Report on the mutagenicity of flavone derivatives and their contribution to advancing scientific knowledge.

Flavonoids, such as quercetin and kaempferol, and their glycosides, are widely distributed in vegetables and fruits. Sugimura, T. et al.

Bridging toxicological properties of environmental chemicals between animals and humans using healthy organoid systems.

The application of organoids derived from animal tissues and human-induced pluripotent stem cells to safety assessments of environmental chemicals has been introduced over the last decade. One of the objectives of this approach is to develop an alternative method for animal toxicological studies, while another is to focus on the local reactions of chemicals in each organ/tissue. One of the most important goals is bridging the toxicological properties of chemicals between animals and humans, which may be compared on a level playing field using healthy organoids derived from both animals and humans in vitro, excluding species difference in the absorption, distribution, metabolism, and excretion properties of chemicals in vivo.

Development of a genotoxicity/carcinogenicity assessment method by DNA adductome analysis.

Safety evaluation is essential for the development of chemical substances. Since in vivo safety evaluation tests, such as carcinogenesis tests, require long-term observation using large numbers of experimental animals, it is necessary to develop alternative methods that can predict genotoxicity/carcinogenicity in the short term, taking into account the 3Rs (replacement, reduction, and refinement). We established a prediction model of the hepatotoxicity of chemicals using a DNA adductome, which is a comprehensive analysis of DNA adducts that may be used as an indicator of DNA damage in the liver.

DNA Repair and Mutagenesis of ADP-Ribosylated DNA by Pierisin.

Pierisin is a DNA-targeting ADP-ribosyltransferase found in cabbage white butterfly (). Pierisin transfers an ADP-ribosyl moiety to the 2-amino group of the guanine residue in DNA, yielding -(ADP-ribos-1-yl)-2'-deoxyguanosine (-ADPR-dG). Generally, such chemically modified DNA is recognized as DNA damage and elicits cellular responses, including DNA repair pathways.

Pierisin, Cytotoxic and Apoptosis-Inducing DNA ADP-Ribosylating Protein in Cabbage Butterfly.

Pierisin-1 was serendipitously discovered as a strong cytotoxic and apoptosis-inducing protein from pupae of the cabbage butterfly against cancer cell lines. This 98-kDa protein consists of the N-terminal region (27 kDa) and C-terminal region (71 kDa), and analysis of their biological function revealed that pierisin-1 binds to cell surface glycosphingolipids on the C-terminal side, is taken up into the cell, and is cleaved to N- and C-terminal portions, where the N-terminal portion mono-ADP-ribosylates the guanine base of DNA in the presence of NAD to induce cellular genetic mutation and apoptosis. Unlike other ADP-ribosyltransferases, pieisin-1 was first found to exhibit DNA mono-ADP-ribosylating activity and show anti-cancer activity in vitro and in vivo against various cancer cell lines.

Evaluation of the Mechanisms Involved in the Development of Bladder Toxicity following Exposure to Occupational Bladder Cancer Causative Chemicals Using DNA Adductome Analysis.

Occupational exposure to aromatic amines (AAs) is an important risk factor for urinary bladder cancer. This study aimed to evaluate the toxicity of AAs and analyze the carcinogenic mechanisms in rat bladder by comprehensive analysis of DNA adducts (DNA adductome). DNA was extracted from the bladder epithelia of rats treated with AAs, including acetoacet--toluidine (AAOT) and -toluidine (OTD), and adductome analysis was performed.

Induction of DNA Damage in Mouse Colorectum by Administration of Colibactin-producing , Isolated from a Patient With Colorectal Cancer.

Background/aim: Among colorectal cancer-associated intestinal microbiota, colibactin-producing (clb) bacteria are attracting attention. We aimed to clarify the interaction between clb Escherichia coli and normal colorectal epithelial cells in vivo and in vitro.

Materials And Methods: Five-week-old female Balb/c mice were divided in an untreated group, a group treated with clb E.

Establishment of Novel Genotoxicity Assay System Using Murine Normal Epithelial Tissue-Derived Organoids.

Short-/middle-term and simple prediction studies for carcinogenesis are needed for the safety assessment of chemical substances. To establish a novel genotoxicity assay with an mimicking system, we prepared murine colonic/pulmonary organoids from delta mice according to the general procedure using collagenase/dispase and cultured them in a 3D environment. When the organoids were exposed to foodborne carcinogens-2-amino-1-methyl-6-phenylimidazo(4,5-)pyridine (PhIP) and acrylamide (AA)-in the presence of metabolic activation systems, mutation frequencies (MFs) occurring in the gene dose-dependently increased.

Complex Modulating Effects of Dietary Calcium Intake on Obese Mice.

Background/aim: Οverweight and obesity are risk factors for chronic diseases. Dietary calcium has been reported to exert anti-obesity effects. However, the complex modulating effects of calcium intake on obese mice have not been clarified.

-Anisidine Dimer, 2-Methoxy--(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis.

Monocyclic aromatic amines, -toluidine (-Tol) and its structural analog -anisidine (-Ans), are IARC Group 1 and Group 2A urinary bladder carcinogens, respectively, and are involved in metabolic activation and DNA damage. Our recent study revealed that 2-methyl--(2-methylphenyl) benzene-1,4-diamine (MMBD), a -semidine-type homodimer of -Tol, was detected and identified in an reaction of -Tol with S9 mix and urinary samples of -Tol-exposed rats. Potent mutagenic, genotoxic, and cytotoxic activities were reported with MMBD, suggesting its involvement in urinary bladder carcinogenesis.

U.S.-Japan cooperative medical sciences program: 22nd International Conference on Emerging Infectious Diseases in the Pacific Rim.

This review summarizes the presentations given at the 22nd International conference on Emerging Infectious Diseases in the Pacific Rim. The purpose of this annual meeting is to foster international collaborations and address important public health issues in the Asia-Pacific region. This meeting was held in Bangkok in February 2020 and focused on emerging virus infections.

New horizons of DNA adductome for exploring environmental causes of cancer.

Chemical carcinogenesis is focused on the formation of DNA adducts, a form of DNA damage caused by covalent binding of a chemical moiety to DNA. The detection of carcinogen-DNA adducts in human tissues, along with demonstration of mutagenicity/carcinogenicity in experimental systems, and validation of adducts as biomarkers of environmental exposure and indicators of cancer risk in molecular epidemiological studies suggests a pivotal role of DNA adducts in cancer development. However, accurate measurement of DNA adducts in varied biological samples is challenging.

Comprehensive analysis of DNA adducts (DNA adductome analysis) in the liver of rats treated with 1,4-dioxane.

1,4-Dioxane is a genotoxic carcinogen, and its mutagenic properties were recently observed in the liver of guanine phosphoribosyl transferase (gpt) delta transgenic rats. However, the mechanisms of its genotoxicity remain unclear. We analyzed DNA adduct formation in rat livers following 1,4-dioxane treatment.

Novel -Toluidine Metabolite in Rat Urine Associated with Urinary Bladder Carcinogenesis.

-Toluidine (-Tol), a monocyclic aromatic amine, causes bladder cancer in humans and experimental animals and is therefore classified as a Group 1 carcinogen (IARC) in which the carcinogenicity of -Tol is involved in metabolic activation, DNA damage, and DNA adduct formation. In the DNA adduct formation mechanism, -Tol is metabolized by -hydroxylation, -acetoxylation, and then deacetoxylation to produce an electrophilic nitrenium ion, which is able to bind to a DNA base, such as dG-C8. Therefore, dG-C8--Tol is thought to be a plausible DNA adduct of -Tol exposure.

Genotoxicity of micro- and nano-particles of kaolin in human primary dermal keratinocytes and fibroblasts.

Introduction: Kaolin is a clay mineral with the chemical composition AlSiO(OH). It is an important industrial material, and is also used as a white cosmetic pigment. We previously reported that fine particles of kaolin have genotoxic potency to Chinese hamster ovary CHO AA8 cells, and to the lungs of C57BL/6 J and ICR mice.

Biological significance of aminophenyl-β-carboline derivatives formed from co-mutagenic action of β-carbolines and aniline and o-toluidine and its effect on tumorigenesis in humans: A review.

Norharman exists in cigarette smoke and cooked foods and is non-mutagenic among Salmonella strains but mutagenic to S. typhimurium TA98 and YG1024 in the presence of S9 mix and aniline and o-toluidine. Co-mutagenesis of β-carbolines and aniline and o-toluidine occurs through the formation of novel mutagenic aminophenyl-β-carboline derivatives including 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole [aminophenylnorharman] (APNH)] and 9-(4'- amino-3'-methylphenyl)-9H-pyrido[3,4-b]indole [aminomethylphenylnorharman] (AMPNH)].

High information content assays for genetic toxicology testing: A report of the International Workshops on Genotoxicity Testing (IWGT).

We live in an era of 'big data', where the volume, velocity, and variety of the data being generated is increasingly influencing the way toxicological sciences are practiced. With this in mind, a workgroup was formed for the 2017 International Workshops on Genotoxicity Testing (IWGT) to consider the use of high information content data in genetic toxicology assessments. Presentations were given on adductomics, global transcriptional profiling, error-reduced single-molecule sequencing, and cellular phenotype-based assays, which were identified as methodologies that are relevant to present-day genetic toxicology assessments.

DNA Adductome Analysis Identifies -Nitrosopiperidine Involved in the Etiology of Esophageal Cancer in Cixian, China.

Esophageal cancer is prevalent in Cixian, China, but the etiology of this disease remains largely unknown. Therefore, we explored this by conducting a DNA adductome analysis. Both tumorous and nontumorous tissues were collected from patients who underwent surgical procedures at Cixian Cancer Hospital and the Fourth Hospital of Hebei Medical University, which is in a low-incidence area.

Quantitative analysis of mutagenicity and carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in F344 gpt delta transgenic rats.

Quantitative analysis of the mutagenicity and carcinogenicity of the low doses of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the mutagenicity and carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Male F344 gpt delta transgenic rats were fed diets supplemented with 0, 0.

Multifocal origin of occupational cholangiocarcinoma revealed by comparison of multilesion mutational profiles.

Recently identified occupational cholangiocarcinoma among printing workers is characterized by chronic bile duct injuries and precancerous or early cancerous lesions at multiple sites of the bile ducts. These observations suggested the potential multifocal carcinogenesis of the disease. We performed whole-exome analysis of multiple lesions, including the invasive carcinomas and precancerous lesions of four occupational cholangiocarcinoma cases.

Establishment of an in vivo simulating co-culture assay platform for genotoxicity of multi-walled carbon nanotubes.

Engineered nanomaterials (ENM) are now used in a wide variety of fields, and, thus, their safety should urgently be assessed and secured. It has been suggested that inflammatory responses via the phagocytosis of ENM by macrophages is a key mechanism for their genotoxicity. The present study was conducted to establish a mechanism-based assay to evaluate the genotoxicity of ENM under conditions simulating an in vivo situation, featuring a co-culture system of murine lung resident cells (GDL1) and immune cells (RAW264.