The effect of 5‐bromodeoxyuridine on the postnatal development of the rat testis

Barasch, Jonathan; Bressler, Robert S.

doi:10.1002/jez.1402000102

Cited by 9 publications

(4 citation statements)

References 27 publications

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“…The huge impact of this method on the scientific progress in the field and some initial data demonstrating the BrdU application during pregnancy in rodents did not have any obvious toxic effects on the progeny in terms of litter size, pup weight and neurological function (Miller and Nowakowski 1988), led to the neglection of any possible side effects of BrdU incorporation. This is surprising, since earlier studies had demonstrated quite unambiguously that BrdU has detrimental effects on fetal and (n=5) neonatal development (Garner 1974;Agnish and Kochhar 1976;Pollard et al 1976;Barasch and Bressler 1977). Moreover, more recent work has demonstrated that BrdU impairs proliferation of mouse and human fibroblasts, of lymphocytes, and of carcinoma cell lines in vitro (Poot et al 1994;Diermeier et al 2004).…”

Section: Discussionmentioning

confidence: 75%

The dark side of BrdU in neural stem cell biology: detrimental effects on cell cycle, differentiation and survival

et al. 2011

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5-Bromo-2'-deoxyuridin (BrdU) is frequently used in anaylsis of neural stem cell biology, in particular to label and to fate-map dividing cells. However, up to now, only a few studies have addressed the question as to whether BrdU labeling per se affects the cells to be investigated. Here, we focused on the potential impact of BrdU on neurosphere cultures derived from the adult rat brain and on proliferation of progenitors in vivo. In vitro, neurospheres were pulsed for 48 h with BrdU, and cell proliferation, cell cycle, differentiation, survival and adhesion properties were subsequently analyzed. BrdU inhibited the expansion of neural progenitors as assessed by MTS assay and increased the fraction of cells in the G0/G1-phase of the cell cycle. Moreover, BrdU increased cell death and dose-dependently induced adherence of NPCs. Cell adherence was accompanied by a reduced amount of active matrix-metalloproteinase-2 (MMP-2). Furthermore, BrdU repressed neuronal and oligodendroglial differentiation, whereas astroglial fate was not affected. In contrast to the in vitro situation, BrdU apparently did not influence endogenous proliferation of NPCs or neurogenesis in concentrations that are typically used for labeling of neural progenitors in vivo. Our results reveal so far uncharacterized effects of BrdU on adult NPCs. We conclude that, because of its ubiquitous use in stem cell biology, any potential effect of BrdU of NPCs has to be scrutinized prior to interpretation of data.

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Section: Discussionmentioning

confidence: 75%

The dark side of BrdU in neural stem cell biology: detrimental effects on cell cycle, differentiation and survival

et al. 2011

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“…This method has the advantage over the more traditional 3 [H]thymidine labelling in that it can be detected immunohistochemically, which can be combined more easily with various phenotypic markers such as those used for neuronal or glial cells. However, there are many reports of its toxicity during embryonic (Garner, 1974; Agnish & Kochhar, 1976; Pollard et al ., 1976; Dribin & Jacobson, 1978; Bannigan & Cottell, 1991; Nagao et al ., 1997; Kolb et al ., 1999; Tencer & Brachet, 2000) and neonatal development (Barasch & Bressler, 1977). This toxicity has led to malformations in the offspring when BrdU has been injected into the mother during gestation, with time of administration during development and doses used being critically important in determining the abnormalities reported.…”

Section: Introductionmentioning

confidence: 99%

5‐Bromo‐2′‐deoxyuridine is selectively toxic to neuronal precursors in vitro

Caldwell

Svendsen

2005

Eur J of Neuroscience

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The effect of 5-bromo-2'-deoxyuridine (BrdU) incorporation on the phenotype of progeny derived from expanded E18 rat striatal precursors was examined. BrdU was administered to cultures for 24 h prior to differentiation. Results revealed that there was selective toxicity of this compound to developing TuJ1+ neurons, but not glia, at concentrations used in most labelling studies. Therefore, a BrdU dose-response curve from 0.2 microM to 10 microM was established. The optimum dose of BrdU for labelling cells was 0.2 microM, well below the 1-10 microm recommended concentration. This dose resulted in the survival of significantly more newborn BrdU/TuJ1+ double-labelled neurons and eliminated the toxic effects of BrdU. Administration of 10 microm BrdU resulted in a significant decrease in extracellular regulated kinase (ERK) phosphorylation compared with untreated cultures, this could be completely restored by the administration of either N-methyl-D-aspartate (NMDA) receptor antagonists such as MK801 or the nitric oxide synthesis inhibitor L-methyl-arginine methyl ester (L-NAME). Our results show that high levels of BrdU are selectively toxic to neurons through a mechanism that activates classical cell death pathways. This has implications for labelling studies both in vivo and in vitro.

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“…BrdU competes with thymidine for sites on the replicating DNA strand, and in culture there can be almost total substitution of BrdU for thymidine in the nuclear DNA (Bick and Davidson, 1974). At various concentrations, BrdU has been found to produce various cellular abnormalities both in vitro (Stockdale et al, 1964;Wilt and Anderson, 1972;Trencer and Brachet, 1973;Agnish and Kochhar, 1976a,b;Pollard et al, 1976;Barasch and Bressler, 1977;Dribin and Jacobson, 1978) and in vivo (DiPaolo, 1964;Meller et al, 1973;Webster et al, 1973;Younkin and Silberberg, 1973;Yu, 1976;Bannigan and Langman, 1979;Shah et al, 1991;Nagao et al, 1997).…”

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confidence: 99%

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

et al. 1999

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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.

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The effect of 5‐bromodeoxyuridine on the postnatal development of the rat testis

Cited by 9 publications

References 27 publications

The dark side of BrdU in neural stem cell biology: detrimental effects on cell cycle, differentiation and survival

The dark side of BrdU in neural stem cell biology: detrimental effects on cell cycle, differentiation and survival

5‐Bromo‐2′‐deoxyuridine is selectively toxic to neuronal precursors in vitro

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

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