Genes and Environment最新文献

Background: 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.

Results: 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.

Conclusion: 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.

Background: 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.

Results: 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.

Conclusion: The G^O:A pair induced the action-at-a-distance mutations through base excision by the MUTYH glycosylase.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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.

Introduction: 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.

Findings: 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.

Conclusion: 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.

Background: 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.

Results: 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.

Conclusions: 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.

Background: Toluene diisocyanates (TDIs) are high-production-volume chemicals widely used in polyurethane manufacturing. A typical commercial-grade TDI (TDI; 2,4-toluene diisocyanate: 2,6-toluene diisocyanate; 80:20), CAS: 26471-62-5, is mutagenic in Salmonella typhimurium with an S9 metabolic activation mix and induces chromosomal aberrations in Chinese hamster lung cells without S9 mix. While oral administration of TDI has been reported to be carcinogenic in female mice and rats of both sexes, its in vivo mutagenicity remains poorly understood. This study aimed to clarify the in vivo mutagenicity of orally administered TDI. In vivo mutagenicity was evaluated following the Organisation for Economic Co-operation and Development Test Guideline 488 (OECD TG488). MutaMouse females were orally dosed with TDI at 0 (corn oil; vehicle control), 250, 500, or 1,000 mg/kg/day for 28 days. Mutant frequencies (MFs) in the liver and glandular stomach were analyzed three days post-final dosing. Positive controls received intraperitoneal injections of N-ethyl-N-nitrosourea (ENU) at 100 mg/kg/day for two days, with MFs assessed ten days after the final dose.

Results: Significant increases in lacZ MFs were observed in the liver at 1,000 mg/kg/day, while MFs in the glandular stomach remained unchanged. Positive controls demonstrated significantly elevated MFs in both the liver and glandular stomach.

Conclusions: These findings indicate that orally administered TDI is mutagenic in mice, supporting its classification as a mutagenic carcinogen.

N-nitrosopyrrolidine (NPYR) is a volatile nitrosamine that is thought to be a human carcinogen. It is found in air, wastewater, food, and feed. Photo-activation of NPYR can occur as it drifts through the environment. We previously found that NPYR irradiated in phosphate buffer was directly mutagenic without metabolic activation or simultaneous irradiation. Here, we aimed to determine NPYR activity after UVA irradiation. The mutagenic activity of irradiated NPYR was relatively stable, and ~ 23% of it persisted after 168 h of storage at 37 °C. Micronuclei (MN) were also found without metabolic activation in human-derived keratinocytes (HaCaT cells) after NPYR irradiation in vitro and the peripheral blood reticulocytes (PBRs) of mice with inhibited cytochrome-P450-mediated metabolism then injected with irradiated NPYR in vivo. The active photoproduct of NPYR is thought to be genotoxic to bone marrow, resulting in MN formation in PBRs. The action spectrum of MN formation in PBRs exposed to NPYR irradiated with monochromatic light was plotted along the absorption curve. The production ratio of active NPYR photoproduct followed the NPYR absorption curve. Genotoxicity becomes systemic with externally irradiated NPYR that penetrates the skin or when NPYR is irradiated just under the skin and enters the systemic circulation. Risk analyses of public health-related volatile N-nitrosamines generated via environmental photoactivation including NPYR, should be considered.

This article outlines the history and development of Genes and Environment, the official journal of the Japanese Environmental Mutagen and Genome Society (JEMS). In the 1970s, there was growing concern about the mutagenicity of chemical substances, leading to the establishment of JEMS. The society began publishing its journal, Environmental Mutagen Research, and renamed Genes and Environment in 2006 to focus on gene-environment interactions and promote international collaboration. The journal transitioned to free-access and started publishing in English to expand its reach globally.From 2012, the journal partnered with BioMed Central (BMC) to become an open-access publication, leading to its inclusion in Scopus, PubMed, and SCIE, and an improvement in its CiteScore and Impact Factor. JEMS also sought funding from Japan's Grants-in-Aid for Scientific Research (KAKENHI) to support international dissemination of research.Despite progress, challenges remain, such as limited submissions from certain regions and a need for greater global recognition. To further internationalize JEMS, efforts are being made to elevate the quality of research and broaden membership diversity, with a focus on making JEMS' activities and publications more accessible to the global scientific community.