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Environmental and Molecular Mutagenesis

Atsushi Hakura, Hajime Sui, Jiro Sonoda, Tomonari Matsuda, Takehiko Nohmi
In vitro studies indicate that DNA polymerase kappa (Polκ) is able to accurately and efficiently perform DNA synthesis using templates containing various types of DNA damage, including benzo[a]pyrene (BP)-induced N2 -deoxyguanosine adducts. In this study, we examined sensitivity of inactivated Polk knock-in (Polk-/- ) mice to BP carcinogenicity in the colon by administering an oral dose of BP plus dextran sulfate sodium (DSS), an inflammation causing promoter of carcinogenesis. Although colon cancer was successfully induced by BP plus DSS, there was no significant difference in tumor incidence or multiplicity between Polk-/- and Polk+/+ mice...
January 8, 2019: Environmental and Molecular Mutagenesis
Clotilde Maurice, Stephen D Dertinger, Carole L Yauk, Francesco Marchetti
Procarbazine hydrochloride (PCH) is a DNA-reactive hematopoietic carcinogen with potent and well-characterized clastogenic activity. However, there is a paucity of in vivo mutagenesis data for PCH, and in vitro assays often fail to detect the genotoxic effects of PCH due to the complexity of its metabolic activation. We comprehensively evaluated the in vivo genotoxicity of PCH on hematopoietic cells of male MutaMouse transgenic rodents using a study design that facilitated assessments of micronuclei and Pig-a mutation in circulating erythrocytes, and lacZ mutant frequencies in bone marrow...
December 28, 2018: Environmental and Molecular Mutagenesis
Julie A Cox, Edwin P Zwart, Mirjam Luijten, Paul A White
To develop an improved in vitro mammalian cell gene mutation assay, it is imperative to address the known deficiencies associated with existing assays. Primary hepatocytes isolated from the MutaMouse are ideal for an in vitro gene mutation assay due to their metabolic competence, their "normal" karyotype (i.e., neither transformed nor immortalized), and the presence of the MutaMouse transgene for rapid and reliable mutation scoring. The cells were extensively characterized to confirm their utility...
December 27, 2018: Environmental and Molecular Mutagenesis
Guo-Qiao Zheng, Guang-Hui Zhang, Han-Tian Wu, Yu-Ting Tu, Wei Tian, Yan Fang, Ye Lu, Shi-Yang Gong, Ya-Nan Zhang, Li-Bo Yu, Hong Zhang, Hua Shao, Paul Brandt-Rauf, Zhao-Lin Xia
Vinyl chloride monomer (VCM) is a confirmed carcinogen. The effects of VCM on telomeres and the gene expression of telomere complex proteins, shelterin, have not been well studied but could be of potential relevance to the carcinogenic mechanism of VCM and the health surveillance of VCM-exposed workers. Quantitative polymerase chain reaction was performed to measure relative telomere length (RTL) and gene expression of shelterin proteins among 241 VCM-exposed workers and 101 internal controls from the same plant in Shandong, China...
December 22, 2018: Environmental and Molecular Mutagenesis
Sabrina Wilde, Nina Queisser, Christian Holz, Marian Raschke, Andreas Sutter
The in vitro micronucleus test according to OECD Test Guideline 487 (TG 487) is widely used to investigate the genotoxic potential of drugs. Besides the identification of in vitro genotoxicants, the assay can be complemented with kinetochore staining for the differentiation between clastogens and aneugens. This differentiation constitutes a major contribution to risk assessment as especially aneugens show a threshold response. Thus, a novel method for automated MN plus kinetochore (k+) scoring by image analysis was developed based on the OECD TG 487...
December 18, 2018: Environmental and Molecular Mutagenesis
Ning Ding, Sam A Miller, Sudha S Savant, Heather M O'Hagan
At sites of chronic inflammation epithelial cells undergo aberrant DNA methylation that contributes to tumorigenesis. Inflammation is associated with an increase in reactive oxygen species (ROS) that cause oxidative DNA damage, which has also been linked to epigenetic alterations. We previously demonstrated that in response to ROS, mismatch repair (MMR) proteins MSH2 and MSH6 recruit epigenetic silencing proteins DNA methyltransferase 1 (DNMT1) and Polycomb repressive complex 2 (PRC2) members to sites of DNA damage, resulting in transcriptional repression of tumor suppressor genes (TSGs)...
December 11, 2018: Environmental and Molecular Mutagenesis
L H Pottenger, G Boysen, K Brown, J Cadet, R P Fuchs, G E Johnson, J A Swenberg
The interpretation and significance of DNA adduct data, their causal relationship to mutations, and their role in risk assessment have been debated for many years. An extended effort to identify key questions and collect relevant data to address them was focused on the ubiquitous low MW N7-alkyl/hydroxyalkylguanine adducts. Several academic, governmental, and industrial laboratories collaborated to gather new data aimed at better understanding the role and potential impact of these adducts in quantifiable genotoxic events (gene mutations/micronucleus)...
December 10, 2018: Environmental and Molecular Mutagenesis
Pedro Aurio Maia Filho, Jamilly Florêncio Pereira, Tarcísio Paulo de Almeida Filho, Bruno Coêlho Cavalcanti, Juliana Cordeiro de Sousa, Romélia Pinheiro Gonçalves Lemes
Sickle cell anemia (SCA) is a hereditary hematological disease that is characterized by a point mutation in the beta globin S gene and has no specific treatment; hydroxyurea (HU) is the only therapeutic agent used in clinical practice. In the present study, we evaluated the deoxyribonucleic acid (DNA) damage index (DI) and chromosomal damage in leukocytes of adult patients with SCA with and without HU. The DI was assessed by the comet assay and chromosomal damage by the leukocyte micronucleus test of adult patients treated with HU (SCA-HU) and without the use of HU (SCA-NoHU)...
December 7, 2018: Environmental and Molecular Mutagenesis
Xiao-Fei Jiao, Qiu-Man Liang, Di Wu, Zhi-Ming Ding, Jia-Yu Zhang, Fan Chen, Yong-Sheng Wang, Shou-Xin Zhang, Yi-Liang Miao, Li-Jun Huo
Fluorene-9-bisphenol (BHPF), a substitute of bisphenol A (BPA) used in the production of the so-called "BPA-free" plastics, has now been shown to be released from commercial plastic bottles into drinking water and has strong anti-estrogenic activity in mice, which suggests that BHPF is also an environmental toxin. However, whether BHPF exposure has effects on mouse oocyte development is unknown. In this study, the influence of acute exposure to BHPF (50-150 μM, 12 hr) on mouse oocyte maturation and its possible mechanisms were investigated...
November 30, 2018: Environmental and Molecular Mutagenesis
Yoon Hee Cho, Yoonhee Jang, Hae Dong Woo, Yang Jee Kim, Su Young Kim, Sonja Christensen, Elizabeth Cole, Soo Yong Choi, Hai Won Chung
Global DNA hypomethylation is proposed as a potential biomarker for cancer risk associated with genomic instability, which is an important factor in radiation-induced cancer. However, the associations among radiation exposure, changes in DNA methylation, and carcinogenesis are unclear. The aims of this study were (1) to examine whether low-level occupational radiation exposure induces genomic DNA hypomethylation; and (2) to determine the relationships between radiation exposure, genomic DNA hypomethylation and radiation-induced genomic instability (RIGI) in industrial radiographers...
November 29, 2018: Environmental and Molecular Mutagenesis
Eunnara Cho, Julie K Buick, Andrew Williams, Renxiang Chen, Heng-Hong Li, J Christopher Corton, Albert J Fornace, Jiri Aubrecht, Carole L Yauk
Gene expression biomarkers are now available for application in the identification of genotoxic hazards. The TGx-DDI transcriptomic biomarker can accurately distinguish DNA damage-inducing (DDI) from non-DDI exposures based on changes in the expression of 64 biomarker genes. The 64 genes were previously derived from whole transcriptome DNA microarray profiles of 28 reference agents (14 DDI and 14 non-DDI) after 4 h treatments of TK6 human lymphoblastoid cells. To broaden the applicability of TGx-DDI, we tested the biomarker using quantitative RT-PCR (qPCR), which is accessible to most molecular biology laboratories...
November 29, 2018: Environmental and Molecular Mutagenesis
Fábio Kummrow, Bianca S Maselli, Rafael Lanaro, José Luis Costa, Gisela A Umbuzeiro, Alessandra Linardi
Ayahuasca is a beverage used in religious rituals of indigenous and nonindigenous groups, and its therapeutic potential has been investigated. Ayahuasca is obtained by decoction of the Banisteriopsis caapi that contains β-carbolines (harmine, harmaline, and tetrahydroharmine) plus Psychotria viridis that contains N,N-dimethyltryptamine. Although plants used in folk medicine are recognized as safe, many of them have genotoxic potential. The Salmonella/microsome assay is usually the first line of the mutagenicity evaluation of products intended for therapeutic use...
November 29, 2018: Environmental and Molecular Mutagenesis
Alejandro Mosquera, Ignacio Rego-Pérez, Francisco J Blanco, José Luis Fernández
Relative mean telomere sequence amount was determined by quantitative PCR (qPCR) of peripheral blood leukocyte (PBL) samples obtained at recruitment (n = 310) from individuals from the Osteoarthritis (OA) Initiative consortium. Knees were radiologically evaluated according to the Kellgren-Lawrence (KL) score, ranging from 0 to 4, considering a KL grade ≥ 2 as radiographic evidence of OA (n = 124). Telomere size decreased as baseline KL score increased, being significantly shorter in subjects with KL ≥2 (Mann-Whitney U-test, P < 0...
November 29, 2018: Environmental and Molecular Mutagenesis
Zuquan Weng, Yuhong Shi, Megumi Suda, Yukie Yanagiba, Toshihiro Kawamoto, Tamie Nakajima, Rui-Sheng Wang
Previous experiments showed that high concentrations of ethyl tertiary butyl ether (ETBE) exposure (500-5,000 ppm) significantly resulted in DNA damages in aldehyde dehydrogenase 2 (Aldh2) knockout (KO) mice. This study was aimed to verify the genotoxic effects in three genetic types, Aldh2 KO, heterogeneous (HT), and wild type (WT), of mice exposed to lower concentrations of ETBE (50-500 ppm) by inhalation. Histopathology assessments in the livers, measurements of genotoxic biomarkers in blood and livers, and urinary 8-hydroxydeoxyguanosion (8-OH-dG) for the oxidative DNA damage of whole body were performed...
November 25, 2018: Environmental and Molecular Mutagenesis
Anne Fernandez-Vidal, Liana C Arnaud, Manon Maumus, Marianne Chevalier, Gladys Mirey, Bernard Salles, Julien Vignard, Elisa Boutet-Robinet
The classification of the fungicide captan (CAS Number: 133-06-2) as a carcinogen agent is presently under discussion. Despite the mutagenic effect detected by the Ames test and carcinogenic properties observed in mice, the genotoxicity of this pesticide in humans is still unclear. New information is needed about its mechanism of action in mammalian cells. Here we show that Chinese Hamster Ovary (CHO) cells exposed to captan accumulate Fpg-sensitive DNA base alterations. In CHO and HeLa cells, such DNA lesions require the XRCC1-dependent pathway to be repaired and induce a replicative stress that activated the ATR signalling response and resulted in double-strand breaks and micronuclei...
November 24, 2018: Environmental and Molecular Mutagenesis
Katarzyna H Maslowska, Karolina Makiela-Dzbenska, Iwona J Fijalkowska
Genomes of all living organisms are constantly threatened by endogenous and exogenous agents that challenge the chemical integrity of DNA. Most bacteria have evolved a coordinated response to DNA damage. In Escherichia coli, this inducible system is termed the SOS response. The SOS global regulatory network consists of multiple factors promoting the integrity of DNA as well as error-prone factors allowing for survival and continuous replication upon extensive DNA damage at the cost of elevated mutagenesis. Due to its mutagenic potential, the SOS response is subject to elaborate regulatory control involving not only transcriptional derepression, but also post-translational activation and inhibition...
November 16, 2018: Environmental and Molecular Mutagenesis
Miroslav Mišík, Armen Nersesyan, Claudia Bolognesi, Michael Kundi, Franziska Ferk, Siegfried Knasmueller
One of the main problems of in vitro genotoxicity tests is the inadequate representation of drug metabolizing enzymes in most indicator cell lines which are currently used. We identified recently a human derived liver cell line (Huh6) which detected induction of DNA damage by representatives of different groups of promutagens without enzyme mix and showed that these cells are more suitable in terms of reproducibility and sensitivity as other currently used liver derived lines. We developed a protocol for micronucleus (MN) cytome assays with these cells and validated the procedure in experiments with representatives of different groups of directly and indirectly acting genotoxic carcinogens (MMS, cisplatin, PhIP, IQ, NDMA, B(a)P, AFB1, etoposide, and H2 O2 )...
November 8, 2018: Environmental and Molecular Mutagenesis
Xihan Guo, Xueqin Dai, Juan Ni, Xiaoling Ma, Jinglun Xue, Xu Wang
Geraniin has been reported to specifically induce apoptosis in multiple human cancers, but the underlying mechanism is poorly defined. The spindle assembly checkpoint (SAC) is a surveillance system to ensure high-fidelity chromosome segregation during mitosis. Weakening of SAC to enhance chromosome instability (CIN) can be therapeutic because very high levels of CIN are lethal. In this study, we have investigated the effects of geraniin on the SAC of colorectal cancer HCT116 cells and noncancerous colon epithelial CCD841 cells...
November 7, 2018: Environmental and Molecular Mutagenesis
Bhawana Bariar, C Greer Vestal, Bradley Deem, Donna Goodenow, Mimi Ughetta, R Warren Engledove, Mark Sahyouni, Christine Richardson
Infant acute leukemias are aggressive and characterized by rapid onset after birth. The majority harbor translocations involving the MLL gene with AF9 as one of its most common fusion partners. MLL and AF9 loci contain breakpoint cluster regions (bcrs) with sequences hypothesized to be targets of topoisomerase II inhibitors that promote translocation formation. Overlap of MLL bcr sequences associated with both infant acute leukemia and therapy-related leukemia following exposure to the topoisomerase II inhibitor etoposide led to the hypothesis that exposure during pregnancy to biochemically similar compounds may promote infant acute leukemia...
November 2, 2018: Environmental and Molecular Mutagenesis
Guifang Jin, Lu Cai, Keqi Hu, Yuyi Luo, Yuting Chen, Hansruedi Glatt, Yungang Liu
Human CYP2E1 metabolizes many xenobiotics of low molecular weight, thereby activating various promutagens/procarcinogens. In toxicological studies in vitro, dimethylsulfoxide (DMSO) is a common vehicle for organic compounds. However, it was observed to potently inhibit CYP2E1 activity. We were interested in whether it affects CYP2E1-dependent mutagenic responses. In this study, N-nitrosodiethylamine (NDEA), which is soluble in both water and DMSO, was used as a model promutagen. It induced Hprt gene mutations and micronuclei in a Chinese hamster V79-derived cell line expressing both human CYP2E1 and sulfotransferase (SULT) 1A1 (V79-hCYP2E1-hSULT1A1) even at low micromolar concentrations, but was inactive in parental V79 cells...
November 1, 2018: Environmental and Molecular Mutagenesis
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