Anticancer drug 5-fluorouracil induces reproductive and developmental defects in Caenorhabditis elegans.
In order to examine the chronic effects of anticancer drug 5-fluorouracil (5-FU) on reproduction and development, we exploited Caenorhabditis elegans as a model system. We demonstrate that 5-FU induces cell-cycle arrest and apoptosis of germline cells and reduces by approximately 30-40% the number of mitotic nuclei per gonad arm when compared to untreated worms. This drug also affects vulva development, some animals being vulvaless, as well as dysfunction of vulval and egg laying muscles leading to an 8-10 days delay in reproductive time. Interestingly, 5-FU represses levels of mRNA encoding LIN-29, a transcription factor that affects vulva development and egg laying system. Finally, we demonstrate that RNAi-dependent repression of ung-1 gene, which encodes a uracil-DNA glycosylase, partially abolishes 5-FU effects on embryo hatching. Thus, we proposed that C. elegans could be a useful model system for studying the mechanisms by which 5-FU might affect either embryo, adult or organ development.
Kumar
Sandeep
S
INSERM, UMR991, Liver, Metabolisms and Cancer, F-35033 Rennes, France; IFR140, Université de Rennes 1, F-35043 Rennes, France.
Aninat
Caroline
C
Michaux
Grégoire
G
Morel
Fabrice
F
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005472:Fluorouracil / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D010058:Oviposition / Q000187:drug effects / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051981:Uracil-DNA Glycosidase / Q000235:genetics / Q000378:metabolism; D014844:Vulva / Q000187:drug effects / Q000254:growth & development
D000964:Antimetabolites, Antineoplastic; D029742:Caenorhabditis elegans Proteins; D034741:RNA, Small Interfering; D051981:Uracil-DNA Glycosidase; D005472:Fluorouracil