Genes and Environment最新文献

{"title":"Mitomycin C-induced DNA double-strand breaks are enhanced by catalytical inactivation of DNA polymerase κ in mice.","authors":"Naoko A Wada, Akira Takeiri, Shigeki Motoyama, Kaori Matsuzaki, Kenji Tanaka, Saori Matsuo, Etsuko Fujii-Takeiri, Hiromi Tateishi, Kaoru Matsumoto, Naoko Niimi, Akira Sassa, Petr Grúz, Kenichi Masumura, Masayuki Mishima, Kou-Ichi Jishage, Kei-Ichi Sugiyama, Takehiko Nohmi","doi":"10.1186/s41021-025-00343-x","DOIUrl":"10.1186/s41021-025-00343-x","url":null,"abstract":"<p><strong>Background: </strong>DNA polymerase κ (Polk), a member of Y-family DNA polymerases, plays an important role in translesion DNA synthesis (TLS), allowing DNA replication forks to bypass DNA damage or DNA adducts to continue daughter strand synthesis. Polk is also believed to contribute to the replication-independent repair of DNA lesions such as cross-links. TLS circumvents stalls of DNA replication and promotes gap filling in DNA repair which would otherwise result in DNA double-strand breaks (DSBs) and cell death. Mitomycin C (MMC) is a widely used chemotherapeutic drug which generates DNA cross-links and induces DSBs. To clarify how Polk contributes to the prevention of MMC-induced DSB in various organs or tissues, immunohistochemical staining of γH2AX was conducted in catalytically inactivated Polk knock-in (Polk KI) mice and Polk wild-type (Polk⁺) mice treated with MMC or saline.</p><p><strong>Results: </strong>The γH2AX induction by MMC was enhanced by inactivation of Polk across many organs or tissues to varying degrees. Obvious enhancement was observed in liver, bladder, adrenal cortex, thyroid, and spermatids, whereas less enhancement was shown in brain and retina. The results suggest that Polk plays a role in preventing DSBs caused by MMC in most organs or tissues. Elevated DSB frequencies were observed in both proliferative cells, such as bladder epithelium cells, and less or slowly proliferative cells, such as hepatocytes. Increased DSB levels in inactivated Polk KI mice relative to Polk⁺ mice were also observed in saline-treated mice in the adrenal cortex and other tissues.</p><p><strong>Conclusion: </strong>Polk plays a systemic role in mitigating MMC-induced DSBs, likely through both DNA replication-dependent and -independent mechanisms. Furthermore, Polk appears to protect against DSBs caused by endogenous mutagens in some organs such as the adrenal cortex, prostate, and retina.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"22"},"PeriodicalIF":2.0,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12590760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458324","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":"In vitro and in vivo antimutagenic activity of Echinops spinosus crude extract and its aqueous fraction in mouse bone marrow and spleen.","authors":"Kawthar A Diab, Ayman A Farghaly, Entesar E Hassan, Maha A Fahmy, Emad M Hassan, Zeinab M Hassan","doi":"10.1186/s41021-025-00341-z","DOIUrl":"10.1186/s41021-025-00341-z","url":null,"abstract":"<p><strong>Background: </strong>Echinops spinosus (ES), known as spiny globe thistle, has been widely used in traditional medicine to treat various ailments, such as splenic and renal disorders. However, the genoprotective effect of ES has not been examined previously. This report assessed the in vitro and in vivo genoprotective effects of crude extract of Echinops spinosus (CEES) and its aqueous fraction (AFES) against ethyl methanesulfonate (EMS) in mice. This study applied a battery of genotoxic endpoints, including chromosomal aberrations (CAs), the comet assay, and the micronucleus (MN) assay. Further, GC-MS and HPLC analyses were employed to identify the primary and secondary metabolites in the plant samples, respectively. Total polyphenol and flavonoid contents (TPC and TFC) were also colorimetrically measured. In vitro experiments were conducted using cultured primary mouse bone marrow and spleen. These cells were treated with two concentrations of CEES or AFES (250 and 500 µg/mL; for 24 h), followed by EMS treatment (300 µg/mL; for two hours) before the harvest. For the in vivo experiments, mice were orally administered CEES and AFES (250, 500 mg/kg; for 7 days), with or without intraperitoneal injection with EMS (300 mg/kg; for 24 h).</p><p><strong>Results: </strong>GC-MS analysis demonstrated 25 primary metabolites in AFES, and the nitrogenous compound bis(trimethylsilyl) ethylamine was the main constituent. HPLC analysis reported 17 and 14 secondary compounds in CEES and AFES, respectively, in which chlorogenic acid was the main constituent in both samples. Colorimetric analysis showed that CEES exhibited higher TPC and TFC compared to AFES. Genotoxic results showed that EMS increased the levels of CAs and comet tail formation in vitro bone marrow and splenic cultures. Further, EMS caused chromosomal damage, as indicated by a significant increase in the frequency of CAs and MN in vivo mouse bone marrow cells. Supplementation with CEES and AFES alleviated chromosomal and DNA damage induced by EMS, and this reduction was more pronounced in vivo than in vitro experiments.</p><p><strong>Conclusion: </strong>High-polar constituents primarily mediated the antimutagenic activity of CEES and AFES. Meanwhile, other phytoconstituents in CEES, such as moderately polar and nonpolar constituents, synergistically potentiated the genoprotective activity, resulting in greater efficacy of CEES than AFES.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"21"},"PeriodicalIF":1.9,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12587627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145444615","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":"The Chinese herb component salvianolic acid B induces copper-mediated reactive oxygen species generation and oxidative DNA damage.","authors":"Hatasu Kobayashi, Kiyoshi Fukuhara, Akiko Ohno, Yuichiro Hirao, Hiroshi Katoh, Yurie Mori, Shosuke Kawanishi, Mariko Murata, Shinji Oikawa","doi":"10.1186/s41021-025-00344-w","DOIUrl":"10.1186/s41021-025-00344-w","url":null,"abstract":"<p><strong>Background: </strong>Salvianolic acid B (Sal B), a natural polyphenol with potential therapeutic applications, has been reported to induce reactive oxygen species (ROS) generation. However, its underlying mechanism has not yet been fully elucidated. In this study, we investigated copper-mediated oxidative DNA damage induced by Sal B.</p><p><strong>Results: </strong>Sal B significantly increased the level of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in HL-60 cells, but not in H₂O₂-resistant HP100 cells. The formation of 8-oxodG was inhibited by a Cu(I)-specific chelator. These results suggested that Cu(I) and H₂O₂ play critical roles in this process. In calf thymus DNA, Sal B induced 8-oxodG formation in the presence of Cu(II), which was markedly enhanced in the presence of NADH. Using ³²P-5'-end-labeled DNA fragments, we showed that treatment with Sal B in combination with Cu(II) and NADH caused DNA strand breaks and site-specific base modification, especially at thymine and cytosine residues. These results suggest the involvement of ROS other than •OH and this was further supported by radical scavenger experiments. Furthermore, theoretical calculation data suggest that one of the catechol groups in Sal B is electron-donating. Collectively, these results indicate that Cu(II)-mediated autoxidation of the catechol group in Sal B generates Cu(I) and H₂O₂, likely leading to a Cu(I)-hydroperoxide complex formation and resultant oxidative DNA damage. NADH enhances ROS production and oxidative DNA damage by reducing oxidized Sal B and promoting its recycling.</p><p><strong>Conclusions: </strong>The potential pro-oxidant risk of Sal B should be carefully evaluated when used as a therapeutic agent.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"20"},"PeriodicalIF":1.9,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12574035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408791","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":"Oxidative stress accelerates repeat sequence instability and base substitutions promoting gastrointestinal driver mutations in MSH2 deficient mice.","authors":"Mizuki Ohno, Noriko Takano, Kyoko Hidaka, Fumiko Sasaki, Yasunobu Aoki, Takehiko Nohmi, Teruhisa Tsuzuki","doi":"10.1186/s41021-025-00342-y","DOIUrl":"10.1186/s41021-025-00342-y","url":null,"abstract":"<p><strong>Background: </strong>Loss of DNA mismatch repair (MMR) increases mutagenesis and tumorigenesis. mutS homolog 2 (MSH2), a central component of the MMR pathway, is essential for correcting base-base mismatches and insertion/deletion loops during DNA replication. To investigate how Msh2 deficiency cooperates with oxidative stress to drive mutagenesis and tumorigenesis, we employed an rpsL reporter gene assay using normal tissues before tumor development following treatment with an oxidizing agent.</p><p><strong>Results: </strong>The background mutation frequency in the small intestines of Msh2^-/- mice was over 20-fold higher than that of wild-type mice. In addition to G > A base substitutions, frequent 1-bp deletions in adenine mononucleotide repeats ((A)n) in the rpsL gene were observed. Potassium bromate treatment further increased the mutation frequency, particularly insertion-deletion mutations (indel), in the normal small intestinal epithelium of Msh2^-/- mice before tumor development. Mutation signature analysis from next-generation sequencing data revealed that signatures associated with MMR deficiency (SBS15, SBS44, and ID2) and clock-like processes (SBS1 and SBS5) were consistently detected across all Msh2^-/- tumors, similar to those observed in human MMR-deficient cancers. ID2, which involves 1-base deletions occurring in (A/T)_n tracts of six bases or longer, supports the findings of the rpsL assay. Microsatellite instability (MSI) analysis showed that indel mutations at (A)n loci detected using the rpsL assay reflect genome-wide MSI. Msh2^-/- tumors frequently harbored driver mutations, such as frameshift mutations in short tandem repeats within Apc and G > A substitutions in Ctnnb1, both of which activate the Wnt signaling pathway. Oxidative stress further accelerated these mutational processes.</p><p><strong>Conclusion: </strong>Oxidative stress promotes repeat-associated mutagenesis, which manifests as MSI and base substitutions in MMR-deficient intestinal tissues, thereby enhancing the mutator phenotype and increasing the overall mutation burden. This process can be sensitively captured using our rpsL assay, which serves as a functional indicator of MMR deficiency and replication instability in normal tissues before tumor formation. This increases the likelihood of driver mutations in oncogenes and tumor suppressor genes, ultimately accelerating early tumorigenesis. This study demonstrated that MSH2 is essential for maintaining genome stability under oxidative conditions and functions as a key suppressor of oxidative stress-induced tumorigenesis.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"19"},"PeriodicalIF":1.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12548293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354588","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":"Action-at-a-distance mutations by 8-oxo-7,8-dihydroguanine: adenine pair triggered by MUTYH.","authors":"Ruriko Fukushima, Tetsuya Suzuki, Hiroyuki Kamiya","doi":"10.1186/s41021-025-00340-0","DOIUrl":"10.1186/s41021-025-00340-0","url":null,"abstract":"<p><strong>Background: </strong>8-Oxo-7,8-dihydroguanine (8-hydroxyguanine, G^O) is a major damaged base caused by oxidation. Misincorporation of dATP opposite G^O by DNA polymerases leads to a G:C→T:A transversion at the damaged site via G^O:A intermediate formation. The G^O:A pair is also formed by 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate incorporation opposite A. The G^O:C and G^O:A pairs are both repaired through the base excision repair (BER) pathway to suppress the G:C→T:A mutations. G^O:C also induces action-at-a-distance mutations around the damaged base. These untargeted mutations seem to be induced through the excision of G^O from G^O:C by DNA glycosylases, such as OGG1 and NEIL1, in the BER pathway. The adenine base of G^O:A is excised by a specific adenine DNA glycosylase, MUTYH, and this excision potentially induces action-at-a-distance mutations.</p><p><strong>Results: </strong>In this study, plasmid DNA bearing a G^O:A pair was introduced into human U2OS cells to investigate the untargeted mutations by the G^O:A pair. The G^O:A pair induced action-at-a-distance mutations at C bases in 5'-TpC-3' of the G^O-strand, in contrast to those by G^O:C, which elicit mutations at G bases of 5'-GpA-3'. Furthermore, the untargeted mutations were suppressed by the MUTYH knockdown.</p><p><strong>Conclusion: </strong>The G^O:A pair induced the action-at-a-distance mutations through base excision by the MUTYH glycosylase.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"18"},"PeriodicalIF":1.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12529804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307811","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":"Smoking and the risk of prostate cancer: a review of risk and disease progression.","authors":"Ishvaria Sundaresan, Nallasivam Palanisamy, Radha Saraswathy","doi":"10.1186/s41021-025-00338-8","DOIUrl":"10.1186/s41021-025-00338-8","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer is still the most common malignancy affecting men worldwide, with causes ranging from genetics to environmental and lifestyle factors. This review narrows its attention to investigate smoking as a risk factor for the start and progression of prostate cancer. While age, ethnic differences, family history, and genetic abnormalities such as BRCA1 and BRCA2 remain important, smoking-particularly long-term and heavy use-emerges as a modifiable risk factor that needs deeper consideration. Though this review attempts to offer a worldwide perspective on smoking and prostate cancer risk, we also include a focus on new research from India, given the country's particular regional patterns and growing evidence.</p><p><strong>Methods: </strong>A systematic review of PubMed, Scopus, and Web of Science was undertaken using \"smoking\" and \"prostate cancer.\" The criteria for selecting articles were relevancy, developing research, and accessibility. The exclusion criteria eliminated non-human research and associated issues. This study examined worldwide patterns, however primarily focused on tobacco use and prostate cancer in India according to recent findings. Regional research emphasised smoking and prostate cancer risk patterns and mechanisms.</p><p><strong>Results: </strong>Tobacco use is still a substantial risk factor for several malignancies, including prostate cancer. Globally, smoking has been associated with an increased risk of getting prostate cancer, with research indicating that smokers had a greater prevalence of aggressive illness. Tobacco usage is very common in India owing to a variety of cultural, societal, and economic variables; hence it is a key focus of this research. The effect of tobacco in prostate cancer risk in India is still being studied, and the data shows that smoking in the Indian population may worsen the development and progression of prostate cancer, similar to worldwide patterns but with regional differences.</p><p><strong>Conclusions: </strong>Understanding how smoking affects prostate cancer may improve prevention and early diagnosis, which has public health consequences. These methods may involve targeted screening or lifestyle changes. This review emphasis smoking as a key prostate cancer risk factor, focusing on new Indian findings. More research is required to assess smoking's full impact on prostate cancer risk, particularly in different populations and locations.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"17"},"PeriodicalIF":1.9,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12512299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258008","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":"Genetics and environmental determinants of Alzheimer's disease and related dementias in older Africans: a narrative review.","authors":"Tobi Olajide, Oluwatimilehin Oladapo, Chukwuebuka Asogwa, Gideon Olajide, Ayomide Oyekan, Ayomide Fatola, Timileyin Olanrewaju, Damola Oyegbile, Ikechukwu Ugbo, Henry Oyoyo, Ridwan Kamarudeen, Olawale Famakin","doi":"10.1186/s41021-025-00332-0","DOIUrl":"10.1186/s41021-025-00332-0","url":null,"abstract":"<p><p>The burden of Alzheimer's disease and related dementias (ADRD) is rising in Africa, yet research remains limited compared to high-income regions. This narrative review investigated the genetic and environmental determinants of ADRD in older African populations, with a focus on the apolipoprotein E (APOE) gene. Although APOE ε4 is a strong risk factor for Alzheimer's disease globally, its role in African populations appears less pronounced and variable, likely due to genetic diversity, evolutionary adaptations, and environmental interactions. We discussed the epidemiology of dementia in Africa, contrasting urban and rural patterns, and examined the distribution and effects of APOE alleles across African regions. Additionally, we reviewed how environmental exposures-including malaria, hypertension, HIV, heavy metals, pesticides, vitamin D deficiency, and air pollution-interact with APOE genotypes to influence cognitive decline. Critical challenges such as healthcare disparities, diagnostic inconsistencies, and underrepresentation in genomic studies were highlighted. Finally, we emphasized the need for longitudinal, multicenter research and initiatives like the African Dementia Consortium to bridge knowledge gaps and inform culturally tailored interventions for dementia prevention and care in Africa.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"16"},"PeriodicalIF":1.9,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250814","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":"DNA cross-link repair deficiency enhances human cell sensitivity to colibactin-induced genotoxicity.","authors":"Masanobu Kawanishi, Osamu Tsubohira, Ai Ueshima, Yuuta Hisatomi, Yoshimitsu Oda, Michio Sato, Noriyuki Miyoshi, Michihiro Mutoh, Hideki Ishikawa, Keiji Wakabayashi, Takashi Yagi, Kenji Watanabe","doi":"10.1186/s41021-025-00339-7","DOIUrl":"10.1186/s41021-025-00339-7","url":null,"abstract":"<p><strong>Introduction: </strong>Colibactin is a small genotoxic molecule of polyketide produced by a subset of enteric bacteria including certain Escherichia coli (E. coli) harbored in the human gut microbiota. Its biosynthesis is governed by a multistep enzymatic process encoded by the polyketide synthase (pks) gene cluster. Colibactin is thought to exert its carcinogenic potential primarily through the induction of DNA interstrand crosslinks (ICLs); however, the precise mechanisms underlying its genotoxicity remain largely unresolved. In this study, we focused on ICL formation and its associated repair pathways to investigate whether colibactin-induced ICLs play a central role in the induction of chromosomal aberrations and inhibition of cell proliferation.</p><p><strong>Findings: </strong>HAP1 cells deficient in FANCD2, a gene essential for ICL repair, and their wild-type counterparts were infected with colibactin producing (clb⁺) E. coli strains isolated from a Japanese colorectal cancer (CRC) patient. Following recovery culture, the frequency of micronucleated (MN) cells was assessed. The results showed that FANCD2-deficient cells exhibited a significantly higher frequency of MN cells compared to wild-type cells. Additionally, the cytotoxicity of the clb⁺ strains was evaluated using the XTT assay. FANCD2-deficient cells demonstrated higher sensitivity to the clb⁺ E. coli strains than wild-type cells.</p><p><strong>Conclusion: </strong>These findings suggest that colibactin, produced by clb⁺ E. coli, can play a role in the formation of ICLs, thereby contributing significantly to the induction of chromosomal aberrations and the inhibition of human cell proliferation.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"15"},"PeriodicalIF":2.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12451999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124416","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":"Epitranscriptomic alterations induced by environmental toxins: implications for RNA modifications and disease.","authors":"Esther Ugo Alum, Regina Idu Ejemot-Nwadiaro, Mariam Basajja, Daniel Ejim Uti, Okechukwu Paul-Chima Ugwu, Patrick Maduabuchi Aja","doi":"10.1186/s41021-025-00337-9","DOIUrl":"10.1186/s41021-025-00337-9","url":null,"abstract":"<p><p>Epitranscriptomics, the study of chemical modifications on RNA molecules, has emerged as a vital regulatory layer in gene expression. Among the numerous RNA modifications, N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine (Ψ) are particularly significant in maintaining RNA stability, splicing, translation, and cellular function. This review specifically explores how environmental toxins such as heavy metals, air pollutants, pesticides, and endocrine-disrupting chemicals can disrupt RNA modifications, leading to pathophysiological consequences. By focusing on major RNA marks and their associated regulatory enzymes (writers, erasers, and readers), we elucidate the molecular mechanisms through which toxins impair RNA processing and translation. These disruptions have been increasingly linked to disease development, including cancer, neurodegenerative disorders, metabolic syndromes, and immune dysfunction. Moreover, the review highlights recent technological advances such as high-throughput sequencing, mass spectrometry, and CRISPR-based RNA editing that enable detection and characterization of epitranscriptomic changes. Importantly, RNA modifications are dynamic and reversible, making them promising candidates for use as early biomarkers of environmental exposure and disease risk. We also discuss emerging non-canonical RNA modifications and their roles in toxicological responses. The potential of RNA-based biomarkers to enhance environmental health monitoring and precision medicine is significant, although challenges such as methodological standardization, context-specific variability, and clinical translation remain. This synthesis offers a focused, mechanistic perspective on the intersection of RNA biology and environmental toxicology, emphasizing the relevance of RNA modifications as both molecular targets and diagnostic tools in assessing the biological impact of environmental insults. </p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"14"},"PeriodicalIF":2.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784146","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":"Whole genome mutagenicity evaluation using Hawk-Seq™ demonstrates high inter-laboratory reproducibility and concordance with the transgenic rodent gene mutation assay.","authors":"Shoji Matsumura, Sayaka Hosoi, Takako Hirose, Yuki Otsubo, Kazutoshi Saito, Masaaki Miyazawa, Akihiro Kawade, Atsushi Hakura, Dai Kakiuchi, Shoji Asakura, Naoki Koyama, Yuki Okada, Satsuki Chikura, Takafumi Kimoto, Kenichi Masumura, Takayoshi Suzuki, Kei-Ichi Sugiyama","doi":"10.1186/s41021-025-00336-w","DOIUrl":"10.1186/s41021-025-00336-w","url":null,"abstract":"<p><strong>Background: </strong>Error-corrected next-generation sequencing (ecNGS) enables the sensitive detection of chemically induced mutations. Matsumura et al. reported Hawk-Seq™, an ecNGS method, demonstrating its utility in clarifying mutagenicity both qualitatively and quantitatively. To further promote the adoption of ecNGS-based assays, it is important to evaluate their inter-laboratory transferability and reproducibility. Therefore, we evaluated the inter-laboratory reproducibility of Hawk-Seq™ and its concordance with the transgenic rodent mutation (TGR) assay.</p><p><strong>Results: </strong>The Hawk-Seq™ protocol was successfully transferred from the developer's laboratory (lab A) to two additional laboratories (labs B, C). Whole genomic mutations were analyzed independently using the same genomic DNA samples from the livers of gpt delta mice exposed to benzo[a]pyrene (BP), N-ethyl-N-nitrosourea (ENU), and N-methyl-N-nitrosourea (MNU). In all laboratories, clear dose-dependent increases in base substitution (BS) frequencies were observed, specific to each mutagen (e.g. G:C to T:A for BP). Statistically significant increases in overall mutation frequencies (OMFs) were identified at the same doses across all laboratories, suggesting high reproducibility in mutagenicity assessment. The correlation coefficient (r²) of the six types of BS frequencies exceeded 0.97 among the three laboratories for BP- or ENU-exposed samples. Thus, Hawk-Seq™ provides qualitatively and quantitatively reproducible results across laboratories. The OMFs in the Hawk-Seq™ analysis positively correlated (r² = 0.64) with gpt mutant frequencies (MFs). The fold induction of OMFs in the Hawk-Seq™ analysis of ENU- and MNU-exposed samples was at least 14.2 and 4.5, respectively, compared to 6.1 and 2.5 for gpt MFs. Meanwhile, the fold induction of OMFs in BP-exposed samples was ≤ 4.6, compared to 8.2 for gpt MFs. These observations suggest that Hawk-Seq™ demonstrates good concordance with the transgenic rodent (TGR) gene mutation assay, whereas the induction of mutation frequency by each mutagen might not directly correspond.</p><p><strong>Conclusions: </strong>Hawk-Seq™-based whole-genome mutagenicity evaluation demonstrated high inter-laboratory reproducibility and concordance with gpt assay results. Our results contribute to the growing evidence that ecNGS assays provide a suitable, or improved, alternative to the TGR assay.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"13"},"PeriodicalIF":1.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741975","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}