Hong Liu, Ryo Inoue, Mihoko Koyanagi, Shim-Mo Hayashi, Gen Watanabe, Kentaro Nagaoka
{"title":"Comparison of the fecal bacterial microbiota in mice, rats, and pigs after oral administration of alpha-glycosyl isoquercitrin.","authors":"Hong Liu, Ryo Inoue, Mihoko Koyanagi, Shim-Mo Hayashi, Gen Watanabe, Kentaro Nagaoka","doi":"10.2131/jts.49.151","DOIUrl":"10.2131/jts.49.151","url":null,"abstract":"<p><p>Alpha-glycosyl isoquercitrin (AGIQ) is composed of isoquercitrin and its glucosylated derivatives and has many biological activities, including anti-inflammatory, antioxidant, and anti-cancer properties. However, the effect of AGIQ administered orally on gut microbiota composition remains unclear. The objective of this study was to evaluate the effect of AGIQ on the gut microbiota of animals in different dose groups. Male rats and mice received different doses of AGIQ (1.5%, 3%, or 5% w/v) in diet for carcinogenic or chronic toxicity studies (rasH2 mice: 6 months; Sprague-Dawley rats: 12 months). Male minipigs received 100, 300, or 1000 mg/kg/day for 28 days. Fecal samples were collected from the different animal species and analyzed using 16S-rRNA gene sequencing. No significant changes were observed in alpha and beta diversity of the gut microbiota. Characteristic bacteria that responded to AGIQ were identified in each animal species, and, interestingly, Kineothrix alysoides, a butyrate-producing bacterium, was commonly detected in all three species, suggesting that it may be related to the biological activities of AGIQ. AGIQ selectively modulated the number of beneficial butyrate-producing commensal bacterium beneficial bacteria without changing the diversity of gut microbiota, which further supports the safe use of AGIQ in food products.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 4","pages":"151-161"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140331802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryoki Kunita, Takafumi Nishijima, Hiroaki Todo, Masaaki Miyazawa
{"title":"Integrating mathematical approaches (IMAS): Novel methodology for predicting dermal absorption rates of chemicals under finite dose conditions.","authors":"Ryoki Kunita, Takafumi Nishijima, Hiroaki Todo, Masaaki Miyazawa","doi":"10.2131/jts.49.219","DOIUrl":"https://doi.org/10.2131/jts.49.219","url":null,"abstract":"<p><p>Quantitative structure permeation relationship (QSPR) models have gained prominence in recent years owing to their capacity to elucidate the influence of physicochemical properties on the dermal absorption of chemicals. These models facilitate the prediction of permeation coefficient (Kp) values, indicating the skin permeability of a chemical under infinite dose conditions. Conversely, obtaining dermal absorption rates (DAs) under finite dose conditions, which are crucial for skin product safety evaluation, remains a challenge when relying solely on Kp predictions from QSPR models. One proposed resolution involves using Kroes' methodology, categorizing DAs based on Kp values; however, refinement becomes necessary owing to discreteness in the obtained values. We previously developed a mathematical model using Kp values obtained from in vitro dermal absorption tests to predict DAs. The present study introduces a new methodology, Integrating Mathematical Approaches (IMAS), which combines QSPR models and our mathematical model to predict DAs for risk assessments without conducting in vitro dermal absorption tests. Regarding 40 chemicals (76.1 ≤ MW ≤ 220; -1.4 ≤ Log K<sub>o/w</sub> ≤ 3.1), IMAS showed that 65.0% (26/40) predictions of DA values were accurate to within twofold of the observed values in finite dose experiments. Compared to Kroes' methodology, IMAS notably mitigated overestimation, particularly for hydrophilic chemicals with water solubility exceeding 57.0 mg/cm<sup>3</sup>. These findings highlight the value of IMAS as a tool for skin product risk assessments, particularly for hydrophilic compounds.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 5","pages":"219-230"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140858801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lung carcinogenicity by whole body inhalation exposure to Anatase-type Nano-titanium Dioxide in rats.","authors":"Tatsuya Kasai, Shigeyuki Hirai, Yuske Furukawa, Kyouhei Misumi, Tomoki Takeda, Yuko Goto, Kenji Takanobu, Kengo Yoneyama, Shotaro Yamano, Hideki Senoh, Yumi Umeda","doi":"10.2131/jts.49.359","DOIUrl":"https://doi.org/10.2131/jts.49.359","url":null,"abstract":"<p><p>To investigate the carcinogenicity of anatase-type nano-titanium dioxide (aNTiO<sub>2</sub>), F344/DuCrlCrlj rats were exposed to aNTiO<sub>2</sub> aerosol at concentrations of 0, 0.5, 2, and 8 mg/m<sup>3</sup>. The rats were divided into 2 groups: carcinogenicity study groups were exposed for two years, and satellite study groups were exposed for one year followed by recovery for 1 day, 26 weeks, and 52 weeks after the end of exposure. In the carcinogenicity groups, bronchiolo-alveolar carcinomas were observed in two 8 mg/m<sup>3</sup>-exposed males, showing an increasing trend by Peto's test. However, this incidence was at the upper limit of JBRC's historical control data. Bronchiolo-alveolar adenomas were observed in 1, 2, 3, and 4 rats of the 0, 0.5, 2, and 8 mg/m<sup>3</sup>-exposed females and were not statistically significant. However, the incidence in the 8 mg/m<sup>3</sup>-exposed females exceeded JBRC's historical control data. Therefore, we conclude there is equivocal evidence for the carcinogenicity of aNTiO<sub>2</sub> in rats. No lung tumors were observed in the satellite groups. Particle-induced non-neoplastic lesions (alveolar epithelial hyperplasia and focal fibrosis) were observed in exposed males and females in both the carcinogenicity and satellite groups. Increased lung weight and neutrophils of bronchoalveolar lavage fluid were observed in the 8 mg/m<sup>3</sup>-exposed carcinogenicity groups. The aNTiO<sub>2</sub> deposited in the lungs of the satellite group rats was decreased at 26 weeks after the end of exposure compared to 1 day after the end of exposure. At 52 weeks after the end of exposure, the decreased level was the same at 26 weeks after the end of exposure.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 8","pages":"359-383"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Investigation of normalization procedures for transcriptome profiles of compounds oriented toward practical study design.","authors":"Tadahaya Mizuno, Hiroyuki Kusuhara","doi":"10.2131/jts.49.249","DOIUrl":"https://doi.org/10.2131/jts.49.249","url":null,"abstract":"<p><p>The transcriptome profile is a representative phenotype-based descriptor of compounds, widely acknowledged for its ability to effectively capture compound effects. However, the presence of batch differences is inevitable. Despite the existence of sophisticated statistical methods, many of them presume a substantial sample size. How should we design a transcriptome analysis to obtain robust compound profiles, particularly in the context of small datasets frequently encountered in practical scenarios? This study addresses this question by investigating the normalization procedures for transcriptome profiles, focusing on the baseline distribution employed in deriving biological responses as profiles. Firstly, we investigated two large GeneChip datasets, comparing the impact of different normalization procedures. Through an evaluation of the similarity between response profiles of biological replicates within each dataset and the similarity between response profiles of the same compound across datasets, we revealed that the baseline distribution defined by all samples within each batch under batch-corrected condition is a good choice for large datasets. Subsequently, we conducted a simulation to explore the influence of the number of control samples on the robustness of response profiles across datasets. The results offer insights into determining the suitable quantity of control samples for diminutive datasets. It is crucial to acknowledge that these conclusions stem from constrained datasets. Nevertheless, we believe that this study enhances our understanding of how to effectively leverage transcriptome profiles of compounds and promotes the accumulation of essential knowledge for the practical application of such profiles.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 6","pages":"249-259"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Transcriptome analysis of cultured human vascular endothelial cells after γ-ray irradiation and correlation analysis with ATP, ADP, and adenosine as secondary soluble factors.","authors":"Tomoya Fujie, Miyabi Kobayashi, Lihito Ikeuchi, Tsuyoshi Nakano, Kazuki Kitabatake, Yo Shinoda, Yasuyuki Fujiwara, Chika Yamamoto, Mitsutoshi Tsukimoto, Toshiyuki Kaji","doi":"10.2131/jts.49.193","DOIUrl":"10.2131/jts.49.193","url":null,"abstract":"<p><p>Vascular endothelial cells serve as barriers between blood components and subendothelial tissue and regulate the blood coagulation-fibrinolytic system. Ionizing radiation is a common physical stimulant that induces a bystander effect whereby irradiated cells influence neighboring cells through signalings, including purinergic receptor signaling, activated by adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), and adenosine as secondary soluble factors. Human vascular endothelial EA.hy926 cells were cultured and irradiated with γ-rays or treated with ATP, ADP, or adenosine under non-toxic conditions. RNA-seq, gene ontology, and hierarchical clustering analyses were performed. The transcriptome analysis of differentially expressed genes in vascular endothelial cells after γ-ray irradiations suggests that the change of gene expression by γ-irradiation is mediated by ATP and ADP. In addition, the expression and activity of the proteins related to blood coagulation and fibrinolysis systems appear to be secondarily regulated by ATP and ADP in vascular endothelial cells after exposure to γ-irradiation. Although it is unclear whether the changes of the gene expression related to blood coagulation and fibrinolysis systems by γ-irradiation affected the increased hemorrhagic tendency through the exposure to γ-irradiation or the negative feedback to the activated blood coagulation system, the present data indicate that toxicity associated with γ-irradiation involves the dysfunction of vascular endothelial cells related to the blood coagulation-fibrinolytic system, which is mediated by the signalings, including purinergic receptor signaling, activated by ATP and ADP.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 4","pages":"193-208"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140331866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Valproic acid elevates HIF-1α-mediated CGB expression and suppresses glucose uptake in BeWo cells.","authors":"Go Kitahara, Kazuma Higashisaka, Yurina Nakamoto, Rena Yamamoto, Wakako Okuno, Momoe Serizawa, Yuji Sakahashi, Hirofumi Tsujino, Yuya Haga, Yasuo Tsutsumi","doi":"10.2131/jts.49.69","DOIUrl":"10.2131/jts.49.69","url":null,"abstract":"<p><p>Placental dysfunction can disrupt pregnancy. However, few studies have assessed the effects of chemical-induced toxicity on placental function. Here, we examined the effects of valproic acid (VPA) as a model chemical on production of hormones and on glucose uptake in human choriocarcinoma cell line BeWo. Cells were treated with forskolin to differentiate into syncytiotrophoblasts, which were then treated with VPA for 72 hr. Real-time RT-PCR analysis showed that VPA significantly increased the mRNA expression of chorionic gonadotropin β (CGB), a hormone that is produced by the placenta in the first trimester of pregnancy, relative to that in the forskolin-only group. It also suppressed the increase in intracellular glucose uptake and GLUT1 level observed in the forskolin-only group. RNA-seq analysis and pathway database analysis revealed that VPA consistently decreased the level of HIF-1α protein and expression of its downstream target genes HK2 and ADM in the hypoxia pathway. Cobalt chloride, a HIF-1α inducer, inhibited CGB upregulation in VPA-treated cells and rescued VPA-induced suppression of glucose uptake and GLUT1 level. Thus, HIF-1α-mediated elevation of CGB expression and suppression of glucose uptake by VPA is a novel mechanism of placental dysfunction.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 2","pages":"69-77"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139723211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Paternal methamphetamine exposure differentially affects first and second generations in mice.","authors":"Sakiko Munetomo-Aoki, Asuka Kaizaki-Mitsumoto, Ryota Nakano, Satoshi Numazawa","doi":"10.2131/jts.49.9","DOIUrl":"https://doi.org/10.2131/jts.49.9","url":null,"abstract":"<p><p>Amphetamine-type stimulants are abused worldwide, and methamphetamine (METH) accounts for a large majority of seized abused drug cases. Recently, the paternal origin of health and disease theory has been proposed as a concept wherein paternal factors influence descendants. Although METH abuse is more common among males, its effects on their descendants were not examined. Therefore, we investigated the effects of paternal METH exposure on F1 and F2 levels in a mouse model. Sires were administered METH for 21 days and mated with female mice to obtain F1 mice. Growth evaluations (number of births, survival rate, body weight, righting reflex, cliff avoidance tests, and wire-hanging maneuver) were performed on F1 mice. Upon reaching six weeks of age, the mice were subjected to spontaneous locomotion, elevated plus-maze, acute METH treatment, and passive avoidance tests. Additionally, RNA-seq was performed on the striatum of male mice. Male F1 mice were mated with female mice to obtain F2 mice. They were subjected to the same tests as the F1 mice. Paternal METH exposure resulted in delayed growth and decreased memory function in F1 mice, overweight in F2 mice, decreased METH sensitivity, and reduced anxiety-related behaviors in female F2 mice. Enrichment analysis revealed significant enrichment of terms related to behavior in F1 and protein folding in F2. These results indicated that the effects of paternal METH exposure vary across generations. The effects of paternal factors need to be examined not only in F1, but also in F2 and beyond.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 1","pages":"9-26"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dihydropyrazine induces endoplasmic reticulum stress and inhibits autophagy in HepG2 human hepatoma cells.","authors":"Shinji Takechi, Madoka Sawai, Yuu Miyauchi","doi":"10.2131/jts.49.313","DOIUrl":"https://doi.org/10.2131/jts.49.313","url":null,"abstract":"<p><p>Dihydropyrazines (DHPs) are formed by non-enzymatic glycation reactions in vivo and in food. We recently reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), which is a methyl-substituted DHP, caused severe oxidative stress and cytotoxicity. However, the molecular mechanisms underlying the cytotoxic pathways of the DHP response remain elusive. Because oxidative stress induces endoplasmic reticulum (ER) stress and autophagy, we investigated the ability of DHP-3 to modulate the ER stress and autophagy pathways. DHP-3 activated the ER stress pathway by increasing inositol-requiring enzyme 1 (IRE1) and PKR-like ER kinase (PERK) phosphorylation and transcription factor 6 (ATF6) expression. Moreover, DHP-3 increased the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), which are downstream targets of PERK. In addition, DHP-3 inhibited the autophagy pathway by increasing the accumulation of microtubule-associated protein 1 light chain 3 alpha-phosphatidylethanolamine conjugate (LC3-II) and p62/sequestosome 1 (p62), while decreasing autophagic flux. Taken together, these results indicate that DHP-3 activates the ER stress pathway and inhibits the autophagy pathway, suggesting that the resulting removal of damaged organelles is inadequate.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 7","pages":"313-319"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Monitoring method for uranium concentration and chemical form in the droplet of rat serum.","authors":"Akihiro Uehara, Izumi Tanaka, Hiroshi Ishihara, Daisuke Akiyama, Akira Kirishima, Shino Homma-Takeda","doi":"10.2131/jts.49.543","DOIUrl":"https://doi.org/10.2131/jts.49.543","url":null,"abstract":"<p><p>A simple monitoring method has been proposed by measuring uranium (U) concentration and its chemical form in serum. The droplet of the 1 µL rat serum specimen was then examined by subjecting it to high energy synchrotron radiation X-ray fluorescence spectroscopy (SR-XRF) and X-ray absorption fine structure (XAFS) to determine the concentration and chemical form of U. The detection limit of U in 1 µL droplet was calculated to be 0.071 µg/g. The U concentration in the specimen obtained from the rat exposed to U was consistent with that determined by inductively coupled plasma mass spectrometry. Uranium in the rat serum was estimated to be hexavalent U based on the standard specimens of tetravalent and hexavanet U. This method developed might be used for monitoring and decorporation of patients at nuclear disasters and environmental pollution.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 12","pages":"543-548"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A simple air-liquid interface exposure system for exposing cultured human 3D epidermis and cornea to PM2.5 collected through cyclonic separation.","authors":"Maori Kono, Masayuki Takaishi, Tomoaki Okuda, Masashi Fujihara, Seisuke Noguchi, Yasuhiro Ishihara","doi":"10.2131/jts.49.61","DOIUrl":"10.2131/jts.49.61","url":null,"abstract":"<p><p>Particulate matter (PM) is among the major air pollutants suspended in the atmosphere. PM2.5 has a particle size of 2.5 µm; it is known to cause inflammation, especially in the respiratory tract and skin. Since the skin acts a primary barrier against harmful environmental substances that may enter the body, it is highly exposed to PM2.5 present in the environment. However, the adverse health effects of PM2.5 exposure on human skin have not been accurately examined due to the lack of a system that exposes human epidermal tissue to the actual environmental concentration of PM2.5. In this study, we developed an air-liquid interface exposure system for exposing cultured human 3D epidermis and cornea to PM2.5 collected through cyclonic separation. PM2.5 suspension was nebulized in an acrylic chamber, and the resulting mist was pumped through a diffusion dryer into a glass exposure chamber. A particle counter was connected to the exposure chamber to continuously measure the spatial mass concentration of PM. Human 3D epidermis was cultured in the exposure chamber. Exposure of the human 3D epidermis to PM aerosol increased interleukin-8 release into the media around 50 µg/m<sup>3</sup>. Mass concentrations above 100 µg/m<sup>3</sup> caused cell death. Furthermore, a human corneal model showed similar responses against PM2.5 exposure as 3D epidermis. The air-liquid interface exposure system developed in this study is considered useful for evaluating the health effects induced by environmental PM2.5 and can be used as an alternative to experiments involving actual human or animals.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 2","pages":"61-68"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139723210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}