Journal of Applied Toxicology最新文献

Type 2 diabetes mellitus (T2DM), the predominant form of diabetes mellitus (DM), has been established as a key etiological factor in male infertility. The incidence of T2DM among reproductive-aged males has shown a progressive annual increase, potentially contributing to the observed decline in fertility rates. As a primary oral hypoglycemic medication in the management of T2DM, metformin requires comprehensive investigation into its impacts on male reproductive function. The effects of metformin, at concentrations within the therapeutic range, on the functional competence of capacitated human sperm were assessed in vitro to elucidate the involved mechanisms. Following exposure in capacitation medium, sperm functions critical for fertilization, such as motility, penetration ability, capacitation, acrosome reaction, and hyperactivation were systematically evaluated. The potential mechanisms such as 5'-AMP-activated protein kinase phosphorylation and tyrosine phosphorylation of sperm in capacitated state were also measured by western blot. The results indicate that metformin, at 40 and 80 μM, markedly reduced the enhancement of sperm parameters induced by HTF++ buffer. This detrimental effect is attributable to the inhibition of both AMP-activated protein kinase (AMPK) activation and tyrosine phosphorylation signaling pathways. Our findings indicate that as a commonly used medicine for T2DM in clinic, the potential negative impact of metformin on fertility should be considered, especially for men of reproductive age who are undergoing glucose management and diabetes treatment.

Silver nanoparticles (Ag-NPs) are being increasingly integrated into biomedical and consumer products; however, their long-term safety is not fully understood. The liver and kidneys demonstrate an apparent susceptibility to the accumulation of Ag-NPs; however, the intensity and reversibility of the consequent toxicity necessitate further investigation. This study aimed to outline the hepatorenal toxic effects of orally administered Ag-NPs and to assess the potential for recovery through longitudinal biochemical, histopathological, and apoptotic assessments. Adult male albino rats were divided into control, Ag-NPs-treated, and recovery groups. Animals were administered oral Ag-NPs at a dosage of 1 mg/kg/day for a duration of 28 days. Biochemical assays of liver enzymes, renal function, and oxidative stress markers were assessed. Histopathological examination and immunohistochemical analysis for Bcl-2 and Bax expression were evaluated. Assessments were conducted immediately after treatment and at 2- and 8-week recovery intervals. Subchronic administration of Ag-NPs led to significant hepatorenal injury, as evidenced by elevated serum levels of ALT, AST, urea, and creatinine, increased malondialdehyde, and reduced antioxidant defenses. Histological analysis revealed hepatocellular degeneration, necrosis, vascular congestion, and renal tubular damage. Immunohistochemistry demonstrated a proapoptotic shift characterized by the downregulation of Bcl-2 and the upregulation of Bax. Longitudinal monitoring revealed significant recovery, with partial resolution of biochemical and structural changes at 2 weeks and near-complete restoration of hepatic function and morphology by 8 weeks. In contrast, renal recovery was relatively delayed. The oral administration of Ag-NPs results in significant, nevertheless predominantly reversible, hepatorenal toxicity, which is mediated through oxidative stress and apoptosis. Longitudinal monitoring has become essential for tracking the evolving patterns of injury and recovery, demonstrating its significance in nanoparticle toxicology and risk assessment. A key innovation of this study is the longitudinal recovery design, which allowed for dynamic evaluation of the progression and reversibility of hepatorenal injury following the cessation of Ag-NPs exposure.

Toxicological assessment is essential in NP approval for health and medical applications. Although 2D cell culture has been widely used, 3D models, especially spheroids, provide better predictive value for toxicological risk assessments since they replicate complex cellular interactions more accurately. In this study, different cytotoxicity assays were used to conduct a comparative nanotoxicological analysis of Adipose Stem Cells (ASC) grown in 2D and 3D (spheroid) systems, based on OECD guidelines. To evaluate the toxicity of nanostructured carbonated hydroxyapatite (nCHA) in ASC spheroids, the Neutral Red Uptake assay, and an ATP quantification assay were used. The results obtained from 2D cell monolayers and 3D spheroids were compared to determine the most suitable assay for spheroid analysis. Moreover, the IC50 for SDS treatment was determined and the spheroid morphology was analyzed after treatment with the nanoparticles. Overall, the three assays confirmed the absence of cytotoxicity of nCHA NPs in the ASC monolayer. In addition, the ATP quantification assay confirmed the absence of cytotoxicity of nCHA NPs in the ASC spheroids. Curiously, SDS cytotoxicity was higher in spheroids than in monolayer cultures, inducing the disaggregation of spheroids in a facile and concentration-dependent manner (IC₅₀ = 9.67 μg/mL in spheroids, approximately eight times lower than the IC₅₀ observed in monolayer cultures, 76 μg/mL). The nCHA NPs were also explored as spheroid functionalization agents. The nanoparticles did not affect ASC spheroids' morphology and diameter, and the nCHA are located mainly in the extracellular matrix of spheroids mimicking the mineral component of bone. Collectively, our findings demonstrated that spheroids are more sensitive than monolayers for evaluating nanoparticle biocompatibility, highlighting the potential of 3D cultures as new advanced models (NAMs) for improved nanotoxicology assessments. Furthermore, the functionalization of ASC spheroids with nCHA NP holds potential both as a 3D osteogenesis model and as a therapeutic product to promote bone regeneration.

This study investigates the effects of occupational carbon dioxide (CO₂) exposure on corneal tissue through Fourier transform infrared (FTIR) spectroscopy and chemometric analysis. Human activities have significantly increased atmospheric CO₂ levels, leading to potential health risks, particularly in confined environments such as mining, submarines, and enclosed workspaces. While CO₂ exposure is commonly associated with respiratory and cardiovascular effects, its impact on ocular health remains underexplored. Rats were exposed to three different CO₂ concentrations (3%, 5%, and 10%) in a controlled chamber for 8 h per day over a 30-day period. Second derivative analysis of corneal FTIR spectra revealed significant alterations in protein secondary structures, lipid composition, and phosphate group alterations, indicating CO₂-induced biochemical changes. Notably, exposure led to a shift in the amide I band from 1650 to 1643 cm^-1, suggesting a transition from α-helix to random coil structures in corneal proteins, which compromises tissue integrity. Changes in lipid hydrocarbon chain vibrations and increased gauche rotamers indicated disruptions in membrane order and fluidity. Additionally, phospholipid and nucleic acid modifications were observed, potentially affecting cellular stability. The study provides valuable insights into corneal bio-molecular alterations due to CO₂ exposure, contributing to a deeper understanding of environmental and occupational eye health risks.

Fentanyl, an ultra-potent synthetic opioid, has traditionally been characterized by its acute toxic effects, particularly respiratory depression. However, accumulating research indicates that its neurobiological influence extends far beyond its short pharmacological window, intersecting with several core mechanisms implicated in major neurodegenerative disorders. This review integrates multiscale evidence to propose a unified conceptual framework in which fentanyl may function not only as an acute neurotoxin but also as a putative accelerator of long-term neurodegenerative vulnerability. Drawing from molecular signaling, cellular stress pathways, glial-neuronal cross-talk, neurovascular regulation, synaptic architecture, and large-scale neural networks, we highlight fentanyl's capacity to trigger a convergent cascade encompassing hypoxic-metabolic reprogramming, mitochondrial fragmentation, TLR4-NF-κB-driven inflammation, NLRP3 inflammasome activation, complement-mediated synaptic pruning, astrocytic EAAT2 downregulation, and blood-brain barrier compromise. These alterations propagate through recursive cross-talk loops that progressively diminish neuronal resilience, destabilize oscillatory coherence, and weaken circuit-level adaptability. Importantly, mechanistic overlaps with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis suggest that fentanyl exposure may be mechanistically associated with processes capable of accelerating disease onset, exacerbating progression, or unmasking latent vulnerabilities, particularly in genetically or metabolically predisposed individuals. By reframing fentanyl as a systems-level destabilizer capable of imprinting persistent neurobiological changes, this model underscores the need for comprehensive biomarker development, longitudinal risk assessment, and targeted neuroprotective interventions. The integrative framework presented herein offers a foundation for predicting the long-term neurological consequences of fentanyl exposure and calls for urgent reconsideration of its role in population-level neurodegenerative risk.

Azo dyes, like Eriochrome Black T (EBT), enter freshwater ecosystems through textile effluent, posing potential risks to fish, which are key bioindicators and significant aquaculture resources. Despite the widespread use of azo dyes, toxicological data about their effects on air-breathing organs (ABOs) is scarce. This study examines the impacts of EBT on two catfish species, Heteropneustes fossilis and Clarias batrachus, selected for their distinctive ABO morphologies, which facilitate interspecific comparison to EBT intoxication. To achieve this goal, acclimatized fishes (both species) were exposed to three sublethal concentrations of the median LC50_96h value of EBT (1, 10, and 20 mg L^-1) for 96 h. Both species showed significantly higher accumulation of EBT, with the ABO of C. batrachus showing more significant accumulation. EBT exposure caused higher levels of lipid peroxidation and a substantial increase in the activities of antioxidant enzymes (such as SOD, GPx, and GR), while reducing catalase (CAT) activity. Histological examination showed structural damage and signs of respiratory distress in the ABOs of both species. Histochemical analysis also showed changes in number, percent area occupancy, and size of mucous cells, highlighting the deteriorating impact of EBT on fishes. Moreover, a careful assessment of the results demonstrated that C. batrachus manifested greater sensitivity to all concentrations of EBT in comparison with H. fossilis. These findings illustrate the susceptibility of fish respiratory organs to dye exposure and highlight the necessity of monitoring azo dye contamination for protecting aquaculture species and freshwater ecosystems.

Sturgeons are particularly vulnerable to the bioaccumulation of trace elements due to their longevity, benthic habits, and slow metabolic turnover. As aquaculture has become the primary global source of caviar, updated information on essential and toxic elements in farmed sturgeon products is needed to assess food safety. Twelve Acipenser baerii at reproductive stage 4 were sampled from a commercial farm in Tehran Province. Caviar was digested using acid-assisted mineralization, and essential (Zn, Cu, Fe, Se) and toxic (Cd, Pb, Cr, As, Hg) elements were quantified. Zinc was the most abundant element (31.0-35.9 mg/kg), while iron (3.0-4.9 mg/kg), copper (0.9-1.8 mg/kg), and selenium (0.38-0.64 mg/kg) fell within expected physiological ranges for farmed sturgeons. Concentrations of toxic elements were consistently low, Cd (0.01-0.07 mg/kg), Pb (0.12-0.20 mg/kg), As (0.07-0.15 mg/kg), Cr (0.14-0.31 mg/kg), and Hg (0.01-0.05 mg/kg), and remained below international safety thresholds. Overall, the trace-element profile of farmed A. baerii caviar indicates low contaminant levels and compliance with current food-safety standards. These results provide updated baseline information for Iranian sturgeon aquaculture and support the safety of caviar produced under controlled farming conditions.

The teratogenic potential of dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, widely used in managing type 2 diabetes, remains poorly characterized. This study investigates the dose-dependent developmental effects of dapagliflozin using a chick embryo model to provide critical insights into its safety during early developmental stages. Fertilized eggs were incubated under controlled conditions, and dapagliflozin was administered at concentrations of 1.0-2.5 mg/mL on embryonic Day 3. Morphometric analysis revealed significant reductions in body weight (up to 47%) in higher-dose groups compared to controls, with survival rates declining sharply (40% mortality) in the 2.5 mg/mL group. Histological examination demonstrated hepatic steatosis, pulmonary emphysema, and cardiac inflammation, alongside neural apoptosis and vascular abnormalities. Reactive oxygen species (ROS) levels, measured via DPPH (2,2-diphenyl-1-picrylhydrazyl), superoxide dismutase (SOD), and chloramphenicol acetyltransferase (CAT) assays, results from DPPH assay showed up to 94.7% of radical scavenging activity in heart tissue, while intracellular oxidative stress is confirmed by SOD and CAT assays, implicating oxidative stress as a central mediator of these abnormalities. This study provides the first comprehensive evidence of dapagliflozin's dose-dependent teratogenicity in a nonmammalian vertebrate model. The findings underscore the need for caution in prescribing dapagliflozin during pregnancy and warrant further investigations in mammalian systems to evaluate its potential implications for human health.

In recent years, one of the most striking consequences of overpopulation and consumption activities worldwide has been the rapid increase in environmental pollutants. Sodium pyrithione (NaPT) is an organosulfur compound commonly used for its antimicrobial and antifungal properties in industrial and personal care products. The primary objective of this study was to determine the impact of NaPT exposure on whole-body vitellogenin (Vtg) levels in adult male zebrafish, a highly relevant model for toxicological studies. As Vtg functions as a key estrogen-responsive biomarker, its induction serves as a critical indicator for assessing endocrine disruption, thereby justifying its selection as the primary endpoint. The adaptation period completed, stocked zebrafish were transferred to experimental aquariums and exposed to 1 and 5 μg/L concentrations of NaPT for 24, 72, 96 h, and 7 days. Commercial ELISA kits determined Vtg levels. The whole-body zebrafish Vtg analysis revealed that Vtg levels were increased at all time intervals, regardless of dose differences, compared to the control group (p < 0.05). Only at 24 h, low and high doses of NaPT had significantly different Vtg levels (p = 0.009). Biocidal products, among the environmental pollutants, have been found to affect time-dependent levels, especially in non-target organisms. The results suggested that NaPT exposure leads to significant alterations in Vtg expression, indicating its potential to interfere with endocrine function in fish. The observed endocrine-disrupting effects of NaPT directly underscore the potential risks marine pollution poses to ecosystem health and, consequently, to human well-being through shared environmental pathways.

Thiram is a dithiocarbamate fungicide that protects turf, fruits and ornamental plants. The purpose of this experiment was to ascertain the toxico-pathological effects of thiram induced toxicity in Cyprinus carpio. The fish were divided into four groups: Group A was kept as control, compared to groups B, C, and D exposed to 40, 80, and 120 μg/L thiram, respectively. The results indicated a significant (p < 0.05) reduction in body weight, while both the absolute and relative weights of gills increased significantly (p < 0.05) in fish exposed to a higher concentration of thiram. Hematological parameters showed significant (p < 0.05) reduction in RBCs, Hb, HCT, LYM, MCV, MCHC, and platelet counts, while neutrophils and leukocytes were significantly (p < 0.05) increased. Oxidative stress parameters (TBARS and ROS) were significantly (p < 0.05) increased, while antioxidant enzymes (GSH, POD, CAT, and SOD) were significantly (p < 0.05) decreased. Moreover, comet assay showed significantly (p < 0.05) higher percentile rate of DNA damage in gills tissues of treated fish exposed to 80 and 120 μg/L thiram compared to control fish. Moreover, results showed severe histopathological changes in the gills like aneurysm, degeneration of cartilaginous cores, disruption of primary lamellae, necrosis of lamellar pillars and atrophy of lamellae. Hence, thiram demonstrates severe detrimental effects on physical and hematological parameters, induces oxidative stress, affects anti-oxidant enzyme activity, causes DNA damage and leads to histopathological alterations in the gills tissues of the freshwater fish.