Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse

Rosenquist, Thomas A.

doi:10.1152/ajprenal.00716.2010

Cited by 4 publications

(6 citation statements)

References 64 publications

(63 reference statements)

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“…However, for the C57Bl/6J mice, a resistant strain, renal-injury biomarkers are difficult to detect. 48 The appearance of dA-AL-I adducts in the urine of the C57Bl/6J mice 4 days post-treatment is consistent with the appearance of renal-specific injury markers, but the dA-AL-I adduct levels continue to rise and remain detectable 4 weeks after treatment with AA-I (Figure 6). Thus, dA-AL-I in EUCs is a superior biomarker, revealing exposure, even for the C57Bl/6J mouse normally resistant to AA-induced injury, for a much longer time interval than those of conventional renal-injury biomarkers.…”

Section: ■ Results and Discussionsupporting

confidence: 59%

“…The dA-AL-I adduct was detected in the EUCs of mice 4 days post-treatment with AA-I, and the levels of dA-AL-I in the EUCs continued to increase over the 25 days postdosing period. The dA-AL-I adduct is likely derived from urothelial cells shed from the upper and lower urinary tracts and tubular epithelial cells from the kidney. , The kinetics and the time course of the appearance of EUCs harboring dA-AL-I adducts are consistent with the kinetics of urinary biomarkers of kidney injury following a single dose of AA-I in mice . Urinary biomarkers of kidney injury and dysfunction have been examined in AA-I-sensitive and AA-I-resistant mouse strains .…”

Section: Resultsmentioning

confidence: 73%

“…48 Urinary biomarkers of kidney injury and dysfunction have been examined in AA-I-sensitive and AA-I resistant mouse strains. 48 In the AA-sensitive mouse strain, such markers appear in urine two to four days after treatment with a single dose of AA-I and return to pre-treatment levels over the following week. However, for the C57Bl/6J mouse, a resistant strain, renal injury biomarkers are difficult to detect.…”

Section: Resultsmentioning

confidence: 99%

“…The UPLC-MS 3 20,21 The kinetics and the time course of the appearance of EUCs harboring dA-AL-I adducts are consistent with the kinetics of urinary biomarkers of kidney injury following a single dose of AA-I in mice. 48 Urinary biomarkers of kidney injury and dysfunction have been examined in AA-I-sensitive and AA-I-resistant mouse strains. 48 In the AA-I-sensitive mouse strain, such markers appear in urine 2 to 4 days after treatment with a single dose of AA-I and return to pretreatment levels over the following week.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Method for Biomonitoring DNA Adducts in Exfoliated Urinary Cells by Mass Spectrometry

et al. 2018

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Tobacco smoking contributes to about 50% of the bladder-cancer (BC) cases in the United States. Some aromatic amines in tobacco smoke are bladder carcinogens; however, other causal agents of BC are uncertain. Exfoliated urinary cells (EUCs) are a promising noninvasive biospecimen to screen for DNA adducts of chemicals that damage the bladder genome, although the analysis of DNA adducts in EUCs is technically challenging because of the low number of EUCs and limiting quantity of cellular DNA. Moreover, EUCs and their DNA adducts must remain viable during the time of collection and storage of urine to develop robust screening methods. We employed RT4 cells, a well-differentiated transitional epithelial bladder cell line, as a cell-model system in urine to investigate cell viability and the chemical stability of DNA adducts of two prototypical bladder carcinogens: 4-aminobiphenyl (4-ABP), an aromatic amine found in tobacco smoke, and aristolochic acid I (AA-I), a nitrophenanthrene found in Aristolochia herbaceous plants used for medicinal purposes worldwide. The cell viability of RT4 cells pretreated with 4-ABP or AA-I in urine exceeded 80%, and the major DNA adducts of 4-ABP and AA-I, quantified by liquid chromatography-mass spectrometry, were stable for 24 h. Thereafter, we successfully screened EUCs of mice treated with AA-I to measure DNA adducts of AA-I, which were still detected 25 days following treatment with the carcinogen. EUCs are promising biospecimens that can be employed for the screening of DNA adducts of environmental and dietary genotoxicants that may contribute to the development of BC.

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Section: ■ Results and Discussionsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Method for Biomonitoring DNA Adducts in Exfoliated Urinary Cells by Mass Spectrometry

et al. 2018

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“…With the advent of nanopore/semiconductor DNA sequencing methods [55] and other next generation sequencing technologies, the analysis of AA-associated mutations in circulating tumor cells, or in exfoliated cells in urine could be explored in strategies for noninvasive measurements and prospective study design. It would also be important to investigate the role of genetic factors in DNA repair and of enzymes involved in forming DNA adducts, thereby shaping mutation patterns and influencing cancer risk [56;57]. …”

Section: Discussion and Future Directionsmentioning

confidence: 99%

Analysis of TP53 mutation spectra reveals the fingerprint of the potent environmental carcinogen, aristolochic acid

Hollstein

Moriya

Grollman

et al. 2013

Mutation Research/Reviews in Mutation Research

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Genetic alterations in cancer tissues may reflect the mutational fingerprint of environmental carcinogens. Here we review the evidence that support the role of aristolochic acid (AA) in inducing a mutational fingerprint in the tumor suppressor gene TP53 in urothelial carcinomas of the upper urinary tract (UUT). Exposure to AA, a nitrophenathrene carboxylic acid present in certain herbal remedies and in flour prepared from wheat grain contaminated with seeds of Aristolochia clematitis, has been linked to chronic nephropathy and UUT. TP53 mutations in UUT of individuals exposed to AA reveal a unique pattern of mutations characterised by A to T transversions on the non-transcribed strand, which cluster at hotspots rarely mutated in other cancers. This unusual pattern, originally discovered in UUTs from two different populations, one in Taiwan, and one in the Balkans, has been reproduced experimentally by treating mouse cells that harbour human TP53 sequences with AA. The convergence of molecular epidemiological and experimental data establishes a clear causal association between exposure to the human carcinogen AA and UUT cancer. Despite bans on the sale of herbs containing AA, their use continues, raising global public health concern and an urgent need to identify populations at risk.

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Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity

Chang¹,

et al. 2017

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Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse

Abstract: Rosenquist TA. Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse.

Cited by 4 publications

References 64 publications

Method for Biomonitoring DNA Adducts in Exfoliated Urinary Cells by Mass Spectrometry

Method for Biomonitoring DNA Adducts in Exfoliated Urinary Cells by Mass Spectrometry

Analysis of TP53 mutation spectra reveals the fingerprint of the potent environmental carcinogen, aristolochic acid

Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity

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