympathetic ganglia and brain
Z Zhao1, W J Crossland, J S Kulkarni
1Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48202, USA.
Abstract:
Previous work has shown that nucleosides produce apoptosis in sympathetic ganglion (SG) cells in vitro. The present study examined the effects of nucleosides on the development of the chick embryo in vivo with special attention to the SG and the optic tectum of the central nervous system. In the presence of an adenosine deaminase inhibitor, adenosine and 2'-deoxyadenosine (2'-dAdo) produced different toxicity patterns: both adenosine and 2'-dAdo were toxic to E3 embryos, but only 2'-dAdo was toxic at later stages (E6 1/2, E11). Dosage experiments on E6 1/2 embryos showed that adenosine was less toxic than 2'-dAdo and that 2'-dAdo in sublethal doses was teratogenic. We also examined the effects of 2'-dAdo on embryonic chicken SG and optic tectum in vivo to determine whether sublethal doses of 2'-dAdo produced cell death in these centers on E6 1/2 and 10. In the E6 1/2 SG, 2'-dAdo produced significant neuron loss (83%) and a decrease in SG volume (65%); however, at E10, there was only minor cell loss (7%) and no significant change in SG volume. In the optic tectum at E6 1/2, cell loss was confined mainly to the tectal ventricular zone, but there was little sign of cell loss in this organ at E10. Since cell production is vigorous in the SG and optic tectum at E6 1/2 but relatively low at E10, 2'-dAdo appears to work by stopping cell proliferation. The ineffectiveness of 2'-dAdo at E10 may result from the lethality of 2'-dAdo to the embryo at low concentrations (30 microM) in vivo, well below the apoptosis-inducing concentrations employed in vitro (100-300 microM). These data extend previous findings showing that purine and pyrimidine metabolism plays an important role in development.
Insights
2'-deoxyadenosine (2'-dAdo) causes developmental toxicity and cell loss in chick embryos, particularly affecting the sympathetic ganglion and optic tectum by inhibiting cell proliferation. Its in vivo toxicity at low concentrations limits its use in later developmental stages.
Area of Science:
- Developmental biology
- Neuroscience
- Toxicology
Background:
- Nucleosides are known to induce apoptosis in sympathetic ganglion (SG) cells in vitro.
- Understanding nucleoside effects on embryonic development is crucial for identifying potential teratogens and developmental disruptions.
Purpose of the Study:
- To investigate the in vivo effects of adenosine and 2 -deoxyadenosine (2 -dAdo) on chick embryo development, focusing on the sympathetic ganglion (SG) and optic tectum.
- To determine the developmental toxicity and teratogenic potential of 2 -dAdo at different embryonic stages.
Main Methods:
- Administration of adenosine and 2 -dAdo to chick embryos at various developmental stages (E3, E6 1/2, E11) in the presence of an adenosine deaminase inhibitor.
- Dosage experiments to assess toxicity and teratogenicity of 2 -dAdo in E6 1/2 embryos.
- Histological examination of SG and optic tectum in E6 1/2 and E10 embryos exposed to sublethal doses of 2 -dAdo to quantify cell loss and volume changes.
Main Results:
- 2 -dAdo exhibited differential toxicity, being toxic at early (E3) and later (E6 1/2, E11) stages, whereas adenosine was toxic only at E3.
- Sublethal doses of 2 -dAdo were teratogenic and caused significant neuron loss (83%) and volume reduction (65%) in the E6 1/2 SG, and cell loss in the optic tectum's ventricular zone.
- At later stages (E10), 2 -dAdo showed minimal cell loss in the SG and optic tectum, suggesting an effect on cell proliferation rather than cell death in actively developing tissues.
- In vivo lethality of 2 -dAdo at 30 microM was observed, which is lower than concentrations causing apoptosis in vitro.
Conclusions:
- 2 -dAdo significantly impacts early embryonic development, leading to cell loss and teratogenicity by inhibiting cell proliferation in the developing nervous system.
- The developmental stage is critical, with 2 -dAdo primarily affecting actively proliferating tissues.
- The lower in vivo toxicity threshold of 2 -dAdo compared to in vitro studies highlights the complexity of nucleoside metabolism in embryonic development and its role in purine and pyrimidine pathways.