Archives of Toxicology最新文献

Nanoagrochemicals aim to increase safety and sustainability, representing an alternative to conventional agrochemicals. Given the infancy of this field, the risk-benefit analysis for nano-enabled agrochemicals remains unresolved. New Approach Methodologies (NAMs), such as omics, are high on the agenda to move beyond standard hazards, as the investigation of the mechanisms of toxicity deliver valuable information to understand the risks. NUCOP-M^®, a Cu-based commercial formulation containing nano-features, was previously assessed in Enchytraeus crypticus (Oligochaeta), impacting survival and reproduction based on the standard OECD Enchytraeid Reproduction Test (28 days) and its extension (56 days). The aim of the present study was to understand the mechanisms of toxicity of NUCOP-M^® at sublethal concentrations (100 and 500 mg Cu/kg soil of NUCOP-M^®) in short and longer exposure (2, 21 days) using a high-throughput gene expression microarray (NAMs) containing probles for 44,000 genes (a 4 × 44 K microarray). Results showed high transcriptomic response after 21 days exposure, although after 2 days there was an indication of increase in intracellular transport. At 21 days, the gene expression profile was compatible with effects on embryo development, which could be linked to reproductive effects observed at 28- and 56-days of exposure. Several of the genes found up-regulated points towards mitochondrial stress and activation of mechanisms to cope with oxidative stress. This study provides important insights into the mechanisms of toxicity of nanoagrochemicals in non-target species, filling a significant knowledge gap.

Gentamicin (GEN), an aminoglycoside antibiotic, induces nephrotoxicity primarily via mitochondrial dysfunction. This review summarizes mechanisms including reactive oxygen species (ROS) overproduction, mitochondrial DNA (mtDNA) damage, impairment of oxidative phosphorylation, and mitochondrial permeability transition pore (mPTP) activation. These mitochondrial alterations lead to adenosine triphosphate (ATP) depletion, apoptosis, and renal injury. In addition to apoptotic pathways, necrotic cell death can also be triggered, further aggravating kidney damage. Furthermore, GEN has been reported to directly interfere with mitochondrial ribosomes and gene expression, highlighting mitochondria as both targets and amplifiers of cellular toxicity. Therapeutic approaches targeting mitochondrial integrity, including antioxidants and mitochondrial transplantation, demonstrate potential nephroprotection. Additional strategies such as mPTP, stimulation of mitochondrial biogenesis, and pharmacological modulators of mitochondrial respiration have also shown promise in experimental studies. Understanding mitochondrial mechanisms underlying gentamicin-induced renal injury is crucial for developing targeted therapeutic strategies. A more comprehensive knowledge of mitochondrial regulation, organelle crosstalk, and early biomarkers of dysfunction will facilitate translation into clinical practice. Overall, preserving mitochondrial function represents a promising avenue for reducing nephrotoxicity while maintaining the antibacterial efficacy of GEN.

Phosphorus is commonly part of the diets in developed countries, both as a natural component of protein-rich foods and as a food additive. Consumption of food containing high amounts of phosphate as a food additive has continued to rise over time, resulting in increasing dietary exposure to phosphate. In 2019, an evaluation of phosphoric acid and phosphates conducted by the European Food Safety Authority (EFSA) identified young populations as groups with exposures exceeding the Acceptable Daily Intake (ADI), and also raised concern that the current ADI may not be sufficiently protective for individuals with an impaired renal function, which may account for 10% of the general population. The Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) critically reviewed the safety of dietary phosphate, with a particular focus on the kidney as the primary target organ, taking into account the occurrence and content of phosphate in food, the most recent exposure estimates, the bioavailability of phosphate from different sources, the evidence linking excessive phosphate intake to kidney damage in animal models and humans as well as the exceedance of the current ADI in children. Moreover, the SKLM identified data gaps and research needs that should be addressed to improve the risk assessment of phosphate, with a special focus on vulnerable population groups. Based on the presented evidence, the Commission concludes that excessive dietary phosphate intake warrants further attention regarding possible health effects in vulnerable population groups or at exposure levels exceeding the ADI. Finally, the SKLM suggests a battery of risk management measures to reduce dietary exposure to phosphate, particularly in infants, toddlers and children, and to protect patients with chronic renal diseases.

Pyrazinamide (PZA) has been approved for the treatment of tuberculosis in clinical practice. However, its adverse effects, particularly hepatotoxicity, have raised concerns. The present study aimed at exploring the potential relationship between PZA-induced hepatotoxicity and its metabolites resulting from metabolic activation. Glutathione (GSH) conjugates with confirmed structures were detected in mouse cytosol incubations containing PZA or pyrazinoic acid (POA, a major metabolite of PZA) supplemented with glutathione (GSH). Such GSH metabolites were also observed in both liver homogenates from mice administered with PZA and mouse primary hepatocytes exposed to PZA. Aldehyde oxidase (AO) and xanthine oxidase (XOD) were identified as key enzymes in the metabolic activation of PZA and POA. Both vitamin C (VC) and N-acetylcysteine (NAC) were found to reduce the generation of GSH conjugates derived from PZA and POA in incubation systems. Additionally, VC alleviated the susceptibility of hepatocytes to PZA-induced cytotoxicity. Consecutive administration of PZA for 7 days resulted in a marked elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice, and PZA-derived hepatic protein adduction was detected. Allopurinol administration attenuated the elevated serum ALT and AST in company with a reduction in the formation of GSH conjugates. This work provides solid evidence for the correlation between the metabolic activation of PZA and PZA-induced hepatotoxicity, enhancing the understanding of the underlying mechanisms of PZA toxicity in terms of molecular chemical structure.

Tributyltin (TBT) is an environmental contaminant that induces diverse toxic effects in mammals, but the cellular mechanisms underlying adaptation to TBT stress remain poorly understood. Conjugation of ATG8s to single membranes (CASM) is a noncanonical LC3‑lipidation pathway activated by various stressors, distinct from canonical autophagy. We previously showed that TBT reduces lysosomal acidity and inhibits autophagy in SH-SY5Y cells. Furthermore, we observed TBT-induced LC3-II accumulation, which was reduced by bafilomycin A₁, and tubular LC3-positive structures as hallmarks of CASM. In this study, we investigated whether TBT activates CASM. TBT (700 nM) induced LC3-II accumulation, which was completely blocked by bafilomycin A₁ in SH-SY5Y and HeLa cells. Unlike autophagy, TBT induced LC3-II accumulation even under class III PI3K inhibition by wortmannin and in FIP200-knockout cells. Salmonella effector protein SopF, which inhibits V-ATPase-ATG16L1 association required for CASM, inhibited TBT-induced LC3-II accumulation. In FIP200-knockout cells, TBT induced LC3 accumulation on lysosomes, the primary CASM target. TBT also promoted nuclear translocation of transcription factor EB (TFEB) in a SopF-sensitive manner. Together, these results identify CASM as a lysosomal stress response to TBT, induced via the V-ATPase-ATG16L1 axis, leading to TFEB activation. This mechanism provides a toxicological framework for understanding xenobiotic-induced lysosomal adaptations.

This position paper was collaboratively written during the international expert symposium "EU Chemicals Assessment - Risk- or Hazard-based?" that was organised by the German Federal Institute for Risk Assessment (BfR) in Berlin on November 27th and 28th 2025. Twenty experts from several institutions and European countries considered the scientific merits of both hazard-based and risk-based approaches to chemical safety assessment. While hazard information is essential, it does not reflect real-world exposure conditions that determine the likelihood of harm. On balance, we support a risk-based approach because it enables more proportionate, transparent and scientifically grounded regulatory decisions.

There is increasing concern that thyroid hormone system-disrupting chemicals (THSDCs) may affect brain development during gestation and lactation. THSDCs comprise a wide range of natural and synthetic xenobiotics that activate diverse biological pathways. However, how disruption of specific molecular targets alters maternal thyroid hormone homeostasis and brain development in the offspring warrants further investigation. To address this question, this study investigates the effects of two THSDCs administered to pregnant rats from gestational day 6 through postnatal day 21: 5-propyl-2-thiouracil (PTU, 2.4 mg/kg/day), inhibitor of thyroid hormone synthesis, and pregnenolone-16α-carbonitrile (PCN, 300 mg/kg/day), inducer of hepatic enzymes involved in thyroid hormone metabolism. Circulating and brain thyroid hormone levels, enzymatic activities, and histopathology were assessed in dams and offspring. To further elucidate underlying mechanisms, multi-omics analyses combining proteomics, metabolomics, and spatial transcriptomics were performed on target organs including the thyroid gland, liver, and brain. Exposure to PTU resulted in severe thyroid hormone depletion in both serum and brain, accompanied by structural brain abnormalities, whereas PCN primarily induced hepatic enzyme activity with minimal effect on circulating thyroid hormone levels. Despite these distinct modes of action, multi-omics integration revealed convergent perturbations across molecular layers in the brain, particularly affecting energy metabolism and cytoskeletal organization with more pronounced effects observed following PTU exposure. Overall, multi-omics profiling enabled robust and highly sensitive identification of molecular signatures reflective of PCN exposure, without significant evidence of associated adverse toxicological effects. This approach highlights the value of multi-omics for mechanistic characterization and predictive assessment of THSDC-induced neurodevelopmental toxicity.

We herein present the development and application of a forensic mass spectrometry-based procedure simultaneously targeting hard keratins from human hair adducted with sulfur mustard (SM) and its structural analogues sesquimustard (Q) and O-lost (T). These alkylating chemicals represent blister agents banned by the Chemical Weapons Convention (CWC). The procedure was applied to an authentic hair sample of an SM-poisoned patient and thus allowed for the first time the proof of exposure to SM based on keratin adducts in a real case of poisoning. Whereas adducts of SM were detected, those of Q and T were not found. Contact of SM, Q and T with hair induced the alkylation of side chains of glutamic acid (E*) residues in diverse hard keratins (adduct formation). For analysis hair proteins were subjected to lysis to make them soluble and subsequently to proteolysis with pepsin to generate adducted peptides. Micro liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (µLC-ESI MS/HR MS) allowed the detection of the three biomarker peptides AE*IRSDL, FKTIE*EL and LE*TKLQF. The characteristic alkyl-chain hydroxyethylthioethyl (HETE) was attached by SM, hydroxyethylthioethylthioethyl (HETETE) derived from Q and the hydroxyethylthioethyloxyethylthioethyl (HETEOETE)-moiety originated from exposure to T. Accordingly, we herein present an extended and improved forensic method for the biomedical verification of hair exposure to blister agents. Due to the currently growing threat by chemical warfare agents we also included some general toxicological and bioanalytical remarks of SM poisoning helpful not only for physicians and toxicologists.