Chemical Research in Toxicology最新文献

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.

Tobacco and cannabis smoke are both complex chemical mixtures generated through combustion of biomass material. The presence of free radicals in tobacco smoke has been established for nearly seven decades. Despite similarities between cannabis and tobacco smoke and the known presence of radicals in the latter, analysis of free radicals in cannabis smoke has yet to be conducted. In this work, electron paramagnetic resonance (EPR) spectroscopy was used to detect short-lived radicals and environmentally persistent free radicals (EPFRs) in cannabis smoke. Spin-trapping techniques were employed to aid in identification of the short-lived radicals. Congruent with findings from studies conducted on tobacco smoke, short-lived free radicals were detected in the gas phase, and EPFRs were detected in the particle phase of cannabis smoke. Gas phase results indicate the presence of oxygen-centered radicals in cannabis smoke, though the shape of the resulting EPR spectra differs slightly from that of tobacco smoke. Particle phase results for cannabis match well with those from previous studies conducted on tobacco smoke, regardless of the spin trap used (or lack thereof). Quantitative findings indicate that cannabis smoke contains approximately the same radical concentration as tobacco smoke, on the order of 10¹⁵ gas-phase spins and 10¹⁴ particle-phase spins per cannabis preroll or tobacco cigarette. The impacts of burning method (continuous vs puffing) and cannabinoid composition on radical concentrations were also investigated here. While puffing was observed to lower radical concentrations, the cannabinoid composition of the strain of cannabis burned had no observable impact on the amount or identity of free radicals detected.

Nicotine has been used in e-cigarettes for many years; however, recently, nicotine analogs have risen in popularity. E-cigarettes containing nicotine analogs such as nicotinamide and 6-methylnicotine are currently sold without regulatory oversight. They are marketed as safer alternatives to nicotine-containing products, although there is little or no scientific evidence to support this claim. This study investigated the nicotine analog, nicotinamide (NA), along with its major degradant, 3-cyanopyridine (3CP), which is produced when NA is vaped. Upon heating and aerosolization, both chemicals are present in the exposure dose. Dose–response curves are created for relative concentrations of NA and 3CP, and an isobologram is formed to investigate their mixture effects. NA is toxic at concentrations greater than 2637 ppm; however, 3CP is harmful in concentrations as low as 0.0001 ppm. The most significant finding is that the isobologram indicates that the mixture effects are synergistic, where a decrease in viability can be seen in minimal doses of 3CP (i.e., 0.000001 ppm) and 1350 ppm of NA. The interaction index was calculated for each point, and all values were less than 1, indicating a statistically synergistic biological response. The study highlights how such small levels of 3CP can play a large role in inducing toxic responses of a presumed safe chemical (i.e., nicotinamide or niacinamide, a form of vitamin B3 (niacin)). These results indicate that chemical and biochemical reactions, as well as interactions between e-cigarette aerosol components, including nicotine analogs, warrant further investigation.

Allergic diseases affect over one billion people worldwide as a common chronic condition. Conventional treatments often relieve symptoms but lack long-term efficacy or safety. Over the past decade, nanomedicine, i.e., nanoscale drugs and delivery systems, has emerged as a promising alternative that leverages the tunable physicochemical properties of nanoparticles (NPs) and enhances both diagnosis and treatment of hypersensitivity disorders. In diagnostics, nanoparticle-based biosensors have achieved detection limits as low as 42 fg/mL with specificity exceeding 90% for food and aeroallergen proteins. Therapeutic applications comprise various NPs, including gold, silver, iron oxide, carbon-based, lipid-mediated, polymeric, dendrimeric, and virus-like, as delivery vehicles and as immunomodulators. Preclinical models detect >50% reductions in pro-inflammatory cytokines (IL-4, IL-5) and two- to 3-fold reductions in eosinophil infiltration following NP-augmented allergen immunotherapy, with antigen-specific IgE titers reduced by up to 70%. Although such advancement has occurred, nanotoxicology studies highlight dose-dependent organ concentration and prolonged pulmonary half-lives that necessitate rigorous biosafety evaluation. Regulatory and manufacturability concerns remain significant hurdles for clinical translation. This article reviews up-to-date quantitative performance metrics for nanoparticle therapeutics and diagnostics in allergy control, critically examines the toxicity profiles and translational issues, and brings out directions toward individualized, safe nanotheranostic platforms.

Oxidative stress contributes to the damage of biological molecules and is linked to the development of multiple diseases, including liver disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD). In mammals, reduced glutathione (GSH) is a pivotal antioxidant that regulates cellular responses to redox imbalances caused by reactive oxygen and nitrogen species. The presence of reduced GSH within mitochondria is especially crucial for preserving the organelle’s routine performance by eliminating hydrogen peroxide generated under both physiological and pathological conditions. Cumulative evidence indicates that MASLD is associated with a diminished mitochondrial GSH (mGSH) pool, attributed to alterations in mitochondrial membrane fluidity due to cholesterol accumulation. Therefore, strategies aimed at boosting mGSH may offer therapeutic benefits against MASLD-associated liver injury. This study aims to investigate whether l-cysteine-glutathione disulfide (l-CySSG), a proposed GSH donor and precursor, can effectively restore total and mGSH in vitro and in vivo in mice fed cholesterol-enriched (HC) or methionine-choline-deficient (MCD) diets. Additionally, S-adenosylmethionine (SAM), a compound that serves as both a GSH precursor and a membrane fluidizer, along with N-acetylcysteine (NAC), a GSH precursor by providing cysteine, was used as the control molecules in the study. Our findings show that l-CySSG has great potential as a liver protector, especially due to its good oral bioavailability. Although it does not restore GSH levels in the mitochondria as efficiently as SAM does, l-CySSG can still offer protection against liver damage, possibly through mechanisms that are not yet fully understood. Overall, l-CySSG emerges as a promising alternative for treating conditions related to oxidative stress and mitochondrial dysfunction, paving the way for future research and therapeutic development.