5-Fluorocytosine induces fetal skeletal malformations in rats by altering expression of Homeobox genes

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.