Chemical Research in Toxicology最新文献

Accurate toxicity prediction is a critical component of pharmaceutical development and regulatory safety evaluation, traditionally relying on molecular descriptor-based models. This study compares the performance of descriptor-based features (Mordred, RDKit) with embeddings from ten AI language models applied to SMILES strings, chemical names, and simple descriptions, using logistic regression classifiers across the Tox21, ClinTox, and DILIst datasets. For the Tox21 dataset, Mordred achieved the highest average ROC-AUC of 0.855, outperforming language models. However, on specific endpoints, language models showed competitive performance, with MolBERT reaching an average ROC-AUC of 0.801 for SMILES-based embeddings. In contrast, language models outperformed descriptor models on the ClinTox dataset. While RDKit achieved an ROC-AUC of 0.721, GPT-3 reached 0.996 by using simple descriptions. Similarly, for the DILIst dataset, language models surpassed descriptor models, with GPT-3 achieving an ROC-AUC of 0.806 using chemical names, compared to RDKit’s 0.620. These results demonstrate the promise of AI language models in predictive toxicology, particularly for specific toxicity endpoints and datasets. While molecular descriptors remain robust for multiendpoint predictions like Tox21, language models show superior performance on focused toxicity classifications such as ClinTox and DILIst. This study supports the future integration of molecular descriptors with textual embeddings to enhance overall performance and adaptability across diverse toxicity prediction tasks.

The 2018 U.S. Farm Bill inadvertently paved the way for a market of unregulated, hemp-derived cannabinoid vaping products, including cannabidiol (CBD) and Δ8-tetrahydrocannabinol (Δ8-THC). These products contain extremely high cannabinoid concentrations, contaminants, and potentially harmful byproducts from heating, raising concerns about respiratory toxicity. This review examines the regulatory landscape, manufacturing practices, composition, and toxicological mechanisms associated with hemp-derived cannabinoid vaping products. While vaping-related lung injuries, such as E-cigarette or Vaping, Product use-Associated Lung Injury (EVALI), have been linked to vitamin E acetate (VEA), a definitive mechanism of injury has not been established, and cases continue to be reported. Studies reveal multiple mechanisms of lung toxicity associated with cannabinoid vaping, including inflammatory responses, oxidative stress, and damage from contaminants like heavy metals and flavoring agents. Emerging evidence also highlights the formation of reactive cannabinoid quinones (e.g., CBDQ) during vaping, which form covalent adducts with protein cysteine residues, potentially altering their function, and also have the potential to drive oxidative damage through redox cycling. These electrophilic quinones may act as pleiotropic modifiers of cellular function and represent an important, yet understudied, contributor to cannabinoid vaping toxicity. This review identifies key research gaps, including the need for studies on chronic exposure models, mechanisms of lung injury, and the interplay between VEA, cannabinoid quinones, and other harmful byproducts. Additionally, given the potential for both therapeutic benefits and toxic effects, research should investigate optimal temperatures and formulations that balance efficacy and safety over potential toxicity caused by thermal oxidation. Overall, a comprehensive understanding of the toxicological mechanisms of cannabinoid vaping products is essential to guide public health decisions, inform regulatory frameworks, and support the development of safer products.

Apurinic/apyrimidinic (AP) sites are unavoidably generated in the DNA of living organisms by the spontaneous or catalyzed loss of coding nucleobases from the deoxyribose backbone. AP sites can lead to the generation of interstrand DNA cross-links via reactions between the ring-opened AP-aldehyde residue and exocyclic NH₂ groups of nucleobases on the opposing strand of the double helix. Earlier works showed that dG-AP cross-links, which are generated in 2–5% equilibrium yields, can be converted via a reductive amination process to higher yields (15–50%) of a chemically stable alkylamine cross-link when NaBH₃CN is present in the reaction mixture. A dA-AP cross-link can be generated in equilibrium yields of 15–80%, but until now, it has been uncertain whether this cross-link could be reduced to the corresponding alkylamine cross-link by NaBH₃CN. The results presented here show that the dA-AP cross-link can indeed be reduced by NaBH₃CN to generate a chemically stable alkylamine cross-link. However, yields of the reduced dA-AP cross-link are limited by a faster, competing reduction of the AP-aldehyde to the corresponding AP-alcohol by NaBH₃CN. Similarly, faster reduction of the dG-AP cross-link in a 5′CXT/AAG sequence (X = AP), where both guanine and adenine residues compete for reaction with a single AP site, leads to a shift in the major site of the AP-derived cross-link attachment from adenine in the absence of NaBH₃CN to guanine in the presence of NaBH₃CN. The results show that two different nucleobase cross-links can coexist in equilibrium at a single AP site in duplex DNA. Overall, the reductive amination process may prove useful for detecting the dA-AP cross-link in cellular DNA using LC-MS/MS methods similar to those described here. In addition, these methods may be useful for the chemical synthesis of DNA duplexes containing chemically stable, site-specific cross-links.

Airborne fine particulate matter (PM_2.5) exposure has been epidemiologically linked to increased risk of cardiovascular complications, thrombosis, and hypoxia-related disorders. Quinones, prevalent constituents of PM_2.5, are suspected mediators of these health effects. Yet, the molecular mechanisms underpinning these associations remain poorly understood. Red blood cells (RBCs) have a central role in oxygen transport and vascular physiology. Thus, we investigated the effects of four environmentally relevant quinones (70 μg/mL), such as methyl-p-benzoquinone (MBQ), 1,4-naphthoquinone (NQ), 9,10-phenanthrenequinone (9,10-PQ), and 9,10-anthraquinone (9,10-AQ), on human RBCs. MBQ, NQ, and PQ significantly depleted intracellular glutathione, subsequently elevated reactive oxygen species, and triggered lipid peroxidation. Morphological analysis revealed membrane blebbing and surface protrusions of RBCs, indicative of impaired deformability and altered rheology. MBQ and NQ exposure further disrupted membrane proteins, impairing membrane fluidity and compromising membrane integrity. Tandem mass spectrometry confirmed covalent binding of MBQ and NQ to the βCys93 residue of hemoglobin via Michael addition. Native mass spectrometry revealed reduced stability of the α₂β₂ tetramer of hemoglobin. These findings were further corroborated by altered hemoglobin structure, methemoglobin formation, and hemoglobin aggregation. Mechanistically, MBQ and NQ induce RBC damage via both one-electron redox reaction and Michael addition to thiol groups, while PQ acts primarily through redox cycling without direct thiol binding. In contrast, AQ exhibited negligible effects, likely due to its low electrophilicity and steric hindrance. Our findings reveal distinct mechanistic pathways by which environmental quinones compromise RBC structure and function. This study offers a novel molecular link between airborne quinone exposure and pollution-driven health pathologies.

Oxidative damage to RNA is associated with neurodegeneration, cardiovascular diseases, and cancer development. Studies that monitor RNA damage by H₂O₂ often omit the physiological buffer bicarbonate in the reaction, which fails to account for the influence of the buffer on the iron-Fenton reaction. Herein, we monitored two in vitro systems to understand how bicarbonate redirects the iron-Fenton reaction from a hydroxyl radical (HO^•) generator in the absence of bicarbonate to one that predominantly yields carbonate radical anion (CO₃^•–) in the presence of this buffer. Using the HO^•-selective fluorophore terephthalic acid, we found that the Fe(II)–ligand identity impacted the bicarbonate concentration required to transition the Fenton reaction to predominantly yield CO₃^•–. These findings were then corroborated by following the oxidation of guanosine (rG), which reports on oxidation by both radicals, and uridine (rU) oxidation, which responds to only HO^• as the oxidizing species. The studies found that as the Fe(II)–ligand complex stability increased, the bicarbonate concentration inflection point to favor CO₃^•– production and rG oxidation also increased. Regardless of the ligand strength, the crossover values obtained were below physiologically relevant bicarbonate concentrations (<20 mM). Next, Escherichia coli or HEK293T cells were pre-equilibrated with bicarbonate from 0 to 20 mM before a bolus addition of H₂O₂. The bicarbonate-dependent inflection points for favoring CO₃^•– over HO^• (or ferryl) for E. coli (7.3 mM) and HEK293T (11.3 mM) cells differed, but were below physiologically relevant concentrations, supporting the hypothesis that the cellular iron-Fenton reaction normally yields CO₃^•–. The redox-cycling compound menadione was used for continuous in-cell generation of H₂O₂ to find bicarbonate dependencies in oxidation reactions of RNA. The studies herein point toward the redirection of the iron-Fenton reaction in cells to predominantly yield CO₃^•– that selectively damages rG sites in the transcriptome.

Inhalation exposure to nanoplastic particles (NPPs) can lead to significant pulmonary toxicity; however, the effects of environmental processing on their toxicity remain poorly understood. This study examines the toxicity of polystyrene (PS) NPPs on lung cells following controlled atmospheric aging. Human bronchial epithelial cells (16HBE) were cultured in vitro at the air–liquid interface and acutely exposed to oxidized PS NPPs through electrostatic precipitation. Expression of proinflammatory genes interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) was significantly elevated at 6 and 48 h postexposure to aged NPPs, with corresponding increases in interleukin-6 (IL-6) protein levels supporting an inflammatory response. The oxidative stress marker heme oxygenase-1 (HO-1) also showed significantly increased expression at 6 h postexposure, supported by protein analysis. Atomic force microscopy (AFM) and aerosol mass spectrometry (AMS) revealed increased surface roughness and oxygen to carbon ratios in the atmospherically aged NPPs. Together, these results demonstrate that atmospheric aging alters the chemical composition and surface morphology of PS NPPs, enhancing proinflammatory and oxidative stress responses in bronchial epithelial cells, highlighting the critical role of environmental processing in determining the toxicity of nanoplastics.

Despite increased recognition of the adverse impacts of PCB exposure on human health, comprehensive risk assessments, particularly regarding inhalation exposure and effects on the developing fetus, are lacking. Out of all PCB congeners, lower-chlorinated PCBs have been more prevalent in indoor and outdoor atmospheres. Thus, we investigated in vivo toxicokinetics and placental transfer of radiolabeled [¹⁴C]-PCB52 (0.157 mg/kg administered intratracheally) in Sprague–Dawley rats at gestational day 11 ± 1. Following dosing, 99.4 ± 0.5% of the administered dose was distributed to the systemic circulation. Radioactivity disappeared biexponentially following lung exposure, with 41.1% of the dose retained after 96 h. PCB52 was rapidly distributed to the maternal serum, lung, heart, and liver, with subsequent accumulation in the ovaries, brain, white and brown adipose, muscle, and mammary glands. The time to reach a maximum concentration in the maternal serum was 0.21 h, with an apparent terminal elimination half-life of 40.7 h. The peak concentration of [¹⁴C]-PCB52 and its metabolites in the placenta, fetus, and amniotic fluid was achieved 1.7 h after exposure, with a fetal half-life of 34.8 h. The maternal serum level was significantly correlated with levels in amniotic fluid, placenta, fetus, and the maternal brain. However, PCB52 exposure in the placenta, fetus, and amniotic fluid was limited with their respective maternal serum exposure ratio values of 0.5, 0.27, and 0.05. These results demonstrate for the first time a comprehensive whole-body disposition of PCB52 in dams and fetuses after lung exposure during gestation. PCB52 and its metabolites accumulate predominantly in the ovaries, brain, and mammary glands. The apparent half-life of PCB52 in developing fetuses and placenta is comparable to that of maternal serum. This study provides novel quantitative foundations for the development and evaluation of physiologically based toxicokinetic modeling to inform the exposure and risk assessment for public health decisions.

The electronic cigarette has been suggested as a safer alternative to the conventional tobacco cigarette. However, some vaping products have been shown to have cardiovascular effects, although this remains controversial. Several clinical studies have identified a possible alteration of endothelial function due to exposure to e-cigarette aerosols. However, the underlying biological mechanisms responsible for this observation in humans are still unclear. Thus, the development of preclinical mechanistic studies seems necessary. The aim of this review is, therefore, to provide a comprehensive overview of preclinical studies addressing the question of how e-cigarettes may cause endothelial dysfunction, a predictive marker of cardiovascular events. 53 papers were included in the analysis. We analyzed these papers qualitatively and quantitatively and discussed their limitations. We found that while 30% of in vitro studies showed no effect of e-cigarette aerosols on endothelial cells 26% showed variable effects, and 44% showed a significant adverse effect on endothelial function. In vivo studies were more consistent, with the vast majority (96%) reporting negative effects of e-cigarettes on endothelial function. We concluded that e-cigarettes should not be considered harmless in terms of cardiovascular effects, as they may impair endothelial function through various mechanisms such as oxidative stress and inflammation. However, more studies with standardized and optimized designs are still needed to distinguish the role of nicotine, which is known to affect the cardiovascular system, from that of other components in e-cigarette aerosol.

Mycotoxins are toxic secondary metabolites produced by fungi that contaminate food worldwide and pose serious health risks to humans and livestock. According to the Food and Agriculture Organization, nearly one-fourth of global food crops are affected. India’s climatic conditions, including unseasonal rains and flash floods, create a favorable environment for mold growth and mycotoxin contamination by increasing grain moisture levels. Survey data suggest that fumonisin B1 is the most prevalent mycotoxin in Indian food commodities, followed by aflatoxin B1 and combined aflatoxins. While aflatoxin B1 is frequently detected, more studies have focused on aflatoxins than fumonisin B1, with fewer studies specifically analyzing fumonisin B1 in Indian food samples. Despite this, the highly reported incidence of fumonisin B1 suggests that it may be more widespread than currently recognized. This review is the first to comprehensively compile and analyze all available survey data on mycotoxins in Indian food commodities. It examines their prevalence, toxicological impact, and associated risks for consumers. Food safety regulations concerning mycotoxins in India are less stringent than those enforced by the European Union or the United States Food and Drug Administration. This regulatory gap raises concerns about food security, especially since mycotoxin contamination in India often exceeds permissible limits. As the world’s most populous country, accounting for 17.76% of the global population, India faces significant challenges due to mycotoxins in food. Given its role as a leading producer and exporter of agricultural commodities, the issue extends beyond national borders, impacting global food trade and safety. Strengthening food safety regulations, increasing surveillance, and promoting awareness are crucial steps toward mitigating mycotoxin risks. This review serves as a valuable resource for researchers, policymakers, and consumers concerned with food safety and public health.

Experimental genotoxicity data are required for pesticidal and biocidal active substances prior to regulatory approval, while for their metabolites and impurities, in silico predictions are often accepted. Nonetheless, the extent to which these compounds are represented in publicly available genotoxicity databases remains unclear. Herein, we utilize chemical space methods to define the overlap between pesticide substances (active substances, metabolites, and impurities) and activity data for six genotoxicity test types commonly employed in regulatory toxicology: the Ames test, the in vitro mammalian cell gene mutation test, the in vitro micronucleus test, the in vitro chromosomal aberration test, the in vivo micronucleus test, and the in vivo chromosomal aberration test. After merging and performing structure standardization on 18 public pesticide/biocide databases, we identified 4826 unique substances. Within 19 public genotoxicity databases, 19,897 substances had at least one data point in at least one genotoxicity test. The chemical space overlap between the pesticide substances and each genotoxicity set was evaluated by calculating physicochemical descriptors and molecular fingerprints, which were visualized by using dimensionality reduction methods. The chemical space of pesticide substances is well represented by substances with Ames test data and, to varying degrees, by substances with data from the other genotoxicity tests, with particularly low coverage for in vivo chromosomal aberration. The major scaffolds identified in pesticide substances were present in all of the genotoxicity data sets. Compared to pesticide substances, the genotoxicity data sets were enriched in functional groups characteristic of genotoxic compounds, such as annulated rings, but depleted in pesticide-typical structural motifs like halogens. Chemical space methods can assist regulatory toxicologists in understanding regions of pesticide substance chemical space that are well- or poorly characterized by genotoxicity data. This understanding is important for the accurate and targeted use of databases and data-based nontesting methods in line with regulatory requirements.