Effects of prenatal exposure to 5-fluoro-2'-deoxyuridine on developing central nervous system and reproductive function in male offspring of mice.
The effect of 5-fluoro-2'-deoxyuridine (FrdU) on the developing brain and postpubertal reproductive function of male mouse offspring treated prenatally was investigated. FrdU was administered intraperitoneally to pregnant ICR mice at 1.5, 3, 6, 12.5, 25, and 50 mg/kg/day on days 8 through 13 of gestation or 12.5, 25, and 50 mg/kg/day on days 14 through 18 of gestation. Dams were allowed to deliver spontaneously. Dams treated with FrdU at 12.5, 25, and 50 mg/kg/day on days 8 through 13 of gestation did not deliver because of entire intrauterine death of embryos. Male offspring were aged for 10 or 15 weeks and then cohabited with untreated female mice for assessment of reproductive performance. Histological examination of the testis, epididymis, prostate, and seminal vesicle of offspring at 12 weeks of age, and sperm analysis of offspring at 12 or 17 weeks of age were performed. Dose-dependent decreases in body weight gain were noticed throughout the life of offspring. A marked decrease in the copulation rate was noted in the group treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation. However, neither histological examination of testes and sex-accessory glands nor sperm analysis revealed adverse effects of FrdU on the reproductive function in the male offspring of dams treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation. There were no significant differences in the relative weight of testes and epididymides between the group treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation and the control group. Absolute brain weight in the groups treated with FrdU on days 8 through 13 of gestation significantly decreased, while relative brain weight increased in the group treated at 6 mg/kg/day on days 8 through 13, and at 25 and 50 mg/kg/day on days 14 through 18 of gestation. Dilatation of the lateral and third ventricles was observed in all of the male offspring of dams treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation, when inspected at 12 and 17 weeks of age. In the subsequent study, ICR mice were treated intraperitoneally with FrdU at 6.25-100 mg/kg on day 12 of gestation, and the fetuses obtained 24 h after treatment. Histological observation was performed in the ventricular zone of telencephalon, and in the ependymal and mantle layers of diencephalon in the fetal brain. The incidence of pyknotic cells in these areas was increased linearly with increasing FrdU dose. From these results and our previous findings, we suggest that damage to the central nervous system, a substantial neuronal deficit, resulting from excessive cell death in the developing brain may lead to reproductive dysfunction after puberty.
Nagao
T
T
Department of Reproduction Biology, Hatano Research Institute, Food and Drug Safety Center, Kanagawa, Japan. nagaot@kb3.so-net.or.jp
Kuwagata
M
M
Saito
Y
Y
D000014:Abnormalities, Drug-Induced; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001921:Brain / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004822:Epididymis / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005467:Floxuridine / Q000633:toxicity*; D006128:Growth / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D012098:Reproduction / Q000187:drug effects*; D013737:Testis / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine