Effects of prenatal exposure to 5-bromo-2'-deoxyuridine on the developing brain and reproductive function in male mouse offspring.
The effect of prenatal exposure to 5-bromo-2'-deoxyuridine (BrdU) on the brain and reproduction in mice was studied. ICR mice were treated intraperitoneally (i.p.) with BrdU at 200 mg/kg on Day 10, 13, or 15 of gestation, or with BrdU at various doses (100 to 800 mg/kg) on Day 10 of gestation. In both experiments, dams were allowed to deliver, and male offspring were aged for 10 weeks and then cohabited with untreated females. In the phase-specificity study, the copulation rate was significantly decreased in the group treated on Day 10 of gestation, while the rate in the groups treated on Day 13 or 15 was comparable to the control level. In the dose-dependency study, copulation rates in the groups treated with BrdU at 200, 400, and 800 mg/kg were significantly lower than the control level, while the rate in the group treated with BrdU at 100 mg/kg was comparable to the control level. Masculine sexual behavior in the group treated with BrdU at 800 mg/kg was markedly impaired. Neither histopathologic changes of testis and sex-accessory glands nor alterations of sperm motility and concentration were observed in the offspring of the highest dose group. Dilatation of the third ventricles was observed in the highest dose group, whereas the relative brain weight in this group was comparable to that in the control group. In the subsequent study, ICR mice were treated i.p. with BrdU at various doses (25 to 800 mg/kg) on Day 10 of gestation, and the embryos were obtained 24 h after treatment. Histopathologic evaluation was performed in the ventricular zone of the telencephalon as well as ependymal and mantle layers of diencephalon (hypothalamus). The incidence of pyknotic cells in these areas was increased linearly with increasing BrdU dose and the incidence in the ependymal and mantle layers of the diencephalon was higher than that in the ventricular zone of the telencephalon. From these results, we conclude that damage to the central nervous system resulting from excessive cell death in the developing brain, particularly in the ependymal and mantle layers of the diencephalon (hypothalamus) may lead to reproductive dysfunction in postpubertal male offspring.
Laboratory of Reproductive and Developmental Toxicology, Hatano Research Institute, Food and Drug Safety Center, Kanagawa, Japan. nagaot@kb3.so-net.or.jp
T
T
Nagao
M
M
Kuwagata
Y
Y
Saito
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001973:Bromodeoxyuridine / Q000633:toxicity*; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005837:Genitalia, Male / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D012098:Reproduction / Q000187:drug effects*; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013081:Sperm Motility / Q000187:drug effects
D001973:Bromodeoxyuridine