Abstract:
:Combinations of antiretroviral drugs that include nucleoside reverse transcriptase inhibitors (NRTIs) are superior to single-agent regimens in treating or preventing HIV infection, but the potential long-term health hazards of these treatments in humans are uncertain. In earlier studies, our group found that coexposure of TK6 human lymphoblastoid cells to 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI), the first two NRTIs approved by the FDA as antiretroviral drugs, produced multiplicative synergistic enhancement of DNA incorporation of AZT and mutagenic responses in both the HPRT and TK reporter genes, as compared with single-drug exposures (Meng Q et al. [2000a]: Proc Natl Acad Sci USA 97:12667-12671). The purpose of the current study was to characterize the mutational specificity of equimolar mixtures of 100 microM or 300 microM AZT + ddI at the HPRT and TK loci of exposed cells vs. unexposed control cells, and to compare the resulting mutational spectra data to those previously found in cells exposed to AZT alone (Sussman H et al. [1999]: Mutat Res 429:249-259; Meng Q et al. [2000b]: Toxicol Sci 54:322-329). Molecular analyses of HPRT mutant clones were performed by reverse transcription-mediated production of cDNA, PCR amplification, and cDNA sequencing to define small DNA alterations, followed by multiplex PCR amplification of genomic DNA to define the fractions of deletion events. TK mutants with complete gene deletions were distinguished by Southern blot analysis. The observed HPRT mutational categories included point mutations, microinsertions/microdeletions, splicing-error mutations, and macrodeletions including partial and complete gene deletions. The only significant difference or shift in the mutational spectra for NRTI-treated cells vs. control cells was the increase in the frequency of complete TK gene deletions following exposures (for 3 days) to 300 microM AZT-ddI (P = 0.034, chi-square test of homogeneity); however, statistical analyses comparing the observed mutant fraction values (measured mutant frequency x percent of a class of mutation) between control and NRTI-treated cells for each class of mutation showed that the occurrences of complete gene deletions of both HPRT and TK were significantly elevated over background values (0.34 x 10(-6) in HPRT and 6.0 x 10(-6) in TK) at exposure levels of 100 microM AZT-ddI (i.e., 1.94 x 10(-6) in HPRT and 18.6 x 10(-6) in TK) and 300 microM AZT-ddI (i.e., 5.6 x 10(-6) in HPRT and 34.6 x 10(-6) in TK) (P < 0.05, Mann-Whitney U-statistic). These treatment-related increases in complete gene deletions were consistent with the spectra data for AZT alone (ibid.) and with the known mode of action of AZT and ddI as DNA chain terminators. In addition, cotreatments of ddI with AZT led to substantial absolute increases in the mutant fraction of other classes of mutations, unlike cells exposed solely to AZT [e.g., the frequency of point mutations among HPRT mutants was significantly increased by 130 and 323% over the background value (4.25 x 10(-6)) in cells exposed to 100 and 300 microM AZT-ddI, respectively]. These results indicate that, at the same time that AZT-ddI potentiates therapeutic or prophylactic efficacy, the use of a second NRTI with AZT may confer a greater cancer risk, characterized by a spectrum of mutations that deviates from that produced solely by AZT.
journal_name
Environ Mol Mutagenjournal_title
Environmental and molecular mutagenesisauthors
Meng Q,Su T,O'Neill JP,Walker VEdoi
10.1002/em.10073subject
Has Abstractpub_date
2002-01-01 00:00:00pages
282-95issue
4eissn
0893-6692issn
1098-2280journal_volume
39pub_type
杂志文章abstract::The in vivo model Drosophila melanogaster was used here to determine the detrimental effects induced by silver nanoparticles (AgNPs) exposure. The main aim was to explore its interaction with the intestinal barrier and the genotoxic effects induced in hemocytes. The observed effects were compared with those obtained b...
journal_title:Environmental and molecular mutagenesis
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abstract::A multicolor fluorescence in situ hybridization (FISH) method was developed to detect aneuploidy and diploidy in epididymal sperm of rats using DNA probes specific for chromosomes 4 and Y. Fourteen healthy young-adult rats from three strains were evaluated: inbred Fisher 344/N/ehs, outbred Sprague-Dawley, and outbred ...
journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:
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abstract::As a contribution to the second round of rodent carcinogenesis prediction organised by the U.S. National Institute of Environmental Health Sciences (NIEHS), speculative predictions for 30 chemicals currently under evaluation in U.S. National Toxicology Program (NTP) rodent bioassays are presented. Core chemical data r...
journal_title:Environmental and molecular mutagenesis
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journal_title:Environmental and molecular mutagenesis
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journal_title:Environmental and molecular mutagenesis
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journal_title:Environmental and molecular mutagenesis
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.2850140304
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.20420
更新日期:2008-12-01 00:00:00
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.2850140403
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.22426
更新日期:2021-01-26 00:00:00
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/(sici)1098-2280(1998)32:4<351::aid-em9>3.0
更新日期:1998-01-01 00:00:00
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.21984
更新日期:2016-01-01 00:00:00
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.20629
更新日期:2011-05-01 00:00:00
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journal_title:Environmental and molecular mutagenesis
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更新日期:2015-03-01 00:00:00
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.20668
更新日期:2012-01-01 00:00:00
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.20436
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.2850170403
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journal_title:Environmental and molecular mutagenesis
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.1031
更新日期:2001-01-01 00:00:00
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章,评审
doi:10.1002/em.20559
更新日期:2010-07-01 00:00:00
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journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.20180
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journal_title:Environmental and molecular mutagenesis
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doi:10.1002/em.21834
更新日期:2014-03-01 00:00:00
abstract::Human exposure to airborne particulate matter (PM) is associated with adverse cardiopulmonary health effects, including lung cancer. Ambient PM represents a heterogeneous mixture of chemical classes including transition metals, polycyclic aromatic hydrocarbons (PAHs) and their derivatives such as nitro-PAHs, many of w...
journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.22166
更新日期:2018-05-01 00:00:00
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journal_title:Environmental and molecular mutagenesis
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更新日期:2017-10-01 00:00:00
abstract::A recent study conducted by our group showed that the NAT2 fast acetylator genotype is associated with an increasing risk for the development of colorectal cancer (CRC), especially for females. We therefore examined whether a higher risk of CRC in females with the NAT2 fast acetylator genotype was associated with the ...
journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/em.20444
更新日期:2009-03-01 00:00:00
abstract::Understanding chemically induced changes in mutational spectra can aid in deciphering mechanisms of mutagenesis. In this paper, we propose the use of statistical methods that are based upon the mutation frequency, rather than simple mutant counts which have no relationship to the mutation frequency. These methods have...
journal_title:Environmental and molecular mutagenesis
pub_type: 杂志文章
doi:10.1002/(SICI)1098-2280(1996)28:4<405::AID-EM15>3.
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abstract::Noncovalent DNA interactions, e.g., DNA intercalation and DNA groove-binding, have not been well studied relative to covalent interactions largely due to the inability of predicting and detecting such events in intact cells. We have adapted an in vitro bleomycin amplification method for DNA intercalation for use in cu...
journal_title:Environmental and molecular mutagenesis
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