Journal of Toxicological Sciences最新文献

{"title":"Per- and polyfluoroalkyl substances: toxicokinetics, exposure and health risks.","authors":"Yukiko Fujii, Kouji H Harada","doi":"10.2131/jts.50.97","DOIUrl":"10.2131/jts.50.97","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are a group of chemicals containing stable per- or polyfluoroalkyl groups. Recent epidemiological studies have shown that PFAS cause health risks even at low concentrations. This review outlines the toxicokinetics, exposure and health risks of PFAS, with a focus on perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and long-chain perfluoroalkyl carboxylic acids (LC-PFCAs). These compounds are known to interact with various proteins in vivo, including the peroxisomal proliferator-activated receptor-α (PPARα). PFOA and PFOS have been identified as carcinogenic. It is known that PFOA and PFOS are transported by transporters such as organic anion transporter. Significant species differences in the behavior of these compounds exist, with much longer half-lives in humans than in mice and rats. One of the reasons that the half-lives of PFOA and PFOS are long in humans is that their renal clearance is low in humans. For animal toxicity experiments, it is essential that the doses in animal experiments are converted to equivalent doses in humans using pharmacokinetic models. Compared with PFOA, some LC-PFCAs have longer half-lives and accumulate more in the liver. Although tap water is a source of exposure to PFAS, the most common exposure source is food, with seafood being an important source for exposure to PFAS in Japan. PFOS and PFOA concentrations in human blood in Japan have been decreasing in recent years. However, according to clinical guidance published in 2022 by the United States National Academies, most Japanese residents are still in the medium risk group (PFAS concentration in plasma or serum is greater than 2 ng/mL and less than 20 ng/mL) or above. Further research is needed to help reduce exposure, and further risk assessments are required.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 3","pages":"97-104"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537433","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":"Male rat-specific fatty change in liver by DS-1971a: Elevation in phospholipids and adenosine as early responses to the fatty change in male rat-derived primary hepatocytes.","authors":"Kazunori Fujimoto, Hiroyuki Kishino, Jun Hirao, Takanori Maejima, Kazuhiko Mori, Yoshimi Tsuchiya","doi":"10.2131/jts.50.125","DOIUrl":"10.2131/jts.50.125","url":null,"abstract":"<p><p>In a 3-month repeated oral dose toxicity study of DS-1971a, a selective inhibitor of the Nav1.7 voltage-gated sodium channel, fatty change of hepatocytes was observed only in male rats at doses of 100 mg/kg and above. However, this change was not observed in female rats even at the highest dose of 1500 mg/kg. Furthermore, fatty change was not observed in mice and monkeys administered the highest dose of 1000 mg/kg for 6 and 9 months, respectively. To further investigate species differences of this fatty change, lipid accumulation was evaluated by staining with the LipidTOX dye in primary cultured hepatocytes derived from male and female rats, male monkeys, and male and female humans. After exposure to DS-1971a for 72 hr, the staining showed an increase in intensity specifically in male rat-derived hepatocytes in a concentration-dependent manner. Metabolomic analysis using rat-derived primary cultured hepatocytes exposed to DS-1971a for 24 and 72 hr revealed that phospholipids, not neutral lipids like triacylglycerols, and adenosine were elevated in the male-derived hepatocytes. These results suggest that the elevation of phospholipids and adenosine in the hepatocytes may contribute to the specific fatty change observed in male rats.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 3","pages":"125-134"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537432","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":"Induction of VEGF-A expression by methylmercury is mediated by the EGFR-p38 MAPK-COX-2-PKA pathway in cultured human brain microvascular pericytes.","authors":"Eiko Yoshida, Kenta Sakurai, Akishige Hirata, Tomoko Sasaoka, Takashi Hirooka, Tomoya Fujie, Takato Hara, Chika Yamamoto, Yasuyuki Fujiwara, Yo Shinoda, Komyo Eto, Toshiyuki Kaji","doi":"10.2131/jts.50.199","DOIUrl":"10.2131/jts.50.199","url":null,"abstract":"<p><p>Methylmercury is the causative organometallic compound of Minamata disease. Pathological changes in the cerebrum of patients are localized along the deep sulci and fissures of the cerebral cortex such as the calcarine fissure. It has been suggested that the occurrence of brain edema is important for the cerebral damage caused by methylmercury. Previously, we found that methylmercury induces vascular endothelial growth factor-A in cultured human brain microvascular pericytes, which may increase permeability of the brain microvasculature. In the present study, our findings suggest that this induction is mediated via the epidermal growth factor receptor-p38 mitogen-activated protein kinase-cyclooxygenase-2-protein kinase A pathway in cultured human brain microvascular pericytes. These results partly support our hypothesis that methylmercury causes neurotoxicity by activation of intracellular signaling pathways in various cell types, including neurons, macrophages, vascular endothelial cells, and pericytes.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 4","pages":"199-204"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772578","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":"Evaluation of rewarding effects of nitazene analogs: results from conditioned place preference tests and in vivo microdialysis experiments in mice.","authors":"Kyoko Hataoka, Motoki Hojo, Sakiko Nomura, Yoshio Nakagawa, Ayaka Kawai, Mari Nakamura, Kiyomi Ikushima, David B Alexander, Jin Suzuki, Toshinari Suzuki, Akiko Inomata","doi":"10.2131/jts.50.33","DOIUrl":"https://doi.org/10.2131/jts.50.33","url":null,"abstract":"<p><p>In illicit drug markets, the most recently expanding new synthetic opioid subclass is benzimidazoles, also known as nitazenes, which were originally developed as analgesics in the 1950s. The emergence of this classical, potent drug family has attracted extensive research interest in the field of forensic toxicology; however, information on their psychological and physical dependence is very limited. Herein, we evaluated the rewarding effects of four nitazene analogs using a battery of in vivo experiments, with a positive control drug (isotonitazene). The four test materials, metonitazene, etodesnitazene, metodesnitazene, and flunitazene, were administered to male C57BL/6J mice by i.p. administration at 0.5, 2, 20, and 20 mg/kg, respectively. In comprehensive behavioral observation tests, representative opioid-related physiological and behavioral states, including analgesia, stereotypic circling behavior, hyperlocomotion, and Straub tail response, were observed. A set of conditioned place preference tests revealed that all the four analogs induced palatability in mice. Furthermore, measurements of dopamine levels in the nucleus accumbens shell by in vivo microdialysis resulted in significant elevations in all test material-treated groups, suggesting that the nitazenes elicit the rewarding effect through a neural circuit originating from the μ-opioid receptor activation at the ventral tegmental area. Our findings add important data regarding the psychological dependence of nitazenes and highlight the abuse potential of these four materials and other prevailing nitazene analogs.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 1","pages":"33-43"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950773","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":"Toxicity of nickel, copper, and selenium in medaka embryos (oryzias latipes): a comparative study.","authors":"Sylvester Addai-Arhin, Seiya Shino, Masaya Uchida, Hiroshi Ishibashi, Koji Arizono, Nobuaki Tominaga","doi":"10.2131/jts.50.23","DOIUrl":"https://doi.org/10.2131/jts.50.23","url":null,"abstract":"<p><p>The indispensability of biometals nickel, copper, and selenium in pharmaceutical, agricultural, and other industrial applications, coupled with their release from mining processes, has made them potent environmental contaminants, especially when present in aquatic ecosystems at levels above the essential range. The toxicity of these biometals in fish embryogenesis, including their toxicity levels, was studied using medaka embryos. Test solutions (0.001-10 ppm) of the biometals, along with an isotonic solution as a control, were introduced into the embryos using a nanosecond pulsed electric field application. The exposed embryos were cultured at 25 ± 1°C and microscopically observed daily for 14 days in an isotonic solution. Developmental abnormalities and toxicity were observed during the 14-day observation period. All biometals caused some abnormalities in developing embryos at all concentrations. Major abnormalities included delayed development; deformities such as curvature of bones or spines; abnormal formation of the hearts, eyes, and circulatory systems; and mortality. The toxicity of the biometals was significantly different (p < 0.05) from that of the control. Gene expression analysis revealed that 4747, 1961, and 1952 genes were affected by copper, nickel, and selenium, respectively. Copper affected the highest number of genes and caused the highest toxicity. These results indicate that nickel, copper, and selenium can cause toxicity in developing fish embryos at concentrations ranging from 0.01 ppb to 10 ppm. Therefore, there is a need to constantly monitor the levels of these biometals, particularly in aquatic ecosystems, to preserve aquatic life.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 1","pages":"23-32"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950775","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":"Circ_0008272 facilitates cadmium-induced malignant transformation of bronchial epithelial cells through histone modification.","authors":"Hongyu Hao, Yanfang Yang, Jinjin Cui, Lihua Huang","doi":"10.2131/jts.50.263","DOIUrl":"https://doi.org/10.2131/jts.50.263","url":null,"abstract":"<p><p>Cadmium (Cd) exposure through the respiratory system is associated with various respiratory disorders, including lung cancer. Circular RNAs (circRNAs) are increasingly recognized as critical regulators in carcinogenesis. This study employed high-throughput RNA sequencing and quantitative real-time PCR (qRT-PCR) to identify differentially expressed circRNAs in 16HBE cells (Cd-T) after 30 weeks of cadmium chloride (CdCl₂, 5 μmol/L) exposure. Circ_0008272 knockdown inhibited migration, invasion, proliferation, and colony formation in Cd-T cells, whereas its overexpression enhanced these malignant phenotypes. Bioinformatics analyses and RNA-Protein Interaction Prediction (RPISeq) suggested that circ_0008272 promotes tumor-like behavior in Cd-T cells by modulating histone modification pathways. In conclusion, circ_0008272 acts as a tumor-promoting factor in the Cd-induced malignant transformation of 16HBE cells.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 6","pages":"263-272"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199548","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":"Differential response of SNU-1826 colon cells on the autophagy, ER stress, and inflammation during the regulation of microplastic internalization.","authors":"Ayun Seol, Ji Eun Kim, Hee Jin Song, Tae Ryeol Kim, Eun Seo Park, Ki Ho Park, Su Jeong Lim, Su Ha Wang, Seong Cheol Park, Youngwoo Choi, Hyesung Kim, Sungbaek Seo, Dae Youn Hwang","doi":"10.2131/jts.50.361","DOIUrl":"https://doi.org/10.2131/jts.50.361","url":null,"abstract":"<p><p>The internalization mechanism of microplastics (MPs) into human cells has attracted considerable attention because these mechanisms are closely related to the physical and chemical properties of MPs. This study examined the response of human colon cells to autophagy, ER stress, and inflammation during the regulation on the internalization of polystyrene (PS)-MPs (0.4-0.6 μm size). To achieve this, changes in their key markers were analyzed in MPs-treated SNU-1826 cells after a cotreatment with uptake inhibitors or stimulators. The internalization of MPs was significantly higher in SNU-1826 cells than in other cells originated from differential tissues, such as the small intestine, kidneys, and nerves. On the other hand, the internalization of MPs into SNU-1826 cells was suppressed by cytochalasin D (CD) but not by pitstop (Pt). During this inhibition, the levels of the key parameters for autophagy (Light Chain 3-I/II (LC3-I/II) and Beclin1), ER stress (eukaryotic translation initiation factor 2 subunit alpha (EIF2α) and inositol-requiring kinase 1 alpha (IRE1α)), and inflammation (inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6) were suppressed in MPs+CD-treated SNU-1826 cells. In addition, the internalization of MPs into SNU-1826 cells was stimulated by a ZnSO₄ treatment, not by CaCl₂. These stimulation effects were reflected in the alteration of the critical parameters for autophagy, ER stress, and inflammation. Furthermore, the positive correlation was detected between MPs internalization and most parameters for cellular responses although their inhibition is stronger than stimulation. These results suggest that the internalization of MPs into SNU-1826 cells may be strongly associated with the changes in autophagy, ER stress, and inflammation during the regulation of CD and ZnSO₄.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 7","pages":"361-378"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553834","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":"The degree of caspase-3 aggregation determines the selectivity of arsenic-induced cell death.","authors":"Yutaro Yamada, Ryo Ito, Takuya Noguchi, Shuhei Hamano, Kohei Otani, Takaya Komatsu, Yusuke Hirata, Atsushi Matsuzawa","doi":"10.2131/jts.50.351","DOIUrl":"https://doi.org/10.2131/jts.50.351","url":null,"abstract":"<p><p>It is well known that apoptosis is triggered by arsenic. Meanwhile, recent evidence has demonstrated that arsenic also induces a non-canonical form of regulated cell death (RCD) called parthanatos that is triggered by the overactivation of poly (ADP-ribose) polymerase-1 (PARP-1). Here, we provide evidence of a novel mechanistic link between parthanatos and apoptosis induced by arsenic. Exposure to sodium arsenite clearly induced parthanatos in typical cancer cell lines such as HeLa and HT1080 cells, without activation of the apoptotic cascade, including the caspase-3 activation. Of note, we observed aggregation of caspase-3 in response to sodium arsenite, which was abolished by treatment with 4-phenylbutyrate (4-PBA), a chemical chaperone that prevents protein aggregation. Interestingly, in the presence of 4-PBA, sodium arsenite induced apoptosis rather than parthanatos. These findings suggest that the disaggregation of caspase-3 allows arsenic to induce the caspase-3 activation, and subsequent apoptosis. Thus, our results show that the degree of the caspase-3 aggregation may be a critical determinant of the selectivity of sodium arsenite-induced cell death.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 7","pages":"351-359"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553837","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 exposure to methylphenidate causes behavioral abnormalities in grandchildren.","authors":"Ryota Nakano, Riko Ikeda, Yoshitaka Yamazaki, Sakiko Munetomo-Aoki, Haruka Morinaka, Shohei Abe, Hikaru Isobe, Masahiro Hosonuma, Shotaro Kamijo, Asuka Kaizaki-Mitsumoto, Satoshi Numazawa","doi":"10.2131/jts.50.445","DOIUrl":"https://doi.org/10.2131/jts.50.445","url":null,"abstract":"<p><p>Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is widely observed from childhood to adulthood and is treated with methylphenidate (MPH) as a first-line treatment. However, recent findings indicate that the paternal environment preceding conception may influence offspring health, potentially affecting subsequent generations. Moreover, we previously reported that MPH administration to sires reduced anxiety-related behaviors and induced memory impairments in the F1 generation. Therefore, in the present study, we investigated the effects of MPH exposure to sires on development, behavior, and brain gene expression in the F2 generation to extend our previous findings and examine the range of transgenerational effects. Although MPH exposure did not affect the number of births or survival rates, the body weight of mice in the MPH group was significantly lower than those in the control group. Additionally, motor development showed transient delays in early development but normalized by the age of weaning. Behavioral analysis further revealed a pronounced reduction in anxiety-like behaviors in the MPH group, particularly in female mice, with no effect on learning or memory. Finally, transcriptome analysis of the female cortex predicted the activation of neuroplasticity-related pathways, including the S100 family and CREB signaling. Notably, MPH was not administered to male F1 mice whose fathers had been administered MPH. Therefore, the ova of females mated with F1 males were not exposed to MPH. Nevertheless, the confirmation of behavioral abnormalities in the F2 generation strongly suggests that these abnormalities may have been induced by epigenetic changes in germ cells.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 9","pages":"445-457"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959005","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":"Spermidine alleviates sepsis-induced acute kidney injury by suppressing apoptosis and inflammation through modulation of TLR4-mediated signaling.","authors":"Yun Shen, Qinyi Shi, Ting Dai, Yi Cai, Mengting Sheng, Ying Qiu, Ming Yang, Sanhong Hu, Bo Cheng","doi":"10.2131/jts.50.555","DOIUrl":"https://doi.org/10.2131/jts.50.555","url":null,"abstract":"<p><p>Sepsis-associated acute kidney injury (AKI) remains a critical clinical challenge with limited therapeutic options. This study investigated the renoprotective effects of spermidine using sepsis-associated AKI models. In vitro, HK-2 cells were challenged with lipopolysaccharide (LPS) to establish an inflammatory injury model, followed by spermidine treatment (25-100 μM). In vivo, a cecal ligation and puncture (CLP)-induced septic AKI mouse model was employed. Key methodologies included CCK-8 viability assay, flow cytometry apoptosis analysis, western blotting (apoptotic proteins: Bcl-2/Bax/cleaved caspase-9; TLR4/MyD88/TRAF6/p-p65), ELISA (TNF-α/IL-6/IL-1β), TUNEL staining, and histopathological assessment, with spermidine doses of 25-100 μM (cells) and 50 mg/kg (mice). We found that spermidine treatment significantly mitigated renal histopathological damage and improved functional markers, including blood urea nitrogen, serum creatinine, and neutrophil gelatinase-associated lipocalin. Spermidine administration attenuated oxidative stress by restoring antioxidant enzyme activities while reducing lipid peroxidation in renal tissues. Spermidine suppressed apoptosis in both LPS-challenged HK-2 and CLP-injured kidneys, evidenced by reduced apoptotic markers and caspase activation. Furthermore, spermidine inhibited systemic and intrarenal inflammatory cytokine production through modulation of the TLR4/MyD88/NF-κB signaling axis. These findings collectively establish that spermidine alleviates sepsis-induced AKI through coordinated suppression of apoptosis and inflammation mediated by TLR4/MyD88/NF-κB pathway inhibition.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 10","pages":"555-567"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206907","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}