Toxicological Research最新文献

This study investigated the effects of chitooligosaccharides (COS) on proinflammatory cytokines and nuclear factor-κB (NF-κB) activation in particulate matter 10 (PM10)-induced mice. Results demonstrated that COS treatment significantly reduced proinflammatory cytokines, including interleukin (IL)-6 and IL-1β, particularly in the COS_20 group (20 mg/kg body weight of COS). Lower COS doses correlated with a dose-dependent decrease in proinflammatory cytokine levels and inflammatory cell infiltration in bronchoalveolar lavage fluid and lung tissue. COS treatment increased Th2 cell-related biomarkers (IL-4, IL-5, and IL-13), although these decreased at higher doses. Western blotting analysis revealed that COS suppressed NF-κB activation, particularly in the COS_20 group, suggesting that COS may inhibit IκB degradation, preventing NF-κB translocation to the nucleus and subsequent transcription of proinflammatory genes. These findings indicate that COS effectively mitigates the inflammatory response triggered by PM10 exposure, positioning it as a potential functional health supplement for managing pulmonary inflammation and related disorders.

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Supplementary information: The online version contains supplementary material available at 10.1007/s43188-025-00304-0.

Mitochondria are essential for cellular energy production and play a critical role in maintaining overall cellular homeostasis. Mitochondrial dysfunction primarily affects energy-demanding tissues such as heart and skeletal muscle, as well as tissues (e.g., the liver) that are exposed to xenobiotics. In fact, mitochondrial toxicity is recognized as a major contributor to drug-induced liver injury (DILI). However, reliable methods for assessment of mitochondrial toxicity in vitro or in vivo remain lacking. Here, through a series of in vitro and in vivo experiments, we identified amiodarone as a model compound for evaluation of mitochondrial toxicity in hepatocytes and liver tissues. Among five known hepatotoxic agents tested, amiodarone consistently induced characteristic features of mitochondrial toxicity, including reduced mitochondrial membrane potential, elevated mitochondrial reactive oxygen species (ROS), and disrupted mitochondrial dynamics in both primary hepatocytes and surrogate cell lines. Because mitochondrial damage frequently triggers activation of antioxidant defense pathways, we further confirmed increased antioxidant gene expression and serum transaminase level elevation in mice administered with amiodarone. Indeed, the hepatotoxicity induced by amiodarone was significantly enhanced in Nrf2-deficient mice. Our approach, importantly, can be applied to the evaluation of drug-induced mitochondrial damage in the liver.

Supplementary information: The online version contains supplementary material available at 10.1007/s43188-025-00310-2.

Cypermethrin (CYP) is a commonly used type II Pyrethroid pesticide, that normally accumulates in the various body tissues, causing organ dysfunction. In order to reduce its toxicity, we primarily investigated the potential of Bacopa monnieri (BM) extract in the amelioration of CYP-induced hypothyroidism in female Swiss mice. Animals were divided into 4 groups of 6 each. Group I, without receiving any treatment served as control, Group II was orally administered with CYP at 15 mg/kg, while Group III animals were administered only with BM extract at 200 mg/kg, and Group IV received equivalent dose of CYP along with BM extract (CYP + BM). The treatment was continued for 28 days. At the end, serum levels of triiodothyronine (T₃), thyroxin (T₄), and thyroid-stimulating hormone (TSH) were measured. Also, thyroidal histopathology and tissue peroxidation were evaluated. Results revealed that CYP administration induced hypothyroidism in the animals, as indicated by reduced serum thyroid hormones and enhanced TSH levels. Thyroid follicles were of reduced diameter and with flattened epithelium and vacuolated cytoplasm. Also, a significant increase in the body weight and thyroid weight was seen. Further, a decreased expression of TSHr and THR β-1 receptors was also found in this group. Interestingly, the co-administration of BM extract and CYP could ameliorate hypothyroidism in mice. A reversal in the pesticide-induced increase in oxidative stress was also seen in the CYP + BM group, suggesting a reduction in CYP-induced thyroid toxicity. BM was also found to be antiperoxidative. These results suggest the potential of BM extract in the mitigation of cypermethrin-induced Hypothyroidism and its adverse effects. This work further demonstrates the expression of TSHr and THR β-1 and suppression of the oxidative stress in the test extract administered to hypothyroid female mice.

Trichloroethylene (TCE) is widely employed as a cleaning agent in industrial settings. Occupational exposure to TCE can lead to occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). Our previous research has identified damage to renal vascular endothelial cells (ECs) in both OMDT patients and TCE-sensitized mice; however, the underlying mechanisms remain insufficiently understood. Methods: This study aims to elucidate the role of endoplasmic reticulum stress (ERS)-induced ECs ferroptosis in TCE-induced renal injury by developing a TCE-sensitization mouse model. Our findings indicate that ferroptosis in renal ECs is associated with TCE-induced kidney damage, and the ferroptosis inhibitor Fer-1 can mitigate this injury. Notably, ERS can modulate TCE-induced ECs ferroptosis. The PERK inhibitor GSK2606414 can suppress ferroptosis via the Nrf2/HO-1 signaling pathway and reduce trichloroethylene-induced renal injury. In conclusion, TCE sensitization activates ERS through the PERK/eIF2α/ATF4 pathway, with PERK subsequently mediating ferroptosis of renal vascular endothelial cells via the Nrf2/HO-1 signaling pathway, thereby contributing to TCE-related immune kidney injury.

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and treatment-resistant malignancy with a poor prognosis. Among the multifactorial mechanisms implicated in the progression of PDAC, oxidative stress, defined as an imbalance between reactive oxygen species (ROS) and antioxidant defenses, has emerged as a crucial regulator of tumor behavior. While ROS can promote tumorigenesis via genomic instability, oncogenic signaling, and immune evasion, it also exhibits tumor-suppressive potential by inducing apoptosis and disrupting cancer cell metabolism. This dual role of ROS in PDAC is tightly influenced by the tumor mutational landscape, particularly KRAS gene mutations, metabolic reprogramming, and the tumor microenvironment. In PDAC, the generation of ROS promotes chemoresistance, activates hypoxia-inducible factor-1α, and facilitates desmoplastic stromal remodeling via pancreatic stellate cells and cancer-associated fibroblasts. Conversely, the therapeutic increase of ROS beyond tolerable levels induces cancer cell death through apoptosis and autophagy. This review comprehensively summarizes the dual role of ROS in PDAC, with particular emphasis on the molecular mechanisms underlying redox regulation. In addition, ROS-targeting therapeutic agents are categorized into clinically approved drugs, investigational agents, and natural compounds, and their relevance in redox biology is discussed. Finally, emerging therapeutic strategies that leverage redox vulnerabilities are outlined, and future research directions are proposed for the development of redox-modulating PDAC therapies.

Bisphenol A (BPA), a synthetic compound extensively used in the production of polycarbonate plastics and epoxy resins, is a pervasive environmental contaminant and a potent endocrine disruptor. By mimicking oestrogen and binding to oestrogen receptors, BPA interferes with normal hormonal signalling, leading to significant disruptions in reproductive systems. In males, BPA exposure has been linked to reduced sperm count, impaired spermatogenesis, and histopathological alterations in testicular tissue, including disrupted Leydig cell function. In females, it affects ovarian follicle development, disrupts reproductive cyclicity, and causes morphological abnormalities in ovarian tissues. These reproductive effects are exacerbated by BPA-induced oxidative stress, which damages cellular structures and exacerbates hormonal imbalances. The mechanisms underlying BPA's reproductive toxicity involve disruptions in gene expression, signalling pathways, and hormonal homeostasis, highlighting its far-reaching effects on both male and female fertility. This study explores the hormonal havoc caused by BPA exposure, emphasizing its multifaceted impact on reproductive health and the urgent need for mitigative strategies to address its toxicity.

Twenty-three single-ingredient substances, selected from materials labeled as allergens in cosmetic fragrances, were assessed for skin sensitization potential using a defined approach (DA) based on the OECD Guideline 497 Integrated Testing Strategy version 2 (ITSv2). According to the ITSv2, skin hypersensitivity data for these selected substances were integrated. In chemico data (from the Direct Peptide Reactivity Assay, DPRA) and in vitro data (from the human Cell Line Activation Test, h-CLAT) were obtained from existing databases, while in silico data were generated via the automated workflow of the OECD QSAR Toolbox. The DA for skin sensitization, which combines QSAR predictions with DPRA and h-CLAT test results, categorized 17 substances, including 2-benzylideneheptanal, as "Sensitizers"; 5 substances, including 4-methoxybenzyl alcohol, as "Inconclusive"; and citronellol alone was categorized as "Not Classified." The outcomes from the Local Lymph Node Assay (LLNA) for substances identified as skin sensitizers by the DA method demonstrated similar classification patterns to those from DA. These results underscore the necessity of integrating comprehensive in vitro, in chemico, and in silico data for accurate evaluation of potential skin sensitizers. This case study could aid in enhancing the safety assessments of potential skin sensitizers using DA; however, final categorization is subject to validation by regulatory authorities.

Drone pupae of honeybees (Apis mellifera L.) are rich in proteins, carbohydrates, fats, minerals, and vitamins, making them a valuable food ingredient in various regions including Korea, Japan, China, the United States, and parts of Europe. In this study, we investigated the safety of freeze-dried honeybee drone pupae (HDPp) as a potential functional food ingredient using single- and repeated-dose oral toxicity assessments. In the single-dose oral toxicity study, both male and female control groups were evaluated along with three test groups, each consisting of five animals, totaling 40 mice. The administered doses for the test groups were set at 2000, 1000, and 500 mg/kg body weight. The subjects were monitored over a period of 2 weeks following a single administration. Following the guidelines provided by the Korean Ministry of Food and Drug Safety, observations included mortality, changes in body weight, clinical symptoms, and post-mortem examinations of major organs for visual inspection and weight measurement. The repeated-dose oral toxicity study was extended over four weeks, employing the same dosages and methodology as the single-dose study. Additionally, this study incorporated blood and serological evaluations. The results demonstrated no toxicity-related effects in either single-dose or repeated-dose studies, suggesting that HDPp is a safe food ingredient with a lethal dose-50 exceeding 2000 mg/kg.

The Seo-Cheon Janghang Smelter in South Korea closed in 1989 owing to its contribution to environmental pollution. The emissions from the smelter likely affect various environmental media and also pose significant health risks to nearby residents, particularly in relation to exposure to heavy metals such as lead, cadmium, and arsenic. Although the environmental impacts of the smelter are known, long-term follow-up studies on heavy metal exposure in nearby residents remain limited, especially after remediation. This study aimed to assess the levels of heavy metal exposure and associated health effects, particularly on renal and bone health. We analyzed blood and urine samples from 37 volunteers, collecting demographic, lifestyle, and exposure-related data through interviews. Renal function tests and bone mineral density measurements were conducted. The geometric means for blood lead (bPb) and blood cadmium (bCd) were 1.95 μg/dL and 2.68 μg/L, respectively. The mean urinary cadmium (uCd) concentration was 3.74 μg/g cr. Urinary total and harmful arsenic concentrations were 165.7 μg/L and 1.00 μg/L, respectively. The bPb levels significantly decreased from 2008 to 2020, whereas cadmium levels did not show significant change overall. Among 28 participants tested in both years, bCd levels decreased for individuals living > 2 km from the smelter, while remaining stable for those closer. The uCd levels significantly decreased only in individuals who had relocated > 2 km away from the smelter. Despite remediation efforts, uCd levels remain persistently elevated. These findings underscore the need for continuous exposure monitoring and longitudinal health assessments of residents living near the former smelter.

15-Deoxy-Δ^12,14-prostaglandin J2 (15d-PGJ2) plays an important role in cell proliferation and apoptosis with various inhibitory effects. We investigated whether 15d-PGJ2 influence proliferation and apoptosis of human microvascular endothelial cells (HMEC-1), and suppression of the nuclear factor (NF)-κB activity and PI3K/AKT/mTOR signal pathway. Cell proliferation was analyzed using the MTS/PMS and colony formation assays. We analyzed the cell cycle using flow cytometry, while quantitative polymerase chain reaction (qPCR) measured mRNA expression, and immunoblot analysis quantified protein expression. 15d-PGJ2 inhibited cell growth and colony formation. In addition, it reduced the expression of cyclin-dependent kinase 4 and 6 (CDK4/6) and cyclin D1 mRNA but increased p21 mRNA expression. Apoptosis was increased during cell cycle progression and induced, as evident from the expression of apoptosis-related proteins, such as reduced Bcl-2 expression and increased Bax, caspase-3, and caspase-9 expression. Furthermore, the phosphorylation of NF-κB and PI3K/AKT/mTOR proteins was suppressed. This study found that 15d-PGJ2 inhibits cell proliferation, induces apoptosis, and regulates cell cycle- and apoptosis-related gene expression by suppressing the NF-κB and PI3K/AKT/mTOR pathways in HMEC-1 cells.