Convenient screening of the reproductive toxicity of favipiravir and antiviral drugs in Caenorhabditis elegans
Kimiyasu Shiraki, Mizuki Mishima, Noriaki Sato, Yasuo Imoto, Kiyoji Nishiwaki
Heliyon, doi:10.1016/j.heliyon.2024.e35331
Reproductive toxicity is one of the major concerns in drug development. Thus, we have developed its screening system using Caenorhabditis elegans, which has a life cycle of three days and similar coding genes as humans. Antiviral nucleoside analogs used for acute infections are known to cause reproductive toxicity, contraindicated for pregnant women, and are used for comparing their reproductive toxicity in C. elegans and experimental animals. None of the drug treatments affected the number of offspring and the concentrations without toxicity to nematodes were consistent with no cytotoxicity or toxicity in experimental animals or humans. Favipiravir, ribavirin, molnupiravir (NHC), acyclovir, ganciclovir, zidovudine, and thalidomide significantly increased the incidence of arrested embryos but amenamevir, letermovir, and guanosine did not. RNA-dependent RNA polymerase (RdRp) inhibitors, in the order of favipiravir, ribavirin, and NHC increased the incidence of arrested embryos, possibly due to the specificity of favipiravir for RdRp and less cytotoxicity. RdRp inhibitors would impair RNA interference through RdRp expressed by telomerase reverse transcriptase during embryogenesis and cause embryo-fetal toxicity. The incidence of arrested embryos may be affected by differences in the substrate specificity of DNA polymerases and metabolism between C. elegans, animals, and humans. The concordance between the results of the screening system for reproductive toxicity of antivirals in C. elegans and those in experimental animals based on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, reproductive toxicology confirms its appropriateness as a screening system for reproductive toxicity. Favipiravir and zidovudine were the least toxic to C. elegans among the antiviral drugs examined.
Administration period: 0-7 days gestation (until implantation). Summary on the 20th day of gestation to observe the endometrium and foetation. $, Human AUC was based on the following dose: favipiravir, 1600 mg × 2/day (loading dose for influenza patients); ribavirin, 400 mg × 2/day (dose for 60-80 kg patients); valacyclovir, 1000 mg × 3/day (dose for zoster patients). Statistically significant difference from the vehicle control: *, p < 0.05; **, p < 0.01. The table is provided with permission by Fujifilm Toyama Chemical Co., Ltd [17] . The authors obtained permission from Pharmacology & Therapeutics to reuse this table [77] .
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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