Mutation frequency in human lymphocytes increases with age

Trainor, Kevin J.; Wigmore, Dianne J.; Chrysostomou, A.; Dempsey, J.; Seshadri, Ram; Morley, Alexander A.

doi:10.1016/0047-6374(84)90084-8

Cited by 124 publications

(28 citation statements)

References 7 publications

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“…Also, the frequency of somatic mutation at the X-linked HPRT locus in long-term cultured T lymphocytes has been reported to increase with age at a rate of 1.3% per year (26). The results of our studies show that the cell hybrid clones carrying an old-age X chromosome tend to lose the X chromosome's short arm marker MIC2 at a significantly higher rate than those carrying a young-age X chromosome, a result that is consistent with an increase of chromosome fragility as a function of age.…”

Section: Discussionmentioning

confidence: 99%

Chromosomes of older humans are more prone to aminopterine-induced breakage.

Esposito

Fassina

Szabo

et al. 1989

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

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should be noted: in line 15 "a young control" should read "young controls," and in line 17 "an old donor" should read "old donors." Proc. Natl. Acad. Sci. USA Vol. 86, pp. 1302-1306, February 1989 Chromosomes of older humans are more prone to aminopterine-induced breakage ( Communicated by Alexander G. Bearn, October 31, 1988 (received for review April 20, 1988 ABSTRACTWe have adopted a simplified version of the "cell hybrid cotransfer method" to test the hypothesis that human lymphocytes derived from elderly individuals have a higher chromosome instability. Peripheral blood lymphocytes from "old" male individuals and "young" controls were fused with a Chinese hamster cell line (CHO-YH21), yielding 10 HAT-resistant rodent-human clones from the old propositi and 22 from the young controls (HAT = hypoxanthine/ aminopterin/thymidine). Both series of hybrid clones were analyzed with respect to the retention of the enzyme glucose-6-phosphate dehydrogenase and the surface antigen MIC2 identified by monoclonal antibody 12E7, two human X chromosome-linked markers located at opposite ends of the X chromosome. Cell hybrid clones with an X chromosome from a young control retained both markers in about 70% of the cells. In contrast, cell hybrid clones with an X chromosome from an old donor retained the MIC2 marker in only 30% of their cells. Slot-blot hybridization studies have established that the observed loss ofthe MIC2 marker is due to loss of the coding gene, not to suppression of its expression. Similar hybridization studies with molecular probes specific for other regions of the X chromosome suggest preferential chromosomal breakage sites. T lymphocytes from old donors were also found to have an LD50 for aminopterine significantly lower than the concentration of this drug in the HAT medium used to grow the hybrids, suggesting that the higher level of gene loss observed in the X chromosomes from old donors may be directly related to their increased sensitivity to the clastogenic effect of aminopterine. We speculate that the higher rate of chromosomal breakage and of marker loss observed along the "old-age" X chromosomes could be the result of "molecular scars" accumulated with aging at sites of constitutive chromosomal fragility.The contention that the aging process results from the accumulation of somatic mutations is an old one (1-3) and still controversial. It is our belief that one of the main difficulties in approaching the question experimentally has been that the methods available to test this hypothesis have usually been applicable only to subpopulations of somatic cells capable of replicating in culture. To circumvent this limitation, we have used a simplified version of the "cell hybrid cotransfer method" of Goss and Harris (4), which permits screening for chromosome breakage along a well-defined chromosomal target site (in our case, the X chromosome) independent of cell survival. This was done by fusing peripheral blood lymphocytes from the individuals to be tested with the rodent cell line CHO-YH...

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Section: Discussionmentioning

confidence: 99%

Chromosomes of older humans are more prone to aminopterine-induced breakage.

Esposito

Fassina

Szabo

et al. 1989

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

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“…Such studies have been carried out on individuals accidentally [Hakoda et al, 1988a,b], therapeutically [Messing and Bradley, 1985;Nicklas et al, 1990Nicklas et al, , 1991Sala-Trepat et al, 19901 or occupationally [Seifert et al, 19931 exposed to ionizing radiation. However, because of the nature of the cases analyzed, those accidentally and medically exposed to radiation tend to be adults who already show increased levels of background (spontaneous) mutations, as these accumulated with age [Trainor et al 1984;Branda et al, 19931. Moreover, dose estimations for subjects exposed to ionizing radiation in the workplace or during accidents are always questionable, and in these cases the validation of the study requires the establishment of suitable nonexposed control groups for comparative purposes. Because of the extensive individual variation [Cole and Skopek, 19941, the comparison of two different groups can be very complex.…”

Section: Introductionmentioning

confidence: 98%

Increasedhprt mutant frequencies in Brazilian children accidentally exposed to ionizing radiation

Saddi¹,

Curry²,

Nohturfft³

et al. 1996

Environ. Mol. Mutagen.

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“…Biologically plausible values for m 0 were presumed to be between 10 -8 and 10 -7 y -1 , i.e., similar to estimated values pertaining to humans (Trainor et al, 1984;King et al, 1994;Mendelsohn, 1990;Robinson et al, 1994). The background rate b 0 of stem-cell division for nasal epithelium was assumed to be 1 y -1…”

Section: Biologically Based (Mvk) Modeling To Bound Moa Uncertaintymentioning

confidence: 99%

Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

Bogen¹

2007

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A relatively simple, quantitative approach is proposed to address a specific, important gap in the approach recommended by the USEPA Guidelines for Cancer Risk Assessment to address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate "linear" (genotoxic) vs. "nonlinear" (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach-similar to that used in reference dose procedures for classic toxicity endpoints-can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a "nonlinear" toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen.Plausibility bounds on rat-tumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2-and 1,4-naphthoquinone.Bound-specific "adjustment" factors were then used to reduce naphthalene risk estimated by linear extrapolation (under the default genotoxic MOA assumption), to account for the DMOA exhibited by this compound.3

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Mutation frequency in human lymphocytes increases with age

Cited by 124 publications

References 7 publications

Chromosomes of older humans are more prone to aminopterine-induced breakage.

Chromosomes of older humans are more prone to aminopterine-induced breakage.

Increasedhprt mutant frequencies in Brazilian children accidentally exposed to ionizing radiation

Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

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