Reproduction studies of VP 16-213 (II)--Oral administration to rats during the period of fetal organogenesis

Abstract

VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered orally to pregnant Crj: CD (Sprague-Dawley) rats from day 7 through 17 of gestation at dose levels of 1, 3 and 10 mg/kg/day. The summarized results obtained are as follows: VP 10 mg/kg suppressed the maternal body weight increase from day 12 through 20 of gestation. VP 10 mg/kg brought the inhibition of fetal growth accompanied by the lowered values in body weight and body length. Furthermore, the elevated incidences of skeletal anomalies and unossified 5th and 6th sternums, as well as retarded ossification of thoracic vertebrae were also noted in this dose level. VP 10 mg/kg induced anophthalmia, microphthalmia and dilated lateral ventricles in fetuses (F1), as well as unilateral anophthalmia in offspring (F1). VP 10 mg/kg increased the days required for opening of eyelids and descending of testes in offspring (F1), but failed to affect their learning ability, motility, motor activity or emotional development. VP 10 mg/kg suppressed the growth of genital organs in F1 rats of both sexes, but failed to affect their reproductive ability or gestation period. As for F2 newborns derived from F1 rats whose dams had ever received VP 10 mg/kg during the period of fetal organogenesis, the number of implantations and survivors as well as birth indexes lowered due to changes in these items restricted to a few litters. Based on these results, the no-effect dose level of VP under the present experimental condition was estimated to be 3 mg/kg/day against dams and their offspring.