Chemical Research in Toxicology最新文献

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.

Breast cancer resistance protein (BCRP), an important ATP-binding cassette transporter, is mainly responsible for drug efflux from cells, especially in high-expressing tumor cells, and is closely associated with multidrug resistance (MDR). Numerous studies have demonstrated that the inhibition of BCRP can reverse MDR, so inhibiting BCRP is considered to be a promising strategy for cancer treatment. Alkaloids are the primary bioactive ingredients in various traditional Chinese medicines (TCMs), some of which have been reported to reverse MDR by inhibiting BCRP. Our objective was to identify potential inhibitors of BCRP from 130 alkaloids, evaluate the reversion of MDR in TMZ-resistant U251T and T98G cells, and clarify the structure–activity relationships of alkaloids in BCRP inhibition. Among them, eight alkaloids, including sempervirine, reserpine, coptisine chloride, geissoschizine methyl ether, vincristine sulfate, tetrahydroberberine, cyclovirobuxine, and berberrubine, exhibited significant inhibition (>50%) of BCRP in BCRP-MDCK cells, with IC₅₀ ranging from 16.95–94.13 μM. Co-treatment with the inhibitor increased Temozolomide (TMZ) cytotoxicity in TMZ-resistant U251T and T98G cells, with IC₅₀ values declining by 2.1–97.3%. For sempervirine, coptisine chloride, and reserpine, the inhibition appeared to be even greater than the positive inhibitor KO143. Molecular docking analyses elucidated that the inhibitory effect of alkaloids on BCRP was related to π–π stacked, π–alkyl, and π–Sulfur interactions. The pharmacophore model illustrated that aromatic rings and hydrophobic groups may play a critical role in the potency of alkaloid inhibition on BCRP. Taken together, our findings provide valuable information for optimizing alkaloid structure and developing BCRP inhibitors with improved potency and specificity to reverse clinical MDR.

Triclocarban (TCC) is an antiseptic ingredient incorporated into many skin-contact hygiene products, raising public health concerns for its frequent detection in the general population. As the central metabolic organ, the liver plays a key role in lipid synthesis and metabolism; however, the in vivo effects of TCC on hepatic lipid homeostasis remain largely unclear. Herein, a percutaneous TCC exposure model was established based on human-relevant concentrations. An integrated multiomics approach, including hepatic transcriptomics and lipidomics, was applied to explore TCC effects on the liver. We discovered that continuous dermal absorption of TCC significantly disturbed hepatic lipid profiles, as manifested by the decrease in energy storage lipid triacylglycerol (TG) and its synthetic precursor diacylglycerol (DG). Integrated analysis of transcriptomics and targeted validation revealed that TG reduction could result from the decline in lipogenesis, acceleration of fatty acid β-oxidation, and elevated secretion of very-low-density lipoproteins (VLDLs). Cell membrane homeostasis was also disrupted through altering hepatocellular phosphatidylcholine (PC) and phosphatidylethanolamine (PE) levels, which may be related to the activation of endoplasmic reticulum (ER) stress, resulting in the promotion of hepatocyte apoptosis. Together, this work provides novel insights into the causal relationship between TCC exposure and the hepatic metabolic homeostasis.

Cisplatin (DDP) is widely utilized in the clinical treatment of malignant tumors, but its effectiveness is significantly compromised by the adverse effects of acute kidney injury (AKI). Renal tubular cells are primarily responsible for DDP-induced AKI (DDP-AKI); however, the responses of heterogeneous renal tubular cells to DDP exposure have not been thoroughly explored. In this study, we employed a targeted metabolomics approach to investigate the metabolic responses of renal tubular cells in DDP-AKI rats. Tubular cells were isolated from the renal cortex and outer medulla, and a chemical derivatization-based liquid chromatography–tandem mass spectrometry (LC–MS/MS) metabolomics method was applied. Our findings revealed distinct metabolic profiles in tubular cells from the renal cortex and outer medulla, with outer medullary cells exhibiting greater sensitivity to DDP exposure. Further analyses identified the tryptophan pathway as a critical factor contributing to these regional differences. Additional functional investigations showed that intermediate metabolites of the tryptophan pathway alleviated DDP cytotoxicity in both cortical and outer medullary tubular cells primarily through modulation of the Bcl2/Bax and Caspase-3 pathway. This study enhances our understanding of the metabolic characteristics of tubular cells across heterogeneous renal regions in DDP-AKI and facilitates further exploration of the underlying mechanisms of DDP-induced nephrotoxicity.