Archives of Toxicology最新文献

The current study investigated the effects of two per- and polyfluoroalkyl substances (PFASs) named perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) on osteoclastogenesis and explored the underlying mechanisms. The primary bone marrow macrophages extracted from mice were supplied for osteoclast (OC) induction, and exposed to PFOA and PFOS at the doses of 0.25, 2.5, 25, and 75 μM during their differentiation. Real-time PCR and Western blot were used to assess the expression of OC-specific molecules and connexin 43 (Cx43). TRAP staining was performed to identify the mature OCs. Ethidium bromide uptake experiments were adopted to evaluate the hemichannel activity. For mechanism exploration, the hemichannel inhibitor, carbenoxolone (CBX), was used to incubate the cells during PFAS exposure. According to the results of our experiments, the PFASs promoted osteoclastogenesis and enhanced the Cx43 expression and hemichannel activity. After the treatment of CBX, the promoted osteoclastogenesis was significantly down-regulated, indicating the critical role of hemichannels.

Micro- and nanoplastics (MNPs) are emerging environmental threats, with increasing evidence of their profound ecotoxicological and human health impacts. Although these findings highlight the significant toxicity of MNPs, there has been a lack of systematic discussions on the toxicological impacts from the perspective of the physicochemical properties of MNPs. This gap severely restricts in-depth exploration of their toxicity mechanisms and hinders the development of future toxicity mitigation technologies. This review synthesizes current knowledge on the health effects of MNPs, focusing on the factors influencing their toxicity, such as size, material composition, surface properties, and aging processes. We also explore how MNPs interact with environmental pollutants, accumulate in aquatic and terrestrial organisms, and accumulate in human tissues, leading to oxidative stress, inflammation, and endocrine disruption. Despite growing evidence, critical knowledge gaps remain, particularly regarding the long-term exposure effects, mechanisms of toxicity, and the impact of MNPs on vulnerable populations. We discuss limitations in current detection methods and the need for more comprehensive studies to understand the synergistic effects of MNPs in combination with other pollutants. Finally, future research directions are proposed, emphasizing the need for standardized methodologies, in-depth toxicity mechanisms, and the development of effective mitigation strategies.

Liver steatosis resulting from chemical exposure is a growing clinical concern, pointing to the need for early detection in chemical safety assessments. New approach methodologies (NAMs) based on adverse outcome pathway (AOPs) networks are emerging tools to assess the safety of chemicals as an alternative to animal studies. Amongst others, NAM can include a human-based in vitro system linked to a battery of complementary assays, each measuring an individual key event within the respective AOP network. These AOP-based NAMs allow to acquire mechanistic insight, while facilitating the translation of in vitro data into outcomes relevant to hazard assessment. The current review provides pragmatic guidance for developing NAMs entailing an AOP network-driven in vitro testing platform suitable for steatogenic hazard assessment of chemicals, intended for use in academic, industrial and regulatory settings. In a first part, underlying mechanisms for highly specific key events for liver steatosis are described. In a second part, a workflow is provided for the establishment of NAMs, including the selection of human-based in vitro cell models, functional in vitro assays, reference control chemicals, exposure and treatment conditions. In a third part, future perspectives for AOP-based liver steatosis risk assessment are outlined.

Myopericarditis requiring emergency care or hospitalization after COVID-19 mRNA vaccination occurs most frequently in adolescent males. In the acute phase, vaccine-associated heart inflammation is characterized by elevated cardiac biomarkers (troponin, B-type natriuretic peptide), electrocardiographic abnormalities, abnormal cardiac magnetic resonance imaging, elevated interleukins and chemokines, expansion of activated cytotoxic T lymphocytes, and monocyte dysregulation. This adverse event may occur one or two days after the first injection but is far more frequent after the second, suggesting contributions from trained innate immunity and/or cumulative dose effects. A recent mouse study in this journal reported dramatic increases in both cardiac biomarkers two days after the second dose of lipid nanoparticles (LNPs) containing mRNA coding for the Omicron spike, despite absence of histopathological heart damage at 14 days-even after intravenous administration. Here, these findings are discussed in the context of human observations and additional mouse experiments. I propose that endothelial cells (ECs) of the myocardial microvasculature are a preferred off-target for LNPs because of the unique features of myocardial anatomy and perfusion. Endothelial injury via toll-like receptor 4 (TLR4) activation by ionizable lipids and/or endosomal rupture may represent an initiating step ("endothelitis"), followed by recognition of spike-derived peptides presented by ECs to activated monocytes and T lymphocytes. The potential role of the Wuhan spike protein in establishing a trained innate immunity phenotype, and species differences in TLR sensitivity, are considered.

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.

Although intoxication with hexavalent chromium [Cr(VI)] compounds can be fatal to humans, reliable data on chromium toxicokinetics are largely missing. We report on a rare case of intravenous Cr(VI) poisoning and its impact on the scientific understanding of chromium toxicokinetics and red blood cells' (RBCs') lifespan in the human body. The approximate amount of injected chromium was between 0.33 and 0.66 g. Laboratory findings were collected over a half-year period from the time of injection. We monitored kidney function, liver function, RBC parameters, and chromium concentration in RBCs, plasma, and urine. In all samples, the total chromium concentration was quantified by inductively coupled plasma-mass spectrometry. By injecting Cr(VI) into his vein, the patient inadvertently labeled all his RBCs with chromium. This gave us the unique opportunity to calculate the RBC lifespan rather than just to estimate it. Based on RBC breakdown rates, the average lifespan was calculated to be 111 days, and the maximum lifespan to be 141.4 days. At about 24 weeks post-injection, the RBC chromium concentration approached background-exposure values, whereas chromium in plasma reached a plateau considerably higher than the reference value. These results confirm that there is a long-term storage compartment for chromium in the human body, which releases chromium into plasma but leaves the RBC chromium concentration unaffected. Therefore, this singular case of Cr(VI) poisoning provides us with the long-awaited scientific proof that chromium in the RBC fraction is a specific monitoring parameter for exposure to the carcinogen Cr(VI) in occupational and environmental settings.

This Letter to the Editor addresses the recent step by the International Agency for Research on Cancer (IARC) to reclassify pure talc from Group 2B "Possibly carcinogenic to humans" to Group 2A "Probably carcinogenic to humans". This change was made by IARC not based on any new data, but by reassessing previous studies, including an inhalation study on rats and mice performed in the 1980s under the auspices of the National Toxicology Program (NTP). The NTP study, however, found evidence of tumorigenicity in rats only, but not in mice. This contradicts the toxicological principle of "at least two species" for extrapolating carcinogenicity status from animals to humans. Benign and malignant pheochromocytoma, a rare condition identified in the adrenal medulla of rats in multiple NTP studies, played a special role in the IARC talc reclassification, being evaluated as the "unusual" finding requiring a precautionary approach. The Letter argues that combined benign, malignant, and complex pheochromocytoma in rats is irrelevant for the assessment of talc carcinogenicity in humans. However, with the exclusion of pheochromocytoma argumentation, the need for talc reclassification appears to be highly questionable.

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.