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Transplacental antiretroviral therapy with 9-(2-phosphonylmethoxyethyl)adenine is embryotoxic in transgenic mice
J S Lee1, S Mullaney, R Bronson
1Laboratory of Viral Pathogenesis, Dana-Farber Cancer Institute, Boston, MA 02115.
Abstract:
Transgenic Mov-14 mice, which carry the provirus of Moloney murine leukemia virus (Mo-MuLV) in the germ line and begin to produce infectious virus on embryonic day 14, were used to evaluate the ability of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) to cross the placenta and protect embryos from viremia. We have used the Mov-14 model previously to demonstrate the antiviral efficacy and lack of teratogenicity of transplacental therapy with 3'-azido-3'-deoxythymidine (zidovudine, ZDV). PMEA was administered to pregnant females by daily intraperitoneal injection or by osmotic pump. In contrast to ZDV, PMEA was either noneffective in preventing viremia in the offspring or embryotoxic, depending on the dose. The specific toxic effects seen were resorption of pregnancy, low birth weight, and neonatal death. Histopathological analysis of neonatal mice exposed to PMEA showed severe lymphoid depletion of the thymus. We conclude that PMEA therapy is contraindicated for use during pregnancy.
Insights
9-(2-phosphonylmethoxyethyl)adenine (PMEA) did not prevent viremia in transgenic mice and caused toxicity, including pregnancy loss and thymus damage. PMEA therapy is not recommended during pregnancy.
Area of Science:
- Virology
- Pharmacology
- Toxicology
Background:
- The Mov-14 mouse model harbors Moloney murine leukemia virus (Mo-MuLV) and is used to study transplacental antiviral therapies.
- Previous studies demonstrated the efficacy and safety of zidovudine (ZDV) in this model.
Purpose of the Study:
- To evaluate the placental transfer and embryonic safety of 9-(2-phosphonylmethoxyethyl)adenine (PMEA).
- To assess PMEA's efficacy in preventing embryonic viremia in the Mov-14 mouse model.
Main Methods:
- Pregnant Mov-14 mice were treated with PMEA via intraperitoneal injection or osmotic pump.
- Offspring were monitored for viremia, and toxic effects such as pregnancy resorption, low birth weight, and neonatal death were recorded.
- Histopathological analysis of neonatal thymus was performed.
Main Results:
- PMEA was ineffective in preventing viremia in offspring.
- PMEA exhibited dose-dependent embryotoxicity, leading to pregnancy loss, low birth weight, and neonatal mortality.
- Neonatal mice exposed to PMEA showed significant lymphoid depletion in the thymus.
Conclusions:
- PMEA does not effectively cross the placenta to protect embryos from Mo-MuLV viremia.
- PMEA demonstrates significant teratogenic and toxic effects in the Mov-14 mouse model.
- Transplacental PMEA therapy is contraindicated during pregnancy due to its toxicity.