Embryonic and Postnatal Injections of Bromodeoxyuridine Produce Age-Dependent Morphological and Behavioral Abnormalities

Abstract

The mitotic marker 5-bromodeoxyuridine (BrdU) was injected twice daily (60 mg/kg) into pregnant hooded rats on one of embryonic days (E) 11, 12, 13, 15, 17, or 21, or into rat pups on postnatal day (P) 10. The principal findings were the following: (1) BrdU exposure on E11 produces profound effects on body morphology, and animals must be fed a special diet because of chronic tooth abnormalities; (2) BrdU exposure at E17 or earlier produces a change in coat spotting pattern, the precise pattern varying with age; (3) BrdU exposure on E15 or earlier produces a reduction in both brain and body weight; (4) BrdU exposure on E17 or earlier reduces cortical thickness; (5) BrdU exposure on E11-E13 and at P10 reduces cerebellar size relative to cerebral size; (6) spatial learning is significantly affected after injections of BrdU at E11-E17, but the largest effect is on E17; (7) the deficit in spatial learning may be related in part to a reduction in visual acuity; and (8) skilled forelimb ability is most disrupted after BrdU exposure at E15 but is also impaired after injections on E13 or earlier. BrdU thus has teratological effects on body, brain, and behavior that vary with the developmental age of the fetus or infant.

Constitutively Active Cytoplasmic c-Jun N-Terminal Kinase 1 Is a Dominant Regulator of Dendritic Architecture: Role of Microtubule-Associated Protein 2 as an Effector

“…8C, white arrow). This feature has previously been attributed to Golgi-Cox staining of blood vessel epithelial cells (Kolb et al, 1999). This is unlikely to be an artifact because brains from wild-type and knock-out mice were extracted and fixed under identical conditions, and this phenomenon was observed only in knock-out mice.…”

Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus

“…Evidence for BrdU-induced cell death in the embryonic brain has been found with maternal doses of 60 mg/kg (two 60 mg/kg injections, 6 hours apart, Kolb et al, 1999) and 400 -600 mg/kg, but not 300 mg/kg (Bannigan, 1985;Webster et al, 1973;Bannigan and Langman, 1979). Because the dose that provides optimal labeling of S-phase cells in the brain appears to be six times higher in adults than in embryos, it may be that the toxic dose is also six times higher.…”

“…First, it may not be absolutely specific for dividing cells, i.e., BrdU, like [ 3 H]thymidine, could potentially label neurons that are repairing small amounts of DNA in addition to cells replicating their complete genome Selden et al, 1993;Schmitz et al, 1999). Additionally, BrdU may act as a mutagen in cells that incorporate it; high doses of BrdU have been shown to have adverse effects on embryonic and neonatal rats (Bannigan, 1985;Nagao et al, 1998;Kolb et al, 1999). To minimize these potential problems, investi-gators aim to use the lowest dose of BrdU that results in visible labeling.…”

Cell proliferation during the early compartmentalization of the Xenopus laevis inner ear

“…Although BrdU incorporation is a popular and established method for identifying newly replicating cells (Gratzner, 1982;Miller and Nowakowski, 1988;Stone and Cotanche, 1994;Lang et al, 2000), it is known that BrdU can affect normal development and morphology if it is delivered in certain dosage regimens and for long exposure times (Stockdale et al, 1964;Kolb et al, 1999;Pizarro et al, 2004). In this study we minimized deleterious effects of BrdU by optimizing our protocols and with our methods, BrdU administration resulted in zero mortality among experimental animals.…”