Archives of Toxicology最新文献

Unhealthy diets (e.g., higher red meat consumption) and tobacco exposure are major risk factors for colorectal cancer (CRC), contributing the toxic substances exposure of polycyclic aromatic hydrocarbons (PAHs). However, the genetic regulation of PAHs metabolism-related genes involved in CRC susceptibility remains unexplored. To address this gap, we performed a meta-analysis using cross-ancestry genome-wide data, including East Asian populations (Chinese: N_case = 1150, N_control = 1342; Japanese: N_case = 6692, N_control = 27,178) and European (N_case = 78,473, N_control = 107,143) to evaluate the genetic association of 47 PAHs-metabolism-related genes with CRC risk. Expression patterns were derived from Nanjing ColoRectal Cancer cohort (NJCRC) and public datasets, including a total of 828 bulk RNA-Seq samples, 62 samples for cell-type-specific expression samples, and 50 paired protein validation samples. Finally, we observed that rs7927381 C > T in GSTP1 was associated with reduced CRC risk (odds ratio (OR) = 0.94, 95% confidence interval (CI) = 0.92-0.96, P = 1.90 × 10^-7). Intriguingly, it downregulated the GSTP1 expression specifically in plasmablast cells. This effect may be attributed to its location in the DNA-hypersensitive regulatory region with enhancer and promoter activity, which could alter transcription factor binding. Notably, both GSTP1 mRNA and protein level were upregulated in CRC tissues, suggesting its elevation may influence PAHs metabolism through the oxidative phosphorylation and ribosome biological processes, promoting carcinogenesis. In conclusion, we identified GSTP1 rs7927381 as a cross-ancestry genetic variant affecting CRC risk through influencing PAHs metabolizing, offering new insights into the genetic mechanisms underlying CRC.

Smoking is a well-established risk factor for cardiovascular diseases, yet direct evidence linking cigarette smoke (CS) exposure to neointimal formation remains limited. To address this gap, we investigated the effects of CS exposure on neointimal formation using an injury-induced arterial mouse model. Neointimal formation was induced in the femoral artery via mechanical injury with a guidewire, and mice were exposed to CS generated from 3R4F reference cigarettes at a total particulate matter concentration of 600 µg/L for 2 h daily. CS exposure commenced three days prior to injury induction and continued until euthanasia on days 7 or 14 post-injury. CS exposure significantly exacerbated neointimal formation; however, in the absence of injury, it did not induce structural alterations in the femoral artery. In vitro, cigarette smoke extract (CSE) at 0.1%-corresponding to approximately 50 ng/mL nicotine, a clinically relevant concentration in smokers-enhanced the proliferation of aortic smooth muscle cells, a critical process in neointimal development. However, CSE exhibited minimal effects on other cellular processes involved in neointimal formation, including phenotype switching, adhesion, migration, and extracellular matrix deposition. Mechanistically, CSE exposure increased Akt and FOXO3a phosphorylation, leading to a downregulation of p27 and an upregulation of CDK2 and cyclin E, ultimately promoting Rb phosphorylation and cell cycle progression. In conclusion, although CS alone does not appear sufficient to initiate neointimal formation, it significantly exacerbates or accelerates its progression in a primed vascular environment. The promotion of vascular smooth muscle cell proliferation via cell cycle progression may underlie this effect.

Many government agencies and expert groups have estimated a safe dose (aka a "reference dose," [RfD]) for perfluorooctane sulfonate (PFOS). Notably, these agencies have derived safe doses that vary over at least 600-fold range. The range is larger still if one includes the U.S. Environmental Protection Agency (USEPA) current science-policy position under the Safe Drinking Water Act, which is that the only safe dose of PFOS is zero. This wide range in safe dose-estimates is surprising, since PFOS is a relatively well-studied, and ubiquitous, chemical. The Steering Committee of the Alliance for Risk Assessment (ARA) called for health-scientists interested in attempting to understand and, if possible, narrow this range of estimates. An advisory committee of eight scientists from four countries was selected from nominations received, and a subsequent invitation to scientists internationally led to the formation of three teams comprised of 24 scientists from nine countries. Each team independently reviewed toxicologic and epidemiologic data, and developed PFOS safe dose-estimates. All three teams concluded that currently available epidemiologic data could not form a reliable basis for PFOS safe dose-assessments. In contrast, results of bioassays of PFOS in laboratory monkeys and rats did provide usable bases from which serum-concentration-based "points of departure" were derived. After applying several, necessarily imprecise, uncertainty factors, the three groups derived PFOS safe dose-estimates that ranged, narrowly, from 20 to 100 nanograms (ng) of PFOS/kg body weight/day. In contrast, USEPA's current (United States Environmental Protection Agency (USEPA) (2024) Human health toxicity assessment for perfluorooctane sulfonic acid (PFOS) and Related Salts. EPA Document No. 815R24007.) estimate of the safe dose is 0.1 ng of PFOS/kg-day.

The venom of hazardous jellyfish contains harmful substances to human health, such as metalloproteinases, which are challenging to purify. Therefore, identifying substrate sequences using crude venom is crucial for the development of peptide inhibitors. This study utilized a designed peptide library and an abundance-based hydrolysis product analysis approach to identify the substrate sequences of toxin metalloproteinases from Nemopilema nomurai nematocyst venom (NnNV) and further modified these sequences into peptide inhibitors. Specifically, a peptide library comprising 41 potential substrate sequences was constructed and incubated with NnNV. 12 substrate sequences and 14 cleavage sites were identified from the hydrolysis products. In the design of peptide inhibitors, thiol (-SH) and phosphate groups (-PO₃H₂) were used as zinc-binding groups, and sixty derived peptides were obtained. 15 peptide inhibitors were selected for their efficacy in inhibiting toxin metalloproteinase activity, with CPRGQPIIQDV demonstrating the most potent effect. CPRGQPIIQDV mainly presented β-sheet and random coil structures, and significantly reduced the cytotoxicity and pro-inflammatory effects of NnNV on RAW264.7 cells. This study established a method for identifying metalloproteinase substrate sequences using crude jellyfish venom and provided an initial design and screening of peptide inhibitors, offering new insights into the management of jellyfish stings.

Scorpion venom contains a diverse array of bioactive compounds, including peptides, proteins, enzymes, and alkaloids, which hold significant medicinal potential despite their toxicity due to interactions with voltage-gated sodium, potassium, and calcium channels affecting the autonomic nervous system. A comprehensive study analyzing literature from esteemed scientific databases (2000-2025) evaluates the structural and functional properties of these venom components. Enzymes and proteins exhibit anticancer properties through apoptosis induction, angiogenesis inhibition, and immune modulation, while ion channel modulators show promise in treating neurological disorders, pain, and cardiac arrhythmias. Antimicrobial peptides demonstrate high efficacy against multidrug-resistant (MDR) bacteria. Certain alkaloids also offer antioxidant and immunoregulatory benefits. A pioneering study on advanced nano-systems derived from scorpion venom has highlighted their potential to enhance drug delivery and therapeutic efficacy. Translational promise is further supported by advancements in recombinant expression, structure-activity relationship investigations, and innovative delivery strategies, despite challenges such as toxicity and stability. Scorpion venom thus represents a rich source of compounds with significant medicinal and biological applications.

The development of reliable predictive models for nephrotoxic agents remains a critical challenge in drug development, given safety concerns associated with kidney toxicity. Conventional molecular descriptors generally fail to capture essential spatial and electronic features necessary for accurate nephrotoxicity prediction, underscoring the need for novel descriptor approaches. This study presents a novel projection-based method for nephrotoxicity prediction by converting chemical structures into 2D maps for deep learning via 3D spatial transformation to enhance both feature representation and model performance. Both Mollweide and Equirectangular projections were utilized to transform 3D molecular geometries into optimized 2D representations. The 2D molecular maps incorporated three key molecular properties to display the information of atom-based projections showing atomic positions and identities, electrostatic projections visualizing charge distribution, and vdW projections illustrating molecular steric potentials. The Mollweide projection based on atom color demonstrated superior predictive performance, achieving 83% predictive accuracy with an AUC of 0.86, establishing it as the most effective CNN model. The electrostatic and vdW projections transformed atomic spatial data into electrostatically and sterically informative maps, enabling more nuanced molecular pattern recognition and enhanced representation. The reliability of the model was validated through different methods, including independent verification on test set combined with five-fold cross validation as well as comparisons with traditional descriptor-based models using the benchmarking method. Our findings demonstrate that projection-based molecular representations show strong potential for nephrotoxicity screening, opening new possibilities for toxicology prediction and drug safety advancement.

Ayahuasca is a psychoactive brew traditionally used in religious rituals by indigenous Amazonian populations and South American syncretic religions such as Santo Daime and União do Vegetal. Its psychoactive effects are primarily due to N,N-dimethyltryptamine (DMT), while harmine (HRE), a β-carboline alkaloid, inhibits monoamine oxidase (MAO), enabling DMT's oral bioavailability. Recent studies demonstrate Ayahuasca's therapeutic potential in treating substance use disorders, including cocaine use disorder, which involves neurotoxic effects. However, no in vitro studies to date have evaluated the neuroprotective potential of Ayahuasca compounds in this context. This study investigated the effects of DMT and HRE, isolated and combined, on cocaine-induced toxicity in human SH-SY5Y neuroblastoma cells. Cells were exposed for 48 h to various concentrations of DMT and HRE (0.1-1000 µM), cocaine (0.5-5 mM), and DMT:HRE combinations (10:10 to 10:100 µM). The non-toxic concentrations of DMT (10 µM) and HRE (10 µM), both isolated and combined (10:20 µM DMT:HRE), were co-incubated with the lethal concentration 50 (LC₅₀) of cocaine (2.5 mM) to assess neuroprotection. Cell viability was evaluated by MTT assay, apoptosis by flow cytometry using annexin-V/propidium iodide staining, and protein expression of apoptosis-related markers (Bax, Bcl-2, and caspase-8) by western blot. The results showed increased cell viability in co-treatment groups (cocaine + DMT and/or HRE) when compared to cocaine-only groups. Flow cytometry revealed partial to complete protection against apoptosis in co-treated cells. Western blot demonstrated reduced caspase-8 expression in cells treated with Ayahuasca compounds plus cocaine versus cocaine alone. In conclusion, DMT and HRE-isolated and combined-provided partial neuroprotection against cocaine-induced toxicity in SH-SY5Y cells. These findings support Ayahuasca-derived alkaloids as candidates for further investigation in neuroprotection and substance use disorder treatment.

Synthetic cannabinoids (SCs) have been increasingly associated with neurodevelopmental impairment; however, the underlying mechanisms remain poorly understood. In particular, the impact of SCs on mitochondria during neurodifferentiation remains largely unexplored, despite the central role of these organelles in this process. Building upon our previous findings that THJ-2201, a widely used SC, enhances neurite outgrowth in NG108-15 neuroblastoma-glioma cells at biologically relevant concentrations (1 pM-1 μM), we investigated whether this SC influences mitochondrial function, morphology, and dynamics during neurodifferentiation. THJ-2201 exposure caused a 30-40% reduction in intracellular ATP levels in a CB1-dependent manner, along with a 20-30% decrease in TMRE retention during NG108-15 neurodifferentiation. Cells treated with 1 μM THJ-2201 failed to sustain the expected increase in VDAC levels (an indirect marker of mitochondrial mass) during regular differentiation. Concurrently, THJ-2201 elevated PGC-1α levels, a key regulator of mitochondrial biogenesis, by disrupting its translocation to the nucleus. Expression of both fusion (Opa1, Mfn1, and Mfn2) and fission (Drp1 and Fis1) markers exhibited a less pronounced increase between 24 and 72 h in THJ-2201-treated cells. Mitochondrial morphology exhibited alterations in mean area, perimeter, branching, and circularity in the soma after 72 h exposure. Additionally, THJ-2201 reduced mitochondrial mobility in neurites without affecting their average speed or run length and led to a mitochondrial accumulation within neurites, as indicated by decreased Miro1 expression. Overall, these findings suggest that THJ-2201-induced mitochondrial remodelling and redistribution may transiently enhance local energy supply for neurite outgrowth, but at the expense of somatic mitochondrial function, resulting in an overall bioenergetic imbalance.

The increasing use of bee products in the food, cosmetic, and pharmaceutical industries has intensified interest in their therapeutic properties. However, the safety of these natural compounds warrants careful consideration, particularly within the context of pharmacovigilance. This study aimed to conduct an integrative review of the scientific literature and official pharmacovigilance databases (Notivisa, EudraVigilance, FDA/MedWatch, TGA, among others) to identify adverse effects and toxicological risks associated with the use of honey, apitoxin (bee venom), propolis, royal jelly, bee pollen, and beeswax. The findings indicated that although widely used, these products are not free from risk. Reported cases included infant botulism and grayanotoxin poisoning linked to honey; anaphylaxis and fatalities following therapeutic use of bee venom; contact dermatitis and systemic reactions induced by propolis; severe asthma attacks after royal jelly consumption; adulteration of pollen-based supplements with illicit pharmacological substances; and allergic reactions to beeswax in cosmetic products. Allergic responses were the most prevalent type of adverse event, particularly among atopic individuals. These findings highlight the need for appropriate labeling, post-marketing surveillance, and educational campaigns to ensure the safe use of these products. It is concluded that despite their recognized benefits, apitherapeutic products must be used with caution, and the strengthening of pharmacovigilance systems is essential to safeguard public health.

Percutaneous penetration is an important human exposure route, but it is influenced by multiple factors and can vary greatly between different substances and exposure conditions. Furthermore, skin characteristics such as thickness of different anatomic sites may have an effect on percutaneous absorption. Despite a potential relevance for safety measures, little is yet known for occupationally relevant skin sites, like hands. We conducted a human in vivo study aiming to identify the effect of anatomic sites on percutaneous absorption of 2-phenoxyethanol. Two human volunteers were dermally exposed to 2-phenoxyethanol (loading dose: 0.2 mg/cm² skin) at seven different anatomic skin sites with areas of 200 and 400 cm², respectively. Blood and urine samples were collected and analyzed for 2-phenoxyethanol and its two main metabolites up to 48 h post-exposure. Relative absorption ratios showed moderate site differences ranging from 0.89 to 1.64 (compared to the forearm) as the overall renal recovery was between 23 and 43% of applied 2-phenoxyethanol. Inter-individual variability was in a similar range. A notable influence of the exposed site could, however, be observed for the penetration speed which was highest at the forehead and neck, and slowest at the hand palms. Differing ratios of unmetabolized 2-phenoxyethanol and its main metabolite found in blood point to a site-depending intradermal metabolism. This study revealed major findings concerning the velocity of percutaneous penetration at different skin sites, which is relevant for adequate skin protection. The obtained data broaden the knowledge about site-related variations in percutaneous absorption and thus can improve future toxicological evaluations.