Age dependent selection against HPRT deficient T lymphocytes in the HPRT± heterozygous mouse

Deubel, Werner; Bassukas, Ioannis D.; Schlereth, Werner; Lorenz, R.; Hempel, Klaus

doi:10.1016/0027-5107(95)00214-6

Cited by 29 publications

(13 citation statements)

References 35 publications

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“…In the current study, significant increases in Hprt mutant frequencies of 2.4-fold and 1.7-fold over background were found in the AZT and AZT-3TC treatment groups of 13-day-old mice, followed by a rapid decline to control animal values due to selective pressures against Hprt mutant cells and dilution by maturation and trafficking of new T-cells to peripheral blood. The underlying reasons for this pattern in T-cell kinetics and manifestation of Hprt mutants have been considered in detail elsewhere [Jones et al, 1987;Crippen and Jones;1989;Deubel et al, 1996;Walker et al, 1999;Judice 2001].…”

Section: Discussionmentioning

confidence: 99%

Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD‐1 mice to single agents or drug combinations

Torres

Walker

Carter

et al. 2007

Environ and Mol Mutagen

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Experiments were performed to investigate the impact of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) on cell survival and mutagenicity in two reporter genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using cell cloning assays for assessing the effects of individual drugs/drug combinations in (1) TK6 human lymphoblastoid cells exposed in vitro and (2) splenic lymphocytes from male CD-1 mice exposed transplacentally on days 12-18 of gestation. In TK6 cells, dose-related increases in HPRT and TK mutant frequencies were found following 3 days of exposure to AZT or 3TC alone (33, 100, or 300 microM), or to equimolar amounts of AZT-3TC. Compared with single drug exposures, AZT-3TC coexposures generally yielded enhanced elevations in HPRT and TK mutant frequencies. Mutagenicity experiments with ABC alone, or in combination with AZT-3TC, were complicated by the extreme cytotoxicity of ABC. Exposure of cells either to relatively high levels of AZT-3TC short-term (100 microM, 3 days), or to peak plasma-equivalent levels of AZT-3TC for an extended period (10 microM, 30 days), resulted in similar drug-induced mutagenic responses. Among sets of mice necropsied on days 13, 15, or 21 postpartum, Hprt mutant frequencies in T-cells were significantly elevated in the AZT-only (200 mg/kg bw/day) and AZT-3TC (200 mg AZT + 100 mg 3TC/kg bw/day) groups at 13 days of age. These results suggest that the mutagenicity by these nucleoside analogs is driven by cumulative dose, and raises the question of whether AZT-3TC has greater mutagenic effects than AZT alone in perinatally exposed children.

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Section: Discussionmentioning

confidence: 99%

Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD‐1 mice to single agents or drug combinations

Torres

Walker

Carter

et al. 2007

Environ and Mol Mutagen

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“…Additional research of the key variables will be needed to determine whether the observed differences in dose dependence as a function of time and dose rate and radiation source are attributable to differences in lymphocyte population dynamics associated with varying cytotoxicity, differences in the molecular spectra of the induced mutations, or combinations of these and additional factors. Cell proliferation-based selection has been postulated to explain the age dependence of Hprt mutant frequencies in unirradiated, heterozygous Hprt 1/2 female mice [Deubel et al, 1996] and also the shape of the dose dependence of hprt Hprt frequency after exposure of mice to acute doses of X-rays (see mentioned earlier, [Klarmann et al, 1995]). Given the differences in design and dose dependence of mutagenesis among the in vivo radiation studies available to date, and our limited understanding of the key variables, caution is advised in making comparisons among studies employing different dose rates, radiation qualities, and sampling times.…”

Section: Discussionmentioning

confidence: 98%

Studies of thioguanine‐resistant lymphocytes induced by in vivo irradiation of mice

Jones

Burkhart-Schultz

Strout

et al. 2008

Environ and Mol Mutagen

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The frequency of Hprt-deficient lymphocytes in mice after in vivo gamma irradiation, has been found to vary as a function of time elapsed after exposure and irradiation dose. The frequency of mutant lymphocytes in spleen was determined using an in vitro, clonogenic assay for thioguanine-resistant T-lymphocytes. Mice were exposed to single doses of 0-400 cGy from cesium-137 or to eight daily doses of 50 cGy. The time to maximum-induced mutant frequency was 3 weeks. The dose response was strikingly curvilinear at 3-5 weeks after irradiation, but less precisely defined for 10-53 weeks after exposure, being fit by either linear or quadratic dependence. Three weeks after eight daily 50 cGy exposures, mutant frequency was elevated above controls and mice exposed to 50 cGy (which were not distinct from the nonirradiated controls), but only 17% in that of mice given a single 400 cGy fraction. This fractionation effect and the curvilinearity of the early dose-response curve suggested that saturation of repair increased the yield of mutations at higher acute doses. The decline of spleen mutant frequency in mice observed between 5 and 10 weeks after irradiation may reflect selection against some mutants. The marked variation of mutant frequency, as a function of time after irradiation and of dose rate, emphasize the need to evaluate these variables carefully and consistently in future studies.

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“…The selection against HPRT mutant isolates is thought to take place in bone marrow, where purine synthesis is limited to the salvage pathway (41,42). Interestingly, during the life span of HPRT heterozygous female mice, the decrease of HPRT mutant isolates in the juvenile period was much more rapid compared with the decrease in adult stage (43). Such biphasic decrease was attributed to the initial high selection pressure against HPRT mutant isolates in bone marrow and later selection with lower selective pressure in peripheral lymphatic organs (43).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, during the life span of HPRT heterozygous female mice, the decrease of HPRT mutant isolates in the juvenile period was much more rapid compared with the decrease in adult stage (43). Such biphasic decrease was attributed to the initial high selection pressure against HPRT mutant isolates in bone marrow and later selection with lower selective pressure in peripheral lymphatic organs (43). In addition, primary hematopoietic site shifts from liver to bone marrow during the late stage of human fetal development (44); therefore, the decrease in apparent Mf in female infants may be the result of the shift of hematopoietic site along with an increased proliferation rate in the lymphocyte population.…”

Section: Discussionmentioning

confidence: 99%

Gender-specific frequency of background somatic mutations at the hypoxanthine phosphoribosyltransferase locus in cord blood T lymphocytes from preterm newborns

Yoshioka

Vacek

Poseno

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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Limited information is available regarding the frequency, spectrum, and clinical relevance of somatic mutations in the developing fetus. The goal of this study was to determine somatic mutant frequencies (Mfs) at the hypoxanthine phosphoribosyltransferase (HPRT) reporter gene in cord blood T lymphocytes from preterm infants to gain insight into in utero mutational events. Mf determinations were made by using the HPRT T cell cloning assay on cord blood samples from 52 preterm infants. Natural logarithm Mfs (lnMfs) from preterm infants were compared with results from our database for full-term infants. Our analysis revealed higher lnMfs in cord blood T lymphocytes from preterm compared with full-term infants (P ‫؍‬ 0.008). In addition, preterm females had significantly higher lnMfs compared with full-term females (P < 0.001), whereas preterm males were found to have significantly lower lnMfs than preterm females (P ‫؍‬ 0.005). Regression analyses also demonstrate a significant relationship between lnMf and gestational age for preterm females that does not exist for preterm males. These results demonstrate the gender-specific association between Mf and age in humans.Little is known about the clinical effects of spontaneous somatic mutations during fetal development. During embryogenesis, somatic mutational events are influenced by a number of unique factors that are not operative in adults, specifically high rates of DNA replication associated with cellular proliferation, as well as variable expression of enzymes that metabolize genotoxic compounds, V(D

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Age dependent selection against HPRT deficient T lymphocytes in the HPRT± heterozygous mouse

Cited by 29 publications

References 35 publications

Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD‐1 mice to single agents or drug combinations

Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD‐1 mice to single agents or drug combinations

Studies of thioguanine‐resistant lymphocytes induced by in vivo irradiation of mice

Gender-specific frequency of background somatic mutations at the hypoxanthine phosphoribosyltransferase locus in cord blood T lymphocytes from preterm newborns

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