Genes and Environment最新文献

{"title":"Environmental factors in gastric carcinogenesis and preventive intervention strategies.","authors":"Yuzhi Tan, Juntaro Matsuzaki, Yoshimasa Saito, Hidekazu Suzuki","doi":"10.1186/s41021-025-00328-w","DOIUrl":"10.1186/s41021-025-00328-w","url":null,"abstract":"<p><p>Gastric cancer, a significant global health concern, arises from a complex interplay of genetic and environmental factors. Helicobacter pylori (H. pylori) infection is a major risk factor that can be mitigated through eradication strategies. Epstein-Barr virus (EBV) infection causes a distinct subtype of gastric cancer called EBV-associated gastric cancer. The gastric microbiome, a dynamic ecosystem, is also involved in carcinogenesis, particularly dysbiosis and specific bacterial species such as Streptococcus anginosus. Long-term use of proton pump inhibitors and potassium-competitive acid blockers also increases the risk of gastric cancer, whereas non-steroidal anti-inflammatory drugs including aspirin may have a protective effect. Smoking significantly increases the risk, and cessation can reduce it. Dietary factors such as high intake of salt, processed meats, and red meat may increase the risk, whereas a diet rich in fruits and vegetables may be protective. Extracellular vesicles, which are small membrane-bound structures released by cells, modulate the tumor microenvironment and may serve as biomarkers for risk stratification and as therapeutic targets in gastric cancer. This review highlights the multifaceted etiology of gastric cancer and its risk factors and emphasizes the importance of a multi-pronged approach to prevention including H. pylori eradication and modification of lifestyle factors, as well as the potential of microbiome-based and EV-based interventions. Further research is needed to refine risk stratification and to develop personalized prevention strategies.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"5"},"PeriodicalIF":2.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer prevention: past challenges and future directions.","authors":"HeeKyung Seong, Runa Izutsu, Mitsuhiko Osaki, Futoshi Okada","doi":"10.1186/s41021-025-00326-y","DOIUrl":"10.1186/s41021-025-00326-y","url":null,"abstract":"<p><p>Almost 70 years have passed since the molecular mechanism of carcinogenesis was hypothesized to involve multiple gene mutations. More than 1,000 cancer-related genes, including oncogenes and tumor suppressor genes, accelerate carcinogenesis by altering molecular functions and gene expression through mutations and epigenetic changes and have been shown to cause multistep carcinogenesis in several organ cancers. The elucidation of cancer-related gene abnormalities has led to the development of molecular-targeted therapies that focus on driver molecules, known as precision medicine, in addition to conventional treatments such as surgery, radiotherapy, and chemotherapy. Now that the mechanism of cancer development has been largely elucidated, options for cancer treatment and its outcomes have improved, and cancer research is moving to the next stage: cancer prevention. Cancer prevention using chemicals was first proposed approximately 50 years ago. It is the concept of stabilizing, arresting, or reverting precancerous lesions to normal tissues using synthetic vitamin A analogs (retinoids). Cancer chemoprevention is now considered to consist of three elements: \"primary prevention,\" which prevents the development of tumors and prevents benign tumors converting into more malignant ones; \"secondary prevention,\" which aims for early detection through cancer screening and treatment; and \"tertiary prevention,\" which reduces the risk of recurrence and extends the time until death from cancer through treatment. Consequently, there is no clear boundary between the prevention and treatment strategies. Therefore, chemoprevention targets the entire process, from normal cells to precancerous lesions, malignant progression of tumors, and death by cancer. Basic and clinical research has revealed that cancer prevention is influenced by race, regional, and national differences, as well as individual differences such as genetic factors, environmental factors, and lifestyle habits. This review provides an overview of the progress made in cancer prevention and summarizes future directions.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"4"},"PeriodicalIF":2.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"History of the Organisation for Economic Co-operation and Development (OECD) test guidelines for non-animal test methods in Japan.","authors":"Hajime Kojima","doi":"10.1186/s41021-024-00323-7","DOIUrl":"10.1186/s41021-024-00323-7","url":null,"abstract":"<p><p>The number of alternatives to animal tests (non-animal test methods) for human health developed globally account for more than 40% of the test methods in the Organisation for Economic Co-operation and Development (OECD) Guidelines for the Testing of Chemicals (TGs). Within the TGs, the National Institute of Health Sciences (NIHS) has standardized 16 OECD TGs for human health, implemented four major revisions, and developed one test method for the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S10 guidelines on photosafety. This review describes trends in the OECD and Japan that mainly focus on international standardizations of non-animal test methods for human health. Drawing from this experience, I hope Japan will advance new approach methodologies for detecting systemic toxicity, which are in global demand.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"3"},"PeriodicalIF":2.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased matrix metalloproteinase-1 expression by coexposure to UVA and cigarette sidestream smoke and contribution of histone acetylation.","authors":"Ryoma Ito, Yukako Komaki, Yuko Ibuki","doi":"10.1186/s41021-025-00325-z","DOIUrl":"10.1186/s41021-025-00325-z","url":null,"abstract":"<p><strong>Background: </strong>Skin is exposed to various environmental factors throughout life, and some of these factors are known to contribute to skin aging. Long-term solar UV exposure is a well-known cause of skin aging, as is cigarette smoke, which contains a number of chemicals. In this study, combined effect of UVA and cigarette sidestream smoke (CSS) on matrix metalloproteinase-1 (MMP-1) induction was investigated. MMP-1 is the main protease that initiates collagen type I fiber fragmentation in human skin and is associated with aging.</p><p><strong>Results: </strong>Combined exposure to UVA and CSS enhanced MMP-1 induction, accompanied by collagen type I (COL1A1) gene suppression. The basal expression of MMP-1 was higher in senescent cells than in normal cells, with a pronounced increase after coexposure to UVA and CSS. UVA irradiation resulted in global histone H3 acetylation, and we considered this was responsible for the MMP-1 upregulation. Histone deacetylase inhibitors, sodium acetate, propionate, and butyrate, all enhanced the CSS-induced MMP-1 according to the degree of histone acetylation.</p><p><strong>Conclusion: </strong>These results suggest that UVA and CSS additively induce MMP-1, which may lead to skin aging, and that such combined effect may further promote aging in aged skin. UVA-induced histone acetylation may contribute to MMP-1 induction.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"2"},"PeriodicalIF":2.7,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diurnal and daily fluctuations in levels of the urinary oxidative stress marker 8-hydroxyguanosine in spot urine samples.","authors":"Yun-Shan Li, Koichi Fujisawa, Kazuaki Kawai","doi":"10.1186/s41021-025-00324-0","DOIUrl":"10.1186/s41021-025-00324-0","url":null,"abstract":"<p><strong>Background: </strong>Urinary 8-hydroxyguanosine (8-OHGuo) levels serve as a biomarker for oxidative stress and hydroxyl radical-induced RNA damage. Evaluating the diurnal and daily fluctuations in urinary 8-OHGuo excretion levels is essential for understanding its implications. However, research in this area remains limited. In this study, we aim to investigate the diurnal and daily fluctuations in 8-OHGuo levels as well as the factors that influence these variations, using spot urine samples.</p><p><strong>Methods: </strong>Urine samples were collected from seven healthy participants during each urination from the time of awakening until 24:00 h to evaluate diurnal variations. To assess daily fluctuations, urine samples were collected from 18 healthy participants at the time of awakening for 23 consecutive days. The urinary 8-OHGuo levels were measured using an HPLC-ECD method.</p><p><strong>Results: </strong>No significant variations were observed in the diurnal levels of urinary 8-OHGuo among non-smokers. Conversely, the daily variation of 8-OHGuo in the urine of the smoker was significant, with a coefficient of variation of 18.71%. Each individual maintained a characteristic value despite some diurnal fluctuations. Furthermore, the daily levels of 8-OHGuo exhibited a range of variations influenced by lifestyle factors, including mental state, sleep duration, smoking, menstrual cycle, and dietary habits.</p><p><strong>Conclusion: </strong>As a specific marker of RNA oxidation, 8-OHGuo provides unique insights distinct from those provided by the widely used DNA oxidation marker 8-hydroxydeoxyguanosine as an indicator of oxidative stress. Urinary 8-OHGuo could serve as a valuable biomarker for managing and preventing oxidative stress-related diseases, provided that the specific range of daily variations is established. The high daily variation in urinary 8-OHGuo levels necessitates the use of multiple samples to accurately determine individual levels. However, further research with large sample sizes will help to validate these findings.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"1"},"PeriodicalIF":2.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Four functional genotoxic marker genes (Bax, Btg2, Ccng1, and Cdkn1a) discriminate genotoxic hepatocarcinogens from non-genotoxic hepatocarcinogens and non-genotoxic non-hepatocarcinogens in rat public toxicogenomics data, Open TG-GATEs.","authors":"Chie Furihata, Takayoshi Suzuki","doi":"10.1186/s41021-024-00322-8","DOIUrl":"10.1186/s41021-024-00322-8","url":null,"abstract":"<p><strong>Background: </strong>Previously, Japanese Environmental Mutagen and Genome Society/Mammalian Mutagenicity Study Group/Toxicogenomics Study Group (JEMS/MMS toxicogenomic study group) proposed 12 genotoxic marker genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2, and Tubb4b) to discriminate genotoxic hepatocarcinogens (GTHCs) from non-genotoxic hepatocarcinogens (NGTHCs) and non-genotoxic non-hepatocarcinogens (NGTNHCs) in mouse and rat liver using qPCR and RNA-Seq and confirmed in public rat toxicogenomics data, Open TG-GATEs, by principal component analysis (PCA). On the other hand, the U.S. Environmental Protection Agency (US EPA) suggested seven genotoxic marker genes (Bax, Btg2, Ccng1, Cgrrf1, Cdkn1a, Mgmt, and Tmem47) with Open TG-GATEs data. Four genes (Bax, Btg2, Ccng1, and Cdkn1a) were common in these two studies. In the present study, we examined the performance of these four genes in Open TG-GATEs data using PCA.</p><p><strong>Results: </strong>The study's findings are of paramount significance, as these four genes proved to be highly effective in distinguishing five typical GTHCs (2-acetylaminofluorene, aflatoxin B1, 2-nitrofluorene, N-nitrosodiethylamine and N-nitrosomorpholine) from seven typical NGTHCs (clofibrate, ethanol, fenofibrate, gemfibrozil, hexachlorobenzene, phenobarbital, and WY-14643) and 11 NGTNHCs (allyl alcohol, aspirin, caffeine, chlorpheniramine, chlorpropamide, dexamethasone, diazepam, indomethacin, phenylbutazone, theophylline, and tolbutamide) by PCA at 24 h after a single administration with 100% accuracy. These four genes also effectively distinguished two typical GTHCs (2-acetylaminofluorene and N-nitrosodiethylamine) from seven NGTHCs and ten NGTNHCs by PCA on 29 days after 28 days-repeated administrations, with a similar or even better performance compared to the previous 12 genes. Furthermore, the study's analysis revealed that the three intermediate GTHC/NGTHCs (methapyrilene, monocrotaline, and thioacetamide, which were negative in the Salmonella test but positive in the in vivo rat liver test) were located in the intermediate region between typical GTHCs and typical NGTHCs by PCA.</p><p><strong>Conclusions: </strong>The present results unequivocally demonstrate the availability of four genotoxic marker genes ((Bax, Btg2, Ccng1, and Cdkn1a) and PCA in discriminating GTHCs from NGTHCs and NGTNHCs in Open TG-GATEs. These findings strongly support our recommendation that future rat liver in vivo toxicogenomics tests prioritize these four genotoxic marker genes, as they have proven to be highly effective in discriminating between different types of hepatocarcinogens.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"46 1","pages":"28"},"PeriodicalIF":2.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damage.","authors":"Xingxing Shao, Hailang Hou, Huijie Chen, Wan Xia, Xinpu Geng, Jindao Wang","doi":"10.1186/s41021-024-00321-9","DOIUrl":"10.1186/s41021-024-00321-9","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) is the most common histological type of non-small cell lung cancer (NSCLC). Platinum-based chemotherapy, such as cisplatin chemotherapy, is the cornerstone of treatment for LUAD patients. Nevertheless, cisplatin resistance remains the key obstacle to LUAD treatment, for its mechanism has not been fully elucidated.</p><p><strong>Methods: </strong>HSD17B6 mRNA expression data were accessed from TCGA-LUAD database and differential expression analysis was performed. Enrichment analysis of HSD17B6 was conducted by GSEA, and its upstream transcription factors were predicted by hTFtarget. mRNA and protein expression levels of HSD17B6 and GATA1 were assayed by qRT-PCR and WB, and the binding relationship between them was verified by chromatin immunoprecipitation assay and dual luciferase reporter assay. Cell viability and IC₅₀ value of cisplatin-treated cells were measured by cell counting kit-8 assay. Cell cycle was assayed by flow cytometry. DNA damage level and DNA damage marker γ-H2AX expression were assayed by comet assay and western blot, respectively.</p><p><strong>Results: </strong>HSD17B6 was lowly expressed in LUAD tissues and cells and mainly enriched in homologous recombination and mismatch repair pathways. As cell function experiments revealed, overexpression of HSD17B suppressed malignant phenotypes and cisplatin resistance in LUAD cells through DNA damage. Bioinformatics analysis revealed that GATA1 is the upstream regulator of HSD17B6, which was markedly reduced in LUAD tissues and cells. ChIP and dual luciferase reporter assays ascertained the binding of GATA1 to HSD17B6. Knockdown of GATA1 attenuated the effect of overexpression of HSD17B6 on LUAD cell behaviors and cisplatin resistance.</p><p><strong>Conclusion: </strong>Transcription factor GATA1 could activate HSD17B6 to inhibit cisplatin resistance in LUAD through DNA damage, suggesting that GATA1/HSD17B6 axis may be a potential therapeutic target for chemotherapy resistance in LUAD patients.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"46 1","pages":"27"},"PeriodicalIF":2.7,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11654308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A study for the genotoxicity assessment of substances containing probiotic candidates in the in vitro TK6 cell micronucleus test: Influence of low pH conditions and antibiotic supplementation on the test results.","authors":"Yohei Fujiishi, Wakako Ohyama, Emiko Okada","doi":"10.1186/s41021-024-00320-w","DOIUrl":"10.1186/s41021-024-00320-w","url":null,"abstract":"<p><strong>Background: </strong>When assessing the genotoxicity of substances containing probiotic candidates, such as lactic acid-producing bacteria, using the in vitro micronucleus test (MNT), bacterial growth in the test medium may reduce the pH of the medium. The low medium pH is known to induce cytotoxicity and false-positive results. In the TK6 cell system, it is difficult to completely remove the bacteria from the medium by washing post-treatment, leading to bacterial growth during the recovery period in the short-term treatment. In the present study, the low pH range yielding false positives in the TK6 cell MNT was investigated using media supplemented with acetic, lactic, or formic acids, which are non-genotoxic bacterial metabolites. Additionally, to suppress the bacterial growth during the recovery period using antibiotics, i.e., penicillin/streptomycin (P/S), gentamicin sulfate (GM), and amphotericin B (AP), the maximum applicable concentrations of them that did not affect TK6 cell growth or micronucleus induction were determined. Then, we conducted an MNT using a substance containing live lactic acid-producing bacteria to verify the effectiveness of the antibiotics.</p><p><strong>Results: </strong>Acetic, lactic, and formic acids induced micronuclei in TK6 cells (false positive) at an initial pH of ≤ 6.2 and ≤ 6.0 in 3 h treatment with and without S9 mix, respectively, and of ≤ 6.7 in the continuous treatment. Media supplemented with P/S, GM, and AP did not affect TK6 cell growth or micronucleated cell frequencies in the negative and positive controls ≤ 400 unit/mL-400 µg/mL, ≤ 250, and ≤ 20 µg/mL, respectively. In an MNT with fermented milk containing live lactic acid-producing bacteria, supplementation with P/S or GM to media for the recovery cultures suppressed the bacterial growth, decreasing pH, and cytotoxicity.</p><p><strong>Conclusion: </strong>This study revealed the low pH ranges yielding false positives in the TK6 cell MNT under short-term and continuous treatment conditions. These values will serve as references for interpreting the biological relevance of results. Under short-term treatment, optimal antibiotic supplementation in recovery cultures suppressed bacterial growth in the test substance and prevented the decrease in pH that could yield false positives. This approach might be useful for evaluating the genotoxicity of test substances containing probiotic candidates using the MNT.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"46 1","pages":"26"},"PeriodicalIF":2.7,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11654278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the role of oxidative stress and mitochondrial dysfunction in β-damascone-induced aneuploidy.","authors":"Tsuneo Hashizume, Satoru Munakata, Tomohiro Takahashi, Taku Watanabe","doi":"10.1186/s41021-024-00319-3","DOIUrl":"10.1186/s41021-024-00319-3","url":null,"abstract":"<p><strong>Background: </strong>The rose ketone β-damascone (β-Dam) elicits positive results in the in vitro micronucleus (MN) assay using human lymphocytes, but shows negative outcomes in the Ames test and combined in vivo MN and comet assays. This has led to the interpretation that the in vitro MN result is a misleading positive result. Oxidative stress has been suggested as an indirect mode of action (MoA) for in vitro MN formation, with the α, β-unsaturated carbonyl moiety of the β-Dam chemical structure expected to cause misleading positive results through this MoA. In this study, we investigated the role of oxidative stress in β-Dam-induced in vitro MN formation by co-treatment with the antioxidant N-acetyl-L-cysteine (NAC), thereby highlighting a possible link between mitochondrial dysfunction and aneugenicity.</p><p><strong>Results: </strong>β-Dam induced MN formation in both CHL/IU and BEAS-2B cells, with the response completely inhibited by co-treatment with NAC. Moreover, β-Dam induced oxidative stress-related reporter activity in the ToxTracker assay and increased reactive oxygen species levels, while decreasing glutathione levels, in BEAS-2B cells in the high-content analysis. All of these effects were suppressed by NAC co-treatment. These findings indicate that β-Dam elicits oxidative stress, which causes DNA damage and ultimately leads to MN induction. However, no significant DNA damage-related reporter activities were observed in the ToxTracker assay, nor was there an increased number of γH2AX foci in the high-content analysis. These data suggest that MN formation is not a DNA-reactive MoA. Considering recent reports of aneuploidy resulting from chromosome segregation defects caused by mitochondrial dysfunction, we investigated if β-Dam could cause such dysfunction. We observed that the mitochondrial membrane potential was dose-dependently impaired in BEAS-2B cells exposed to β-Dam.</p><p><strong>Conclusions: </strong>These findings suggest that the oxidative stress induced by β-Dam exposure may be explained through an aneugenic MoA via mitochondrial dysfunction, thereby contributing to MN formation in mammalian cells.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"46 1","pages":"25"},"PeriodicalIF":2.7,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local QSAR based on quantum chemistry calculations for the stability of nitrenium ions to reduce false positive outcomes from standard QSAR systems for the mutagenicity of primary aromatic amines.","authors":"Shigeharu Muto, Ayako Furuhama, Mika Yamamoto, Yasuteru Otagiri, Naoki Koyama, Seiji Hitaoka, Yusuke Nagato, Hirofumi Ouchi, Masahiro Ogawa, Kisako Shikano, Katsuya Yamada, Satoshi Ono, Minami Hoki, Fumiya Ishizuka, Soichiro Hagio, Chiaki Takeshita, Hisayoshi Omori, Kiyohiro Hashimoto, Satsuki Chikura, Masamitsu Honma, Kei-Ichi Sugiyama, Masayuki Mishima","doi":"10.1186/s41021-024-00318-4","DOIUrl":"10.1186/s41021-024-00318-4","url":null,"abstract":"<p><strong>Background: </strong>Primary aromatic amines (PAAs) present significant challenges in the prediction of mutagenicity using current standard quantitative structure activity relationship (QSAR) systems, which are knowledge-based and statistics-based, because of their low positive prediction values (PPVs). Previous studies have suggested that PAAs are metabolized into genotoxic nitrenium ions. Moreover, ddE, a relative-energy based index derived from quantum chemistry calculations that measures the stability nitrenium ions, has been correlated with mutagenicity. This study aims to further examine the ability of the ddE-based approach in improving QSAR mutagenicity predictions for PAAs and to develop a refined method to decrease false positive predictions.</p><p><strong>Results: </strong>Information on 1,177 PAAs was collected, of which 420 were from public databases and 757 were from in-house databases across 16 laboratories. The total dataset included 465 Ames test-positive and 712 test-negative chemicals. For internal PAAs, detailed Ames test data were scrutinized and final decisions were made using common evaluation criteria. In this study, ddE calculations were performed using a convenient and consistent protocol. An optimal ddE cutoff value of -5 kcal/mol, combined with a molecular weight ≤ 500 and ortho substitution groups yielded well-balanced prediction scores: sensitivity of 72.0%, specificity of 75.9%, PPV of 65.6%, negative predictive value of 80.9% and a balanced accuracy of 74.0%. The PPV of the ddE-based approach was greatly reduced by the presence of two ortho substituent groups of ethyl or larger, as because almost all of them were negative in the Ames test regardless of their ddE values, probably due to steric hindrance affecting interactions between the PAA and metabolic enzymes. The great majority of the PAAs whose molecular weights were greater than 500 were also negative in Ames test, despite ddE predictions indicating positive mutagenicity.</p><p><strong>Conclusions: </strong>This study proposes a refined approach to enhance the accuracy of QSAR mutagenicity predictions for PAAs by minimizing false positives. This integrative approach incorporating molecular weight, ortho substitution patterns, and ddE values, substantially can provide a more reliable basis for evaluating the genotoxic potential of PAAs.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"46 1","pages":"24"},"PeriodicalIF":2.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}