Chemical Research in Toxicology最新文献

The increasing use of flavored electronic cigarettes (e-cigarettes) raises concerns about their potential impact on the emission of harmful chemicals, particularly carbonyl compounds. This study systematically examines the effects of eight representative flavoring chemicals from four major classes including esters (ethyl acetate, ethyl butyrate), alcohols (menthol, ethyl maltol), aromatic aldehydes (benzaldehyde, vanillin), and terpenes (limonene, linalool) under varying power outputs (50 and 90 W), base liquid composition [propylene glycol (PG)/vegetable glycerin (VG) ratios (80:20, 50:50, and 20:80)], and flavor concentrations (1 and 5 mg/mL). Across all conditions, flavored e-liquids tend to produce carbonyl emissions that are higher than those of unflavored controls. Terpene-based flavors showed the strongest effects, with formaldehyde emissions being up to 2-fold higher and acrolein emissions up to 8-fold higher, frequently exceeding short-term exposure limits. Aromatic aldehydes and alcohols also increased emissions, though to a lesser extent, while esters showed smaller or inconsistent effects. The influence of flavors was further modulated by their concentration, PG/VG ratio, and device power, with higher concentration, VG content, and power amplifying emissions. These results highlight the complex interactions among e-liquid composition, flavor class, and vaping conditions, demonstrating that certain flavorings substantially elevate toxicant emissions. These findings underscore the importance of considering flavor composition, device power, and base material in evaluating the potential health risks associated with e-cigarette use.

Hydroxyacetone was previously detected at high concentrations (up to ∼12 mg/mL) in electronic cigarette (EC) aerosols, including those derived from products associated with adverse health effects. Given the limited understanding of its inhalation toxicology, we investigated hydroxyacetone's impact on human airway epithelial cells. Acute exposures at the air-liquid interface (ALI) using 3D EpiAirway tissues─a surrogate for human tracheobronchial epithelium─were analyzed via proteomics. Differential expression analysis identified numerous affected proteins, with enrichment pointing to alterations in mitochondrial function and actin cytoskeletal disruption as major targets. Ingenuity Pathway Analysis (IPA) highlighted "Mitochondrial Dysfunction" and "NRF2-Mediated Oxidative Stress" among top toxicological categories, and "Nuclear Cytoskeletal Signaling" as a key canonical pathway. To validate and extend these findings, submerged cultures of BEAS-2B cells were exposed to hydroxyacetone (0.01-10 mg/mL) and assessed for mitochondrial activity, oxidative stress, and F-actin integrity. At 1 mg/mL, mitochondrial membrane potential and reactive oxygen species (ROS) increased, with elevated hydrogen peroxide detected in the culture medium. At 10 mg/mL, mitochondrial activity declined significantly, accompanied by cell rounding and apoptotic blebbing within 2 h. F-actin destabilization occurred at 1, 3.33, and 10 mg/mL, with cytoplasmic and perinuclear filaments more affected than cortical actin. Findings from ALI and submerged models were concordant, supporting hydroxyacetone-induced mitochondrial stress, oxidative damage, and cytoskeletal disruption. These results suggest that hydroxyacetone concentrations found in EC aerosols may contribute to respiratory toxicity and warrant further investigation.

Comparative toxicological studies of heterogeneous particulate matter (PM) samples are needed to evaluate the influence of particle chemistry on pulmonary toxicity outcomes. Here, groups of mice were exposed by oropharyngeal aspiration of a 100 μg dose of one of seven PM samples, including three coarse and two fine ambient air PM, and 2 fine emission source PM. Acute inflammatory and lung injury markers in the bronchoalveolar lavage fluid (BALF) were assessed. A weighted chemical correlation network analysis (WCCNA) clustered PM chemical constituents into four modules based on comodulation within samples. These modules and their components were then correlated with lung toxicity end points. One module represented the highest levels of zinc, lead, copper, and tin, and was strongly correlated with BALF neutrophils, macrophage inflammatory protein-2, and several markers of lung injury. A second module represented the highest levels of several toxic transition metals including magnesium, nickel, vanadium, and cobalt, and was strongly correlated with pro-inflammatory interleukin-6, in addition to neutrophils, albumin, and lactate dehydrogenase. A third module, represented by high levels of elemental carbon, nitrate, sulfate, and phosphate, was correlated with pro-inflammatory tumor necrosis factor-α (TNF-α), in addition to BALF protein and other lung injury markers. The final module consisted of 7 elements associated with the 3 coarse crustal PM samples, and these individual elements exhibited moderate correlations with BALF neutrophils and TNF-α. Toxic transition metals produced the greatest effects on lung toxicity, followed by anions and carbon species. These studies demonstrated that chemical and toxicological assessments of heterogeneous samples of PM produce clusters of chemical constituents that can be correlated with separate toxicological outcomes.

Fine particulate matter (PM_2.5) is a complex mixture of air pollutants that may contain hazardous substances and emerging contaminants. It penetrates deep into the lungs, inducing oxidative stress, inflammation, and systemic toxicity, and interacts with O₃, NO₂, SO₂, and organic and inorganic constituents, thereby increasing health risks.

Perfluorohexyloctane (F6H8) is a semifluorinated alkane increasingly used in medical applications. Emerging evidence, however, indicates that this compound can persist in biological systems and influence cellular processes. These observations suggest that the exceptional stability of F6H8, while beneficial for medical performance, may also have implications for long-term biological and health outcomes.

In silico tools offer rapid, cost-efficient alternatives to animal testing in (eco)toxicology. The following ToxWatch highlights the limitations that slow down regulatory application and discusses opportunities that could turn barriers into bridges.

The Centers for Disease Control and Prevention (CDC) recently began addressing critical informational gaps associated with the emergence of novel psychoactive substances (NPSs) through the formation of the Overdose Data to Action (OD2A) biosurveillance program. This program uses public health laboratories (PHLs) to report drug trends in nonfatal and fatal overdose cases, but meeting the OD2A program's goal of reporting use trends in near real-time is a challenge for resource-limited PHLs. New technology that automates NPS testing will help PHLs meet this goal and sustain OD2A testing. This study uses commercially available test kits capable of automating clinical and forensic testing platforms to validate a single liquid chromatography tandem mass spectrometry (LC-MS/MS) analytical procedure for opioids, barbiturates, benzodiazepines, cannabinoids, stimulants, and several other drug classes. Kits incorporated Suspended-State and Just-Go technologies to stabilize NIST-traceable standards and enzymatic buffers at precise concentrations in a format that does not require sample cleanup or dilution prior to LC-MS/MS analysis. OD2A test kits were activated at 37 °C prior to the addition of 10 μL sample aliquots, and hydrolysis of conjugated urinary metabolites was complete after a 90 min incubation inside the autosampler held at 37 °C. Samples were injected directly on the column for LC-MS/MS analysis and method validation. Accuracy, precision, measurement uncertainty, calibration models, reportable range, sensitivity, specificity, carryover, interference, ion suppression/enhancement, and analyte stability met the testing requirements established for toxicology laboratories. Suitability studies using fortified human urine demonstrated that the automated LC-MS/MS method validated for OD2A biosurveillance produces highly accurate and precise results. The LC-MS/MS method was also successfully transferred and validated in an independent state public health laboratory to demonstrate how this new technology can be used to support a national biosurveillance program. This new approach will enable PHLs to provide actionable data in a timely manner.

Since pexidartinib was approved by the FDA for adult patients with tenosynovial giant cell tumor, increasing attention has been paid to its high frequency of adverse reactions. This study purposes to investigate the risk potential of pexidartinib-associated drug-drug interactions (DDIs) from the perspective of UDP-glucuronosyltransferases (UGTs) inhibition. Our results demonstrated that pexidartinib was a pan-inhibitor of UGTs, and it exhibited broad inhibition against 11 human recombinant UGT isoforms at clinically achievable concentrations, with IC₅₀ values ranging from 0.97 to 20.02 μM. Further inhibition kinetic analysis showed that pexidartinib competitively inhibited UGT1A1, UGT1A6, UGT1A7, and UGT1A9, while exhibiting mixed inhibition toward UGT2B15. The K_i,u values for them were calculated to be 4.27 ± 0.28, 1.72 ± 0.12, 1.67 ± 0.11, 0.65 ± 0.13, and 2.37 ± 0.45 μM, respectively. The results of in vitro-in vivo extrapolation (IVIVE) indicated that coadministration of pexidartinib at a clinically approved dose (400 mg twice daily) with the drugs primarily cleared by UGT1A1, UGT1A6, UGT1A7, UGT1A9, and UGT2B15 would result in a higher risk of DDI. In summary, our results provide useful information for the mechanism underlying pexidartinib-induced hepatotoxicity and clinical safe medication of pexidartinib.

Lower urinary tract dysfunction is multifactorial, yet the role of environmental exposure remains poorly investigated. Developmental exposure to polychlorinated biphenyls (PCBs) has been linked to altered voiding in mice; however, the disposition of PCBs in the bladder, their bioactivation, and their effects on cytochrome P450 (CYP) expression remain unclear. We exposed mice to an environmentally relevant PCB mixture via maternal diet during gestation and lactation (vehicle, 0.1, 1, or 6 mg/kg/day). Offspring were euthanized at 6 to 7 weeks of age. PCB and hydroxylated PCB (OH-PCB) levels were quantified in the bladder, liver, blood, and urine. CYP expression was measured in the bladder and liver. PCBs and OH-PCBs accumulated in all tissues in dose- and sex-dependent manners, with higher-chlorinated congeners (e.g., PCB118, PCB138, PCB153, and PCB180) preferentially retained. Females exhibited greater hepatic accumulation, reduced urinary elimination, and distinct CYP regulation characterized by increased hepatic and decreased bladder expression. These findings, for the first time, define the signature of PCBs and OH-PCBs in the bladder and reveal a sex-specific PCB disposition and CYP responses. Our results provide new mechanistic insights into developmental PCB exposure and its potential contribution to voiding dysfunction in wildlife, domestic animals, and humans.

Hemolytik 2.0 (http://webs.iiitd.edu.in/raghava/hemolytik2/) is a comprehensive, manually curated database that provides experimentally validated information on both hemolytic and nonhemolytic peptides. Data were meticulously extracted from peer-reviewed publications and established peptide repositories, including the Antimicrobial Peptide Database, UniProt, the Collection of Antimicrobial Peptides (CAMP-R4), and the data repository of antimicrobial peptides (DRAMP 4.0). This updated version of the original Hemolytik resource comprises 13,215 unique entries from 1645 research articles, representing approximately 7534 unique peptides. Each entry in Hemolytik 2.0 offers detailed annotations, including peptide name, amino acid sequence, biological source and origin, functional characterization, terminal modifications, stereochemistry, structural classification (linear or cyclic), and experimentally determined hemolytic activity. In addition, the database provides molecular representations of peptides in SMILES (Simplified Molecular Input Line Entry System) format, alongside predicted tertiary structures and annotated secondary structural states. Additionally, a RESTful API has been integrated into the Hemolytik 2.0 repository to enable programmatic access and automated retrieval of peptide data. Hemolytik 2.0 serves as a valuable resource for the scientific community, particularly for researchers involved in the design and development of therapeutic peptides, by facilitating the identification and optimization of peptide candidates with minimal hemolytic potential and enhanced safety profiles. In addition, Hemolytik 2.0 is also available on GitHub (https://github.com/raghavagps/Hemolytik2), where users can download the complete systematic data in different formats.