Using in vitro gastrulation models to assess the teratogenicity of antiviral drugs: dolutegravir and remdesivir

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2021

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About 1 in every 33 babies born in the U.S. each year has a major structural birth defect, which is one of the leading causes of infant death. Due to the prevalence of and severe risk associated with birth defects, further investigation into their causes is needed. One of the potential causes of birth defects are teratogens, which include infectious agents such as viruses, as well as the medications that may be prescribed for the treatment of infectious agents. If a woman contracts a virus during pregnancy, it can negatively affect both her health as well as that of the fetus, so proper treatment is imperative. However, the medications may also negatively impact the developing embryo. It is this concept that formed the basis for this study, where the teratogenicity of important antiviral medications (one used to treat HIV and another to treat COVID-19) was examined using in vitro gastrulation models. The in vitro gastrulation models consist of aggregates of mouse or human pluripotent stem cells which undergo axial elongation mimicking the process of gastrulation. As gastrulation is an embryological event critical to generating the basic body plan, a disruption to this process may result in birth defects. Therefore, adverse effects on the growth, elongation, and gene expression in the gastrulation model serve as an indication that exposure to the drugs may be teratogenic. The results of this study demonstrated that both dolutegravir, the anti-HIV medication, and remdesivir, the only FDA-approved treatment for COVID-19, caused significant morphological and molecular changes in the gastrulation model when cell aggregates were exposed to therapeutically relevant concentrations of the drugs. These results suggest that dolutegravir and remdesivir may have teratogenic effects due to the impairment of key developmental processes. This supports the need to seek alternative therapeutic options with a lesser risk to fetal development. The findings also provide insight for further investigations to reveal the mechanisms of their teratogenicity.

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Developmental biology, Toxicology, Dolutegravir, Embryoid bodies, Remdesivir, Teratogen

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96 pages

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