Genes and Environment最新文献

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.

The 47th Annual Conference and the Golden Jubilee Year Meeting of the Environmental Mutagen Society of India (EMSI) and International Conference on Environmental and Molecular Mutagenesis: Genomic Integrity and Implication to Human Health was held at the Department of Biochemistry and Biotechnology, Annamalai University, Tamil Nadu, India, during January 29-31, 2025. Among the 18 international speakers, the former president of The Japanese Environmental Mutagen and Genome Society, the former and present presidents of UK Environmental Mutagen Societies (EMS) and the Office Bearers of the Indian EMS participated in the conference. The pre-conference workshop was held at the same venue one day before the main conference. Plenary and invited lecturers spoke about the assay systems, study parameters, biomarkers of disease onset, regulatory issues, and technological advancements in mutagenicity and carcinogenicity research. In brief: the effects of pesticides, heavy metals, nanoparticles, pharmaceutical impurities, UV-radiation, etc. on DNA damage and alterations in signalling and metabolic pathways were discussed. Discussion on errors in DNA-repair leading to disease-onset, remediation of genotoxicity with phytochemicals, identification of drug candidates, and progress in technological advancements such as error corrected Next Generation Sequencing (ecNGS) justified the theme of the Mutagen Societies. Altogether, 12 plenaries, 37 invited lectures, and general presentations, including 42 oral and 80 posters made the conference a grand success through lively interactive discussions. The organising team and EMSI expressed sincere thanks and gratitude to all the participants.

Background: The mechanism of protein modification by 2,4-alkadienals (ADE), lipid peroxidation products prevalent in fried foods, was investigated through model reactions.

Results: A mixture of 2,4-heptadienal (HDE) and hemin was initially incubated at pH 3.0-7.4, followed by treatment with acetyl-cysteine (AcCys) and acetyl-lysine (AcLys) at pH 7.4. Analysis via HPLC revealed a product with a characteristic UV spectrum as the primary peak. This product was identified as an AcCys-pyrrole-AcLys (CPL) crosslink derived from AcCys, 2-butene-1,4-dial (BDA), and AcLys. Increasing the HDE concentration in the initial reaction led to maximum CPL formation at pH 3.5 in the presence of hemin. Lowering the HDE concentration with a higher Cys/HDE ratio resulted in CPL formation, which was observed at pH 7.4 and 3.5 in the presence of hemin. Upon incubation of ADE and hemin at pH 3.0-3.5, BDA was directly identified as 2,4-dinitrophenylhydrazone. BDA was also detected in the 2,4-decadienal reaction mixture. Additionally, a notable propensity for high BDA-dC adduct formation with hemin under acidic conditions was observed, consistent with the results of CPL assay and BDA-2,4-dinitrophenylhydrazone analysis.

Conclusions: 1) BDA is efficiently generated from ADE in the presence of hemin under gastric conditions, and 2) BDA-derived CPL can also form under physiological conditions (pH 7.4) through the interaction of ADE, hemin, Cys, and Lys. BDA is recognized as the primary reactive metabolite of the suspected carcinogen furan (IARC, 2B). Given that human intake of ADE exceeds that of furan and acrylamide (IARC 2A) by several orders of magnitude, and the estimated hemin concentration in the stomach post-meal is comparable to the present study, a substantial amount of BDA may form in the stomach following consumption of fried foods and meat. The risk assessment of ADE warrants a thorough re-evaluation, based on the toxicity mechanism of BDA.

Background: Bleomycin (Bleo) is a glycopeptide with potent antitumor activity that induces DNA double-strand breaks (DSBs) through free radical generation, similar to ionizing radiation (IR). Therefore, Bleo is considered a radiomimetic drug. However, differences in DNA repair mechanisms between IR- and Bleo-induced DNA damage have not been fully elucidated. Therefore, in the present study, we examined a panel of repair-deficient human TK6 cell lines to elucidate the relative contributions of individual repair factors.

Results: Our comprehensive profiling indicated that both non-homologous end joining (NHEJ) and homologous recombination (HR) contributed to DSB repair induced by X-rays and Bleo. Furthermore, tyrosyl-DNA phosphodiesterase (TDP)-related repair was a significant factor for cellular sensitivity to Bleo treatment. TDP1^-/-/TDP2^-/- cells exhibited greater sensitivity to Bleo than TDP1^-/- or TDP2^-/- cells, but not to X-rays. In addition, we determined whether TDP2 is involved in the repair of Bleo-induced DSBs using a neutral comet assay. In TDP1-deficient cells, knockout of TDP2 resulted in a significant delay in the repair kinetics of DSBs induced by Bleo, but not by X-rays.

Conclusions: The contribution of the TDP-related pathway to DSB repair significantly differed between IR and radiomimetic drugs. The discovery of this novel TDP2-dependent repair of DSBs resulting from radiomimetic drug exposure indicates that TDP1 and TDP2 inhibition in combination with radiomimetic drugs represents a strategy for cancer treatment.