Chemical Research in Toxicology最新文献

Exposure to air pollution plays a significant role in human health. Current methods of measuring human exposure are often limited to outdoor measurements, are time intensive, or are unable to accurately measure certain classes of compounds. This study proposes human hair as a promising indicator of pollution exposure. We present a novel method of hair analysis involving thermal extraction and detection of semivolatile organic compounds using a Vocus 2R proton transfer reaction time-of-flight mass spectrometer (Vocus PTR-TOF-MS). The hair samples were subjected to a temperature ramp spanning three different temperatures: 60 °C, 90 °C, and 120 °C. A hierarchical clustering approach was used to create “clustergrams”, dendrograms comprising chemical fingerprints of the hair samples at each different temperature. Each clustergram grouped the chemicals in the samples by similarity, allowing the determination of potential sources of exposure. Multivariate factor analysis revealed the presence of phthalates and their corresponding metabolites, confirming that this method can detect biomarkers associated with pollution exposure. This method enables the rapid and sensitive detection of a wide spectrum of toxicologically relevant compounds in human hair, providing an initial screening tool for measuring human exposure and assessing health risks.

Graphene-based nanomaterials have transformed biomedical applications due to their exceptional physicochemical properties, and nitrogen (N)-doping further enhances the electrocatalytic activity of graphene. Driven by the demand for safer and more sustainable nanomaterials, in this work, we compared eco-friendly produced N- doped graphene (bD) with conventionally synthesized N- doped graphene (cD) in three different cell lines. Across all cell types and assays, cD was more toxic than bD. In NIH/3T3 fibroblast cells, cD activated the Nrf2 signaling pathway, whereas in HaCaT keratinocytes, it triggered oxidative stress responses and increased the apoptotic population. High doses of cD also affected THP-1-derived macrophages by inducing apoptosis and arresting the cell cycle in the G0/G1 phase. Although high doses of bD were also cytotoxic, overall, its effects were milder than cD. Our results confirm that green exfoliation of N- doped graphene retains its desirable biomedical properties while enhancing its biocompatibility, making bD a safer choice for future biomedical applications.

Nicotine lactate salt is one of the commonly used nicotine salts in electronic cigarette (e-cigarette) formulations, including products that have received Marketing Granted Orders through the FDA’s Premarket Tobacco Product Application (PMTA) evaluation in the US. However, full-life cycle evaluation on nicotine lactate salt remains limited, especially its leaching reactions with heating elements and the potential to influence aerosol composition. This study investigated the chemical effects of nicotine lactate salt on e-cigarette heating coils and potential toxicological consequences of nickel (Ni) leachates using in vitro cells and animal models. The results showed that immersion of heating coils in e-liquid (PG:VG 6:4) containing 2% nicotine lactate salt resulted in a significant increase in Ni concentration in the e-liquid over a period of 4 weeks, with levels rising over time as compared to the nicotine benzoate group. A commercially available disposable e-cigarette (liquid capacity: 9.4 mL; power output: 11 W) was utilized. Similarly, aerosol generated from the e-liquid containing 2% nicotine lactate salt exhibited elevated Ni levels. In vitro cytotoxicity exposure to the Beas-2B, SH-SY5Y, and HepG2 cell lines indicated that the aerosol generated from 2% nicotine lactate e-liquid showed higher toxicity than that of the 2% nicotine benzoate e-liquid, with more pronounced Ni accumulation in cells. In vivo inhalation using C57BL/6J mice demonstrated significant Ni accumulation in mice exposed to the aerosol produced from nicotine lactate salt, particularly in the liver. The corrosion of heating coils of nicotine lactate salt e-liquid was attributed to combined electrochemical and acidic corrosion mechanisms. In conclusion, our findings provide valuable insights into the material compatibility and potential toxicological implications for nicotine lactate-based e-liquids in electronic nicotine delivery systems. More research is needed to fully assess the implications of these preclinical findings.

4-(Methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its major metabolite 4-(methylnitrosamino)-l-(3-pyridine)-l-butanol (NNAL) are tobacco-specific lung carcinogens. Methods have been developed to quantify NNK- and NNAL-specific DNA adducts in preclinical samples but are not feasible to translation due to limited access to target tissues for sufficient DNA. In addition, NNAL-specific DNA or protein adducts have never been detected in clinical samples, which are critical to assess the physiological relevance of NNAL bioactivation and carcinogenesis. We herein reported a highly sensitive and specific LC-MS/MS method to quantify the hydrolyzed product, 1-(3-pyridyl)-1,4-butanediol (PBD), from NNAL-induced protein adduct. This method was applied to a variety of biological samples to assess tobacco exposure and NNAL bioactivation.

Secondary organic aerosol (SOA) accounts for a large fraction of fine particulate matter (PM_2.5) in the atmosphere. Epidemiological studies have shown that SOA has adverse effects on human health. However, the current knowledge of the SOA’s effect on the nervous system remains poorly understood. To address this issue, PC12 cells were incubated in SOA from α-pinene ozonation. The results showed that concentration-dependent increases in reactive oxygen species (ROS) levels lead to a decrease in cell viability, indicating that SOA could induce apoptosis and oxidative stress in cells. The peroxides present in the SOA are identified as major contributors to the apoptotic effect. Furthermore, the apoptosis mechanism was analyzed by Western blotting, revealing activation of the mitochondria-associated Bax/Bcl-2-Caspase-3-PARP signal pathway. In addition, the qPCR result showed that SOA had altered the expression of inflammatory factors, including IL-6, IL-1β, and TNF-α, in PC12 cells. This study investigates the molecular-level evidence of the toxicological impact of SOA on the nervous system, which further evaluates the effects of SOA on health.

Silver nanoparticles (AgNPs), a promising class of metallic nanomaterials with strong antibacterial properties and biomedical potential, are increasingly being used in a variety of consumer products. The widespread application of AgNPs has raised concerns about their toxicological effects, particularly their accumulation in the liver and the associated oxidative stress. However, the precise molecular mechanisms driving these effects remain unclear. In this study, we provide evidence that AgNPs trigger ferroptosis in both mouse hepatocytes and HepG2 cells. Transcriptomic analysis identified ferroptosis is a primary cellular response to AgNP exposure, with Nrf2 serving a protective function. Specifically, AgNPs increased p62 expression, which in turn stabilized Nrf2 by suppressing its interaction with Keap1. Upon activation, Nrf2 enhances the transcription of key antioxidant enzymes, including NQO1 and HO-1, thereby alleviating ferroptosis. Additionally, we discovered that Nrf2 activation regulates iron storage by modulating FTH and FTL expression, thereby mitigating AgNP-induced ferroptosis in hepatocytes. These findings clarify the molecular basis of AgNP-induced ferroptosis in hepatocytes and underscore the crucial role of Nrf2 signaling in counteracting oxidative stress and ferroptosis.

Rational safer chemical design offers economic, social, environmental benefits but faces critical challenges requiring systemic changes in education, funding, interdisciplinary collaboration, and computational innovations for broader industry adoption.

Harmful cyanobacterial blooms (HCBs) are a public health concern and require ongoing surveillance to monitor the negative water quality effects and cyanotoxins associated with these blooms. (+)-Anatoxin-a (ATX) is a potent neurotoxin produced by select cyanobacteria during HCB formation. Many HCB toxins are commonly associated with discolored water; however, ATX can be present in clear water, which results in a high risk of exposure by accidental ingestion for humans and animals. In this work, we used a qualitative, semitargeted liquid chromatography high resolution mass spectrometry (LC-HRMS) method and a discovery data analysis workflow to detect and identify ATX and its predicted mammalian metabolites in urine samples from ATX-dosed mice. Potential compounds were evaluated for identification with product-ion spectral matching to a local library, accurate mass list matching, further data processing and interpretation, and comparison to undosed mice urine samples. As a result, ATX and dihydroanatoxin-a (dhATX) were successfully identified in the dosed mice samples through retention time (RT) and product-ion spectral matching to their respective commercial standards. The positive identification of dhATX suggests its formation as an abundant metabolic product of ATX within mammalian systems. Additionally, multiple chromatographic peaks were observed that matched the exact mass of 3-OH ATX and were further identified by the presence of diagnostic product ions and comparison to a standard synthesized in-house. In total, seven potential ATX metabolites, including dhATX and 3-OH ATX, were detected and characterized in the dosed mice samples. All identified metabolites were either oxidized or reduced forms of ATX, which suggests that oxidation and reduction are the main pathways for endogenous ATX metabolism in mice. These results are among the first reports of metabolic products of ATX in biological samples and provide a metabolic profile of ATX for higher confidence screening for ATX after a suspected exposure event.

Perfluorooctanesulfonate (PFOS) is a persistent environmental pollutant in the per- and polyfluoroalkyl substances (PFAS) class, known to accumulate in the liver and trigger hepatotoxicity. While in vitro studies suggested that fatty acid-binding proteins (FABPs) drive the hepatic accumulation of PFAS, in vivo evidence is entirely lacking. Using wild-type and mice with global deletion of liver-type and intestine-type FABP (L-FABP^–/–, I-FABP^–/–), we measured PFOS toxicokinetics by administering single oral doses (0.1, 0.5, and 5 mg/kg) and tracking blood and excreta levels for 65 days. PFOS levels in various tissues were measured at test end. Additionally, we measured PFAS binding to liver tissues from wild-type and FABP knockout mice. Contrary to previous in vitro findings, FABP deletion did not significantly alter PFOS blood concentrations, tissue distribution, or elimination rates. Elimination half-lives, clearances, and volumes of distribution were consistent across genotypes, suggesting that neither L-FABP nor I-FABP are critical drivers for PFOS in vivo toxicokinetics. In vitro binding assays showed similar liver partition coefficients between wild-type and knockout livers for 15 of 19 PFAS, with small differences for some sulfonamides and fluorotelomer sulfonates. These results challenge the presumed role of L-FABP and/or I-FABP in PFAS toxicokinetics, highlighting the need to explore alternative toxicokinetic mechanisms─such as phospholipid binding and transporter-mediated uptake─driving PFAS distribution and elimination.

Composites are popular materials for, among others, restorative dentistry because of their favorable mechanical and esthetic properties and direct-filling applications. The raw materials for such composites usually consist of filler particles embedded in a matrix of dimethacrylate monomers that are polymerized in situ. Because the raw materials cannot polymerize completely, residual monomers leach out over time. The conjugation of methacrylates with sulfur compounds has been recognized as an important reaction as well as a detoxification pathway; thus, leached monomers are expected to undergo chemical reactions with various biomolecules that contain thiol functionalities. To understand the reaction of dental methacrylate monomers with thiols, we studied the reaction of 2-hydroxyethyl methacrylate (HEMA), triethylene glycol dimethacrylate, urethane dimethacrylate, and bisphenol A diglycidyl methacrylate with the model thiol 2-mercaptoethanol using liquid chromatography coupled to low- and high-resolution mass spectrometry (LC–MS and LC–HRMS). The results indicate that thiols react readily with the conjugated double bond, and with methacrylate half-lives of 7–21 h under pseudo-first-order reaction conditions and at neutral pH. Dimethacrylates first formed a monoaddition product, while thiol addition to the second acrylate moiety was observed on a longer time scale. The reaction of HEMA with l-cysteine and l-glutathione was studied in more detail using HRMS and NMR spectroscopy. The reaction rates were substantially higher than for the reaction with mercaptoethanol, and NMR analysis revealed the presence of two isomeric reaction products. Structural characterization also included the identification and assignment of sulfoxides of HEMA-cysteine and HEMA-glutathione. Using the characterized HEMA–thiols as reference standards for LC–HRMS, we demonstrated the presence of HEMA-glutathione, HEMA-cysteine, their sulfoxides, and a putative HEMA-cysteinylglycine in a human osteoblast-like cell line following exposure to HEMA.