Fundamental Toxicological Sciences

Paper Details

Fundamental Toxicological Sciences
Vol. 7 No. 2 March 27, 2020 p.97-103
Original Article
5-Fluorocytosine induces fetal skeletal malformations in rats by altering expression of Homeobox genes
  • Takayuki Kumamoto (School of Pharmaceutical Sciences, Ohu University /
Takayuki Kumamoto 1) , Mika Senuma 2) , Mai Todoroki 2) , Fumiaki Kumagai 2) , Hajime Imai 3) , Reiko Suzuki 3) , Tetsuo Ogawa 4) , Makiko Kuwagata 5)
1) School of Pharmaceutical Sciences, Ohu University , 2) Laboratory of Safety Evaluation, Hatano Research Institute, Food and Drug Safety Center , 3) School of Dentistry, Ohu University , 4) Faculty of Medicine, Saitama Medical University , 5) Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Science
Keywords: 5-FC (Flucytosine), Homeobox, Thoracolumbar supernumerary rib,, Digital malformation

5-Fluorocytosine (5-FC) is an antimycotic and teratogenic compound. Oral administration of 5-FC to pregnant rats on gestation days (GD) 9 and 13 was shown to induce thoracolumbar supernumerary ribs (TSR, 14th rib) and abnormal digits, respectively, in fetuses. This study investigated the effects of 5-FC on homeobox genes, which control the anterior-posterior-axis. 5-FC (75 mg/kg) was administered orally on GD9 and GD13, and tissues collected from cranial and caudal regions of TSR sites were analyzed. Following 5-FC administration on GD9, the levels of expression of Hoxa10, which determine the position of the thoracic and lumbar vertebrae, were decreased at GD13. Analysis of hindlimbs 6 hours after administration on GD13 showed decreases in expression of Hoxa11, Hoxd12, and Hoxd13, the Hox genes responsible for limb formation from the proximal to distal, and from the anterior to posterior directions. The present findings showed that altered expression of Hox genes contributes to 5-FC teratogenicity.