Journal of Applied Toxicology最新文献

{"title":"Comparison of the Sensitivity of Histopathological and Immunohistochemical Analyses With That of Serum Hormone Measurements for Early Detection of Antithyroid Effects in Rats Treated With Iodide Uptake Inhibitors.","authors":"Hirotoshi Akane, Shinji Takasu, Yuji Ishii, Kohei Matsushita, Mizuho Uneyama, Tomomi Morikawa, Tadashi Kosaka, Hiroaki Aoyama, Kumiko Ogawa, Takeshi Toyoda","doi":"10.1002/jat.70449","DOIUrl":"https://doi.org/10.1002/jat.70449","url":null,"abstract":"<p><p>Serum thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) measurements are widely used to detect antithyroid effects in rodent toxicity studies. However, the assays used to measure these hormones are costly and highly variable depending on the blood sampling and measurement conditions. We previously demonstrated that histopathological evaluation detects the effects of thyroid peroxidase (TPO) inhibitors and thyroid hormone metabolism promoters more sensitively than serum hormone measurements. Here, we examined whether this approach can also improve early detection of antithyroid chemicals that inhibit iodide uptake, an essential step in thyroid hormone synthesis. We compared histopathological and immunohistochemical findings with serum hormone measurements in 6-week-old male Sprague-Dawley rats (five per group) administered ammonium perchlorate (APC) or potassium thiocyanate (PTC) in drinking water for 28 days. Serum T4 decreased at 1000 ppm APC and 5000 ppm PTC, T3 decreased at 1000 ppm APC, and TSH increased at ≥ 100 ppm APC. In contrast, follicular cell hypertrophy was detected at ≥ 10 ppm APC and 5000 ppm PTC, indicating greater sensitivity compared with serum hormone measurements. Decreased T3 and T4 immunostaining showed a sensitivity comparable with that of serum hormone changes, whereas thyroid sodium/iodide symporter (NIS)-immunopositive areas increased at doses that produced no detectable changes in serum hormone levels, suggesting that NIS immunostaining represents the most sensitive marker of iodide uptake inhibition. These results suggest that combining histopathological and immunohistochemical analyses enables sensitive detection of antithyroid effects and provides mechanistic information that cannot be obtained from serum hormone measurements alone.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110183","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":"High-Content Screening Comparison of 1R6F Cigarette Smoke Extract and Selected Heated Tobacco and Electronic Vapour Product Aerosol Extracts in Endothelial and Bronchial Epithelial Cell Models.","authors":"Edgar Trelles Sticken, Konstantinos Papikinos, Fiona Chapman, Roman Wieczorek, Sarah Jean Pour, Torge Evenburg, Sandra Otte, Tiandan Wu, Liam Simms, Matthew Stevenson","doi":"10.1002/jat.70448","DOIUrl":"https://doi.org/10.1002/jat.70448","url":null,"abstract":"<p><p>Cigarettes induce oxidative stress and DNA damage, processes that contribute to cardiovascular and pulmonary disease. High content screening (HCS) is an increasingly valuable tool for comparative toxicology because it enables simultaneous quantification of multiple mechanistic endpoints at single-cell resolution. In this study, HCS was used to compare the biological activity of extracts from reference cigarette 1R6F smoke and aerosol extracts from one heated tobacco product and two electronic vapour products in human coronary artery endothelial cells and bronchial epithelial cells. Endpoints included reactive oxygen species generation, glutathione depletion, γH2AX induction as a marker of DNA double-strand break signalling and NRF2 translocation as an indicator of oxidative stress signalling. 1R6F cigarette smoke extract showed the highest cytotoxic and genotoxic responses, whereas the selected HTP and EVP aerosol extracts generally showed lower potency, with higher minimum effective concentrations across several endpoints under the tested conditions. N-acetylcysteine (NAC) attenuated several responses, supporting oxidative stress as an important contributor to the observed cellular effects. Overall, under the tested in vitro conditions, extracts from the selected HTP and EVP products showed lower potency across several oxidative stress-, genotoxicity- and cytotoxicity-associated endpoints than 1R6F cigarette smoke extract. These findings support product-specific comparative in vitro bioactivity assessment but do not directly establish reduced human health risk, product safety or clinical harm reduction. The study extends previous HCS work by integrating potency-based comparisons, mechanistic interrogation using NAC and cross-tissue evaluation.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110189","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":"Repeated Exposure to a Hair Bleaching Mixture Alters cGAS-STING Pathway Transcripts in Mice.","authors":"Leticia Rodrigues Sampaio, Marjori Lima Boblitz Parente, Ronald Feitosa Pinheiro","doi":"10.1002/jat.70453","DOIUrl":"https://doi.org/10.1002/jat.70453","url":null,"abstract":"<p><p>Hair bleaching products commonly contain ammonia and hydrogen peroxide, chemicals capable of generating reactive oxygen species (ROS). However, their effects on innate immune signaling pathways associated with DNA damage remain poorly understood. We investigated whether repeated topical exposure to a bleaching mixture modulates the cGAS-STING pathway in C57BL/6 mice. Male and female mice were exposed weekly for 10 weeks to a commercial bleaching formulation containing 5.8% ammonia and 12% hydrogen peroxide. A subgroup received N-acetylcysteine (100 mg/kg), an antioxidant treatment, 1 h before each exposure. Gene expression of Cgas, Sting, and Tbk1 was assessed by RT-qPCR in spleen samples, and femoral bone marrow was examined histologically. Male mice exposed to the bleaching mixture showed significant upregulation of Cgas and Sting transcripts compared with N-acetylcysteine-treated animals, whereas Sting expression was also increased relative to controls. Histological evaluation identified clustered megakaryocytes with dysplastic features in two exposed males, whereas female mice showed no transcriptional or histological alterations. These findings suggest that repeated exposure to bleaching chemicals may promote oxidative stress-associated transcriptional changes in the cGAS-STING in a sex-dependent manner. Although additional mechanistic studies are warranted, these preliminary data support further investigation of transcriptional and functional responses involving innate immune DNA-sensing pathways following repeated exposure to hair-bleaching chemicals.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110192","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":"Placental Transfer of PFAS and Their Sex-Specific Associations With Neonatal Thyroid Hormones in a Chinese Birth Cohort.","authors":"Shuhan Li, Yang Li, Xing Liao, Xinshuo Dong, Yunfeng Ma, Ruixin Guo, Yanhua Liu, Jianqiu Chen","doi":"10.1002/jat.70469","DOIUrl":"https://doi.org/10.1002/jat.70469","url":null,"abstract":"<p><p>Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are persistent environmental endocrine-disrupting chemicals that can cross the placental barrier and may disrupt fetal thyroid homeostasis; however, the sex-specific thyroid toxicity of PFAS remains poorly characterized. This study recruited 247 mother-infant pairs from a tertiary hospital in Wuhan, China, and measured PFAS concentrations in maternal and cord serum. The results showed that perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonate (PFHxS) were the predominant PFAS in both maternal and cord serum. Their median concentrations were 5.520, 3.896, and 4.154 ng/mL in maternal serum, respectively, and 7.112, 2.704, and 2.422 ng/mL in cord serum, respectively. Several short-chain PFAS, including perfluoropentanoic acid (PFPeA), perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA), and perfluoropentane sulfonic acid (PFPeS), exhibited relatively high transplacental transfer efficiency (TTE). PFAS with a cord serum detection rate > 90% were selected for subsequent analyses. Spearman correlation analysis showed strong coexposure patterns among several long-chain PFCAs, with the strongest correlations observed among PFDA, PFNA, and PFUdA (r = 0.81-0.89, p < 0.01). PFAS-thyroid hormone correlations were generally weak; only PFHpS was inversely correlated with TSH (r = -0.16, p < 0.01). In multivariable linear regression models, PFHxS was positively associated with TSH in the overall sample (β = 0.085, p < 0.05), whereas PFHxA was inversely associated with FT4 (β = -0.106, p < 0.01). Among female newborns, GenX was inversely associated with TSH (β = -9.411, p < 0.05), whereas PFHxS was positively associated with TSH (β = 0.109, p < 0.05). Among male newborns, PFDA (β = -0.132, p < 0.05), PFHxA (β = -0.137, p < 0.01), PFNS (β = -0.287, p < 0.01), and PFOS (β = -0.029, p < 0.05) were inversely associated with FT4. No individual PFAS was significantly associated with FT3. Formal interaction analysis showed evidence of sex heterogeneity for the PFNS-FT4 association (P for interaction = 0.008). Qgcomp showed nonsignificant overall mixture effects for FT3, FT4, and TSH. Similarly, BKMR showed no statistically significant overall mixture effects or individual PFAS associations with thyroid hormone levels.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110195","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 the Teratogenic Toxicity of Sunset Yellow in Sprague-Dawley Rats.","authors":"Fang Tan, Yanwu Wang, Penghe Liu, Jingfeng Sun, Liying Zhou, Guangqiu Qin","doi":"10.1002/jat.70463","DOIUrl":"https://doi.org/10.1002/jat.70463","url":null,"abstract":"<p><p>Sunset Yellow (SY) is a synthetic azo colorant widely used in food and pharmaceutical products, resulting in increased human exposure. However, studies on its teratogenic toxicity in mammals remain limited. This study aimed to evaluate the effects of prenatal SY exposure on pregnant rats and their fetuses in Sprague-Dawley (SD) rats. Fifty successfully mated female SD rats were randomly assigned to three SY-treated groups (40, 160, and 640 mg/kg SY, respectively), one negative control group (distilled water), and one positive control group (300 mg/kg aspirin). Gavage administration was conducted from gestational day 6 (GD 6) to GD 15 (10 consecutive days). On GD 20, the pregnant rats were euthanized for necropsy; reproductive parameters were recorded, and fetuses were collected for comprehensive developmental evaluation. The results showed that, under the present experimental conditions, SY exposure at all three doses did not adversely affect maternal clinical signs, body weight gain, or reproductive parameters, nor did it cause any deleterious effects on fetal growth, development, or visceral organs. Although a narrower fontanelle was observed at 640 mg/kg compared with the negative control group, given the absence of other developmental toxicity and the normal variation in fontanelle closure, this finding should be considered preliminary and warrants further study.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110122","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 Health-Protective Screening Threshold for Personal Care Products: Metabolomic and Endocrine Mechanisms of Adolescent Reproductive Toxicity in Zebrafish.","authors":"Qinqian Tao, Yongbin Li, Xingmei Chen, Erping Yan, Shisan Xu, Xueping Chen, Jinping Cheng","doi":"10.1002/jat.70466","DOIUrl":"10.1002/jat.70466","url":null,"abstract":"<p><p>Adolescents are uniquely vulnerable to endocrine-disrupting chemicals (EDCs) due to the critical maturation of the hypothalamic-pituitary-gonadal (HPG) axis, yet current safety assessments overlook whole-formulation risks during this developmental window. Using an adolescent zebrafish model, we established a biologically anchored screening threshold and elucidated the molecular mechanisms of formulation toxicity. Direct exposure to personal care products at unadjusted Scientific Committee on Consumer Safety (SCCS)-derived concentrations caused severe systemic overload (F1 survival ≤ 16.87%). High-dilution screening of a 17α-ethinylestradiol (EE2)-spiked model lotion identified a 160× SCCS dilution as the no-observed-adverse-effect level (NOAEL) for reproductive and neurodevelopmental endpoints. Ovarian metabolomics revealed a dichotomous threshold response: The 160× dilution induced focused, adaptive reprogramming of steroid hormone biosynthesis (modulating methionine, tyrosine, and histidine), whereas the 80× dilution triggered an energetic-inflammatory crisis characterized by acylcarnitine accumulation, tricarboxylic acid cycle suppression, and oxidative stress. This metabolic disruption led to hypothalamic AMP-activated protein kinase (AMPK)-mediated gonadotropin suppression and follicular atresia. Although the formulation matrix partially mitigated EE2-induced ovarian failure, it failed to prevent F1 neurobehavioral hypoactivity, implicating parallel thyroid and monoaminergic disruption. Commercial sunscreen validation confirmed product-specific hazards at a 40× dilution, proving that whole-formulation toxicity cannot be predicted from ingredient lists alone. These findings redefine risk assessment by advocating for whole-formulation, mechanism-informed screening. The 160× dilution threshold offers regulators a pragmatic, health-protective benchmark to safeguard adolescent reproductive and neurodevelopmental health through molecular endocrinology-guided toxicology.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110131","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":"TFEB Attenuates Silver Nanoparticle-Induced Pulmonary Ferroptosis by Preserving Lysosomal Integrity and Limiting Iron Dysregulation.","authors":"Chenyu Liu, Haitao Yang, Rui Zhang, Menghao Guo, Shuyan Niu, Yuying Xue","doi":"10.1002/jat.70234","DOIUrl":"10.1002/jat.70234","url":null,"abstract":"<p><p>Silver nanoparticles (AgNPs) possess potent antimicrobial properties but incur substantial pulmonary toxicity upon inhalation, with the respiratory system as their primary target. Although accumulating evidence implicates lysosomal dysfunction and ferroptosis in AgNPs-associated lung injury, the upstream regulatory mechanisms linking lysosomal damage to iron-dependent lipid peroxidation remain elusive. Using ICR mice (intranasal instillation of 20 nm AgNPs at 0, 5, and 50 mg/kg bw for 28 days) and BEAS-2B cells (20 nm AgNPs at 0, 5, 10, and 20 μg/mL for 24 h) as in vivo and in vitro models, we systematically explored AgNPs-induced ferroptotic lung injury, focusing on transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and repair. AgNPs exposure caused dose-dependent cytotoxicity and pulmonary damage, accompanied by iron dyshomeostasis, labile iron accumulation, glutathione depletion, elevated ROS/MDA levels, dysregulated ferroptosis-related proteins, and enhanced lipid peroxidation, hallmarks of ferroptosis, all significantly attenuated by iron chelation (deferoxamine, DFO). Mechanistically, AgNPs induced lysosomal injury (reduced LAMP1/LAMP2, elevated CTSB, impaired membrane integrity, and disrupted luminal pH). Critically, TFEB activation (C1 agonist) mitigated lysosomal damage, restored iron homeostasis, and suppressed ferroptosis, while TFEB knockdown (siRNA) exacerbated these abnormalities. Our findings identify TFEB as a critical protective mediator that facilitates lysosomal repair, counteracts iron dysregulation, and inhibits ferroptosis in AgNPs-exposed lung cells, elucidating AgNPs pulmonary toxicity mechanisms and highlighting TFEB as a potential therapeutic target.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"3605-3621"},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silica Promotes Silicosis via the ROS/NF-κB p65 Signaling-Activated Hypoxia-Lactate Axis in Rats.","authors":"Yuan-Yuan Fu, Yi-Fan Zhou, Hui-Jie Hu, Yan-Rui Liu, Zhao-Qiang Zhang, Gui-Zhi Han","doi":"10.1002/jat.70209","DOIUrl":"10.1002/jat.70209","url":null,"abstract":"<p><p>Hypoxia occurs during silicosis progression; however, the mechanisms by which silica induces hypoxia and its precise role in the pathogenesis remain poorly understood. In this study, 50 male rats were assigned to five groups: a control group, a model group, and three intervention groups. The rats in the model and intervention groups were intratracheally administered a silica suspension only once, whereas the control rats were intratracheally administered phosphate buffer solution (PBS). Then the rats in intervention groups received daily intravenous injections of N-acetylcysteine (NAC) (at doses of 20, 40, and 80 mg/kg, respectively) while the rats in control and model groups received PBS injections. After 60 days, the lung samples were harvested for histopathologic evaluation, and the hypoxia-related proteins (nuclear factor-κB p65 [NF-κB p65], hypoxia-inducible factor-1α [HIF-1α], and vascular endothelial growth factor A [VEGFA]), lactate-metabolism markers (glucose transporter type 1 [GLUT1] and lactate dehydrogenase A [LDHA]), and pulmonary-injury indicators (interleukin-1β [IL-1β] and transforming growth factor-β1 [TGF-β1]) were quantified using Western blot. The results showed that compared with the control group, the lung of the model group exhibited obvious damage and collagen deposition, accompanied by upregulation of the aforementioned cytokines. When NAC was employed to inhibit silica-induced ROS, all of the above phenomena were reversed in a dose-dependent manner. These findings indicated that silica induced pulmonary hypoxia via the ROS/NF-κB p65 pathway, which subsequently triggered inflammation and fibrosis through lactic acid fermentation, ultimately leading to silicosis.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"3561-3572"},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147772261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Pro-Angiogenic Mechanism of Diammonium Glycyrrhizinate Injection in Zebrafish via Transcriptomic Analysis and RT-qPCR Validation","authors":"Jiahao Yu,&nbsp;Shuqing Yu,&nbsp;Xuchang Liu,&nbsp;Ke Xu,&nbsp;Xuanming Zhang,&nbsp;Wenlong Sheng,&nbsp;Kechun Liu,&nbsp;Xiaobin Li,&nbsp;Wei Li","doi":"10.1002/jat.70140","DOIUrl":"10.1002/jat.70140","url":null,"abstract":"<div>\u0000 \u0000 <p>Glycyrrhizic acid (GA) is the main metabolite of the traditional Chinese medicine <i>Glycyrrhiza glabra</i>. Many GA preparations in the pharmaceutical market have good efficacy in hepatoprotection and the treatment of liver diseases. However, the pro-angiogenic effects for GA-based agents have not been researched specifically. Angiogenesis is of vital importance for ischemic diseases, such as diabetic peripheral vascular disease, myocardial ischemia, and cerebral ischemia. The aim of this study was to investigate the pro-angiogenic activity of GA preparations commonly used in clinical practice and screen the representative angiogenesis promotor to further elucidate the mechanism of action. A zebrafish vascular injury model induced by PTK787 was used to assess the pro-angiogenic effect of GA preparations. The pro-angiogenic activity of diammonium glycyrrhizinate injection (DGI) was further systematically evaluated by detecting the growth of the intersegmental vessels (ISVs) and subintestinal vein vessels (SIVs) in zebrafish. The underlying mechanism of action for DGI was explored by transcriptomics analysis and RT-qPCR validation. The results showed that magnesium isoglycyrrhizinate injection (MII), DGI, compound glycyrrhizinate tablets (CGT), and diammonium glycyrrhizinate enteric-coated capsules (DGEC) demonstrated significantly pro-angiogenic effects. Among them, DGI exhibited the strongest activity. Transcriptomic analysis showed that the pro-angiogenic activity of DGI was closely associated with the mTOR signaling pathway. RT-qPCR results indicated that the expression levels of key genes of the mTOR/HIF-1 pathway were significantly upregulated in DGI-treated zebrafish relative to the PTK787 group. GA preparations have an obvious pro-angiogenic effect, in which DGI exerts particularly strong activity, appearing to be mediated mainly by activation of the mTOR/HIF-1 signaling pathway. This study broadens the clinical application of GA agents and provides new insights into the pharmacodynamics and potential mechanisms of DGI as a candidate agent for treating ischemic diseases.</p>\u0000 </div>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"46 11","pages":"3791-3803"},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365663","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 TRPM2-PARP-1 Axis Involvement in Bisphenol A and Nonylphenol-Induced Ferroptosis in Trigeminal Ganglion Cells.","authors":"Betül Yazğan, Musa Tatar, Yener Yazğan, Kıymet Kübra Tüfekci","doi":"10.1002/jat.70245","DOIUrl":"10.1002/jat.70245","url":null,"abstract":"<p><p>Environmental contaminants like bisphenol A (BPA) and nonylphenol (NP) are recognized neurotoxicants; however, the molecular mechanisms underlying their impact on sensory ganglia, specifically the trigeminal ganglion (TG), remain critically underexplored. This study explored the potential of BPA and NP to drive neuronal injury and ferroptosis linked to oxidative stress, acting through the transient receptor potential melastatin 2 (TRPM2)-poly (ADP-ribose) polymerase-1 (PARP1) signaling axis. Forty-two adult male Wistar rats were allocated into seven groups (control, low-dose [25 mg/kg]/high-dose [100 mg/kg] BPA, low-dose [25 mg/kg]/high-dose [100 mg/kg] NP, and low-dose [25 mg/kg]/high-dose [100 mg/kg] BPA + NP) and treated orally for 21 days. We employed a combinatorial approach of biochemical assays and immunohistochemistry to evaluate oxidative stress markers, ferroptosis hallmarks (glutathione peroxidase 4 [GPX4], solute carrier family 7 member 11 [SLC7A11], and transferrin receptor [TfRC]), apoptotic mediators (Caspase-3 and Caspase-9), and inflammatory cytokines, as well as the expression of TRPM2 and PARP-1. Results demonstrated that BPA and NP exposure triggered a robust, dose-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation, concomitant with downregulation of anti-ferroptotic proteins (GPX4 and SLC7A11) and upregulation of TfRC. This toxic insult simultaneously activated apoptotic and inflammatory cascades. Crucially, TRPM2 and PARP-1 were significantly upregulated, implying a potential role for the TRPM2-PARP-1 axis as an upstream modulator of oxidative stress-induced ferroptosis and neuroinflammation. Collectively, these findings provide novel mechanistic insights into phenol-induced neurotoxicity, highlighting the inhibition of the TRPM2-PARP-1 axis as a promising therapeutic strategy to mitigate environmental neurodegeneration in sensory neurons.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"3660-3674"},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}