Archives of Toxicology最新文献

The cytosolic DNA-sensing cGAS-STING pathway and autophagy represent two evolutionarily conserved systems critical for innate immunity and cellular homeostasis. The cGAS-STING pathway detects mislocalized DNA, triggering inflammation via interferon and cytokine production. Conversely, autophagy maintains equilibrium by degrading damaged organelles and pathogens. Crucially, these systems engage in reciprocal regulation: autophagy constrains cGAS-STING hyperactivity through lysosomal degradation of immunostimulatory DNA and STING itself, while cGAS-STING signaling induces autophagy via TBK1-mediated phosphorylation of autophagy adaptors to mitigate self-damage. Dysregulation of this interplay drives pathology. For instance, defective autophagy in systemic lupus erythematosus permits mitochondrial DNA accumulation and cGAS-driven interferonopathy, whereas persistent STING activation in cancers suppresses autophagic tumor surveillance. This review aims to dissect the molecular mechanisms underpinning their crosstalk, delineate its disruption in autoimmune, neurodegenerative, and oncological diseases, and critically evaluate emerging therapies designed to pharmacologically rebalance this axis. These include combining cGAS-STING inhibitors with autophagy enhancers to suppress inflammation in interferonopathies, and pairing STING agonists with autophagy inducers to potentiate antitumor immunity.By synthesizing preclinical and clinical advances, we establish a framework for developing context-specific therapeutics that exploit the cGAS-STING-autophagy circuit-translating mechanistic insights into precision treatments for immune dysregulation disorders.

The lungs are the primary site of exposure to environmental stressors, making them particularly vulnerable to the effects of inhaled nanoplastic particles. Owing to their nanoscale size, nanoplastics penetrate deeper into the respiratory tract than microplastics do and are capable of interacting directly with alveolar cells. This review focuses on the impact of inhaling nanoplastic particles on mitochondrial function in lung tissue, particularly the activation of mitochondrial stress response pathways. Mitochondria, as central regulators of cellular energy and stress responses, exhibit heightened sensitivity to environmental stress. Many studies have shown that nanoplastic exposure disrupts mitochondrial functions, reduces the membrane potential, and induces oxidative stress, possibly causing inflammation and apoptosis. This review underscores the need for advanced research to understand the systemic effects of nanoplastics and their compounded toxicity when combined with other environmental pollutants. Studying the adaptive processes of mitochondria exposed to the stress of inhaled nanoplastics is particularly important because mitochondria are essential for life-supporting functions and cell fate decisions. Given that mitochondria are key cellular targets, studying their behavior may prove useful in finding strategies to reduce the health risks posed by nanoplastic inhalation.

The grouping of chemicals based on common properties or molecular mechanisms of action is pivotal for advancing regulatory toxicology, reducing data gaps, and enabling cumulative risk assessments. This study introduces a novel framework using chemical-gene-phenotype-disease (CGPD) tetramers derived from the Comparative Toxicogenomics Database (CTD). Our approach integrates publicly available toxicogenomics data to identify and cluster chemicals with similar molecular and phenotypic effects. The considered chemicals belong to diverse use groups including pesticides, pharmaceuticals, and industrial chemicals. We validated our method by comparing CGPD tetramer-based clusters with cumulative assessment groups (CAGs) that have been established by EFSA for pesticides and demonstrate strong overlap with established groupings while identifying additional compounds relevant for risk assessment. Key examples include clusters associated with endocrine disruption and metabolic disorders. By bridging omics-derived molecular data with phenotypic and disease endpoints, this framework provides a comprehensive tool for chemical grouping and the support of evidence-based regulatory decision-making to facilitate the transition to next-generation risk assessment methodologies.

Epilepsy is a prevalent neurological disorder characterized by recurrent and unprovoked seizures. Despite the availability of anti-epileptic drugs (AEDs), a significant number of patients are still suffering from drug-resistant epilepsy. Neuropeptide Y (NPY) signaling system has emerged as a potential target for the development of anti-epileptic drugs due to its modulation of epileptic activity. In this study, we investigated the therapeutic potential of our previously discovered Scleractinia-derived NPY-like peptide (TpNPY) in seizure disorders. The anticonvulsant effects of TpNPY were evaluated using PTZ-induced seizures in zebrafish and mice in vivo. Furthermore, the underlying molecular mechanisms of TpNPY were assessed using glutamate-induced excitotoxicity models in HT22 mouse hippocampal cells in vitro. Our findings indicated that TpNPY could alleviate PTZ-induced seizure behavior, reduce the expression of seizure-associated immediate-early genes and the production of Reactive Oxygen Species (ROS) in zebrafish. In mice, TpNPY improved seizure behaviors, decreased inflammatory cytokine levels, and ameliorated abnormal glial activation in a PTZ kindling epileptic model. Besides, the administration of TpNPY could attenuate the PTZ-induced anxiety levels and improve recognition memory deficits. Moreover, TpNPY promotes neurogenesis and neural synaptic plasticity through the BDNF/TrkB signaling pathway. Additionally, TpNPY restored cell injury and attenuated oxidative stress in glutamate-challenged HT22 cells through the Nrf2/HO-1 signaling pathway. These results highlight the potential therapeutic efficacy of TpNPY in the treatment of seizures and provide new insights into the development of coral-derived anti-epileptic peptide-based drugs.

Thyroid hormones are crucial for growth, brain development, metabolism, and organ maturation in developing foetuses. Until 12-14 weeks of gestation, the foetus depends on maternal thyroid hormones before its own thyroid gland begins functioning. Environmental chemical and medication exposure during pregnancy may affect the thyroid hormone supply to the foetus by interfering with placental transport carriers and metabolism. This systematic review evaluated chemical effects on thyroid hormone passage from maternal to foetal circulation, modulated by transporters and enzymes. A search of PubMed, Scopus, and Web of Science identified 24 relevant studies published between 1900 and 2024, including 4 epidemiological studies, 8 in vivo animal studies, and 15 in vitro studies. The review found evidence that persistent organic pollutants, flame retardants, endocrine disrupting chemicals, pharmaceuticals, and other substances can disrupt placental thyroid hormone signalling through various mechanisms. These include alterations in transporter expression and enzyme activity in the placenta. Several studies observed sex-specific effects, with male and female foetuses showing different responses to chemical exposure. In some cases, sex differences were in the degree of change, while in others, the same chemical had opposite effects based on foetal sex. However, many studies used choriocarcinoma cell lines, which may not fully replicate human placental processes. This review highlights the need for further research to elucidate chemical exposure's impact on foetal thyroid hormone status and the role of foetal sex using human physiologically relevant models.

Synthetic cannabinoid receptor agonists (SCRAs) are marketed as 'legal' cannabis alternatives, but are often much more potent and toxic, increasing the risk of (severe) intoxication. Initially sold as herbal preparations, SCRAs are now increasingly found in e-liquids due to the growing popularity of e-cigarettes. Traditional analytical methods, such as (high-resolution) mass spectrometry, can detect these substances but face limitations regarding time and cost, and require sophisticated equipment and frequently updated mass spectral libraries. Additionally, the continuous emergence of new SCRAs, aiming at evading legislation or detection, further challenges these methods. Activity-based screening, evaluating a sample's inherent cannabinoid activity rather than relying on structural identification, offers an effective alternative. Here, an in vitro CB₁/β-arrestin2 recruitment assay utilizing the NanoBiT^® principle was, for the first time, applied to an e-liquid from an intoxicated patient, demonstrating strong cannabinoid activity. Employing the assay to screen a set of 23 e-liquids identified six SCRA positive e-liquids. Moreover, in five e-liquids, a decreased CB₁ activity was observed and experimentally confirmed to be attributable to the presence of the natural cannabinoid cannabidiol (CBD). As this could potentially result in a false-negative screening, an adapted protocol was evaluated, incorporating the injection of a CB₁ agonist, CP55,940, while the assay was running. This improved methodology allowed the detection of both SCRAs and CBD in e-liquids. Furthermore, the fast and 'untargeted' nature of this approach makes it a future-proof method for the detection of SCRAs, serving as an effective first-line screening tool, complementing the conventional analytical techniques.

Nitrosamines (NAs) are a class of compounds designated as probable human carcinogens by the IARC, acting DNA mutagens, participating in alkylating DNA at both N⁷- and O⁶- positions of guanine, particular for N-nitrosodimethylamine (NDMA). In the present study, we report the development of an LC-MS/MS-based assay to simultaneously measure guanine (Gua), O⁶-methylguanine (6MGua), and N⁷-methylguanine (7MGua) in DNA hydrolysates. With the use of three stable isotope internal standards (6-CD₃-Gua, 7-CD₃-Gua, and Gua-¹³C₂,¹⁵N), validation, i.e. determination of selectivity, precision, accuracy, extraction recovery, matrix effect, stability, and feasibility was evaluated by use of the approach developed. This method was used for simultaneous determination of the levels of Gua, 6MGua, and 7MGua in DNA acidic hydrolytes present in a series of samples from human and rat primary hepatocyte treated with NDMA. The stable isotope dilution-based approach was proven to be selective, sensitive, accurate, and convenient, which is a good and convincing in vitro assay for the quantitative analysis of DNA methylation such as 6MGua and 7MGua in Gua.

Adverse outcome pathways (AOPs) have become an internationally recognized framework for chemical risk assessment, linking molecular initiating events (MIEs) to adverse outcomes through measurable key events. Despite their regulatory acceptance in toxicology, no systematic AOPs have yet been developed for vaccines to our knowledge. This commentary argues that extending the AOP paradigm to vaccine adjuvants is both timely and potentially feasible. Adjuvants are chemically defined entities that reproducibly engage innate immune pathways, making them more tractable starting points for immune AOP construction than antigens, which are variable and context-dependent. We illustrate this concept through three exploratory AOP sketches - systemic inflammation, autoimmunity, and hypersensitivity, and provide exemplar biomarker-pathway-adjuvant linkages as a prototype roadmap. Such efforts are not intended to replace existing preclinical, clinical, or pharmacovigilance systems, but to complement them with structured mechanistic context. We propose these as exploratory frameworks to be iteratively refined as evidence accumulates, recognising the complexity and context‑dependence of immune responses. By framing vaccine safety within transparent, testable pathways, immune AOPs could enhance mechanistic understanding of rare adverse events, guide hypothesis-driven use of new approach methodologies (NAMs), and strengthen confidence in vaccine safety science.