Chemical Research in Toxicology最新文献

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.

Chemicals may cause cardiotoxicity by binding to the K⁺ channel encoded by the human ether-à-go-go-related gene (hERG). Given the ever-increasing number of chemicals, developing in silico models to efficiently fill the hERG binding affinity data gap is more desirable than conducting time-consuming experimental tests. However, previous data sets with limited chemical space hindered the development of models with high prediction accuracy and broad applicability domains (ADs). Herein, an expanded hERG binding affinity data set containing diverse categories of chemicals was constructed and subsequently employed to develop machine learning models. ADs of the constructed models were defined by an innovative structure–activity landscape (SAL)-based AD characterization (AD_SAL), which considers activity cliffs within SALs formed by molecules with similar structures but inconsistent bioactivities. The optimal model constrained by the AD_SAL achieved a coefficient of determination up to 0.89 on the external-validation set, which significantly outperformed previous models. The model coupled with the AD_SAL constraint was applied to predict hERG binding affinities for more than 100,000 chemicals from multiple inventories, identifying over 5,000 potential hERG blockers. The model with AD_SAL can serve as an efficient and reliable tool for bridging the hERG-mediated cardiotoxicity data vacancy to support sound chemical management.

Per- and poly fluoroalkyl substances (PFAS) have become a global concern due to their persistence in the environment, contaminating drinking water, air, and soil. Human exposure to PFAS can potentially cause adverse effects due to its bioaccumulation and nonbiodegradability. To fully understand the role of PFAS in human health conditions, it is important to elucidate their roles in cellular toxicity and biotransformation pathways. Noncovalent complexation of PFAS to proteins is one potential mode of toxicity that can be investigated by comparing structural differences between native and bound proteins. In this work, we perform collision-induced unfolding (CIU) using a cyclic ion mobility–mass spectrometer (cIM–MS) to measure the effects of PFAS binding on protein structure. CIU characterizes the unfolding pathway of analytes by measuring changes in analyte size and shape as a function of increasing activation energy. The CIU results of different species can then be compared to determine potential structural changes. This method is demonstrated using ubiquitin as a model protein and three related PFAS: perfluorobutanesulfonic acid (PFBS), perfluorohexanesulfonic acid (PFHxS), and perfluorooctanesulfonic acid (PFOS). All three PFAS have the same sulfonate headgroup but different fluorinated chain lengths. We observed both qualitative and quantitative differences in ubiquitin unfolding based on the number of bound PFAS molecules as well as the PFAS chain length, suggesting that these molecules are not necessarily passive when associated with protein. Primarily, our results demonstrate a rapid, targeted analysis that can characterize the noncovalent complexation of toxins to biological molecules.

Ammonium perfluoro (2-methyl-3-oxahexanoate) (GenX), a substitute for perfluorooctanoic acid, disrupts early-life intestinal homeostasis and impacts neurodevelopment. However, the mechanisms are unclear, and interventions are limited. In this study, pregnant mice were exposed to GenX (2 mg/kg/day) and chlorogenic acid (CGA, 30 mg/kg/day) from gestation day 0 to postnatal day 21. GenX exposure resulted in a significant reduction in birth length, body weight, and colon length in the pups as well as an infiltration of inflammatory cells, glandular atrophy, and a decrease in the number of goblet cells within the colon. Moreover, the expression of ZO-1, occludin, and claudin-5 decreased in the colon, indicating that exposure to GenX may have compromised intestinal barrier function. The GenX group exhibited increased levels of lipopolysaccharide (LPS) in both the serum and cortex, along with increased expression of NLRP3, GSDMD, GSDMD-N, IL-1β, IL-18, and Caspase-1 p10 in the colon and cortex, indicating pyroptosis activation. The elevated protein expression levels of inflammatory factors, including TNF-α, IFN-γ, COX-2, iNOS, p-PI3K, p-AKT, and p-NF-κB in the cortex, indicated the activation of the PI3K/AKT/NF-κB signaling pathway, contributing to the developmental neurotoxicity. CGA treatment improved intestinal barrier function and reduced LPS leakage and inflammation in the cortex, possibly by decreasing LPS translocation and pyroptosis. Taken together, CGA treatment effectively alleviated perinatal GenX exposure-induced intestinal homeostasis disruption and developmental neurotoxicity due to the LPS translocation and activation of pyroptosis.