Chemical Research in Toxicology最新文献

The algal macrolide goniodomin A (GDA) undergoes ring-cleavage under unusually mild, alkaline conditions to form mixtures of stereoisomers of seco acids GDA-sa and iso-GDA-sa. In the primary fragmentation pathway, opening of the macrolide ring occurs by displacement of the carboxyl group by a base-catalyzed attack of the C32 hemiketal hydroxy group on C31, yielding an oxirane-carboxylic acid, named goniodomic acid. The oxirane ring is unstable, undergoing solvolytic opening to form mainly GDA-sa. Experimental support for this pathway obtained by carrying out the ring-opening reaction in H₂¹⁸O resulted in incorporation of the isotopic label at C32 of the seco acid. Collision-induced dissociation (CID) mass spectrometry of Na⁺ and NH₄⁺ ion adducts was employed to establish that ring-opening of the macrolide ring occurred by alkyl-O cleavage. Fragmentation was dominated by Grob-Wharton decarboxylation and retro-Diels-Alder reactions of the labeled seco acids. Direct observation of goniodomic acid was achieved when the ring-opening reaction was carried out under anhydrous conditions. A minor alkyl-O cleavage pathway gives rise to iso-GDA-sa by allylic attack at C29 of GDA or of the oxirane. In the formation of both GDA-sa and iso-GDA-sa, ring-opening is likely to be catalyzed by Na⁺ and NH₄⁺. Reversal of GDA-sa formation can occur in the mass spectrometer. CID fragmentation of the ¹⁸O-labeled GDA-sa restores the oxirane ring but causes preferential loss of the ¹⁸O label from C32.

Acrylonitrile-butadiene-styrene (ABS) is a thermoplastic copolymer commonly used in the electronics, automotive, and construction industries. In the aquatic environment, the formation of microplastics from larger-sized plastic waste occurs naturally, induced by physical, chemical, and biological processes that promote the aging of these particles. Here, we investigated the interactions between the freshwater amphipod Hyalella azteca and ABS microplastics (10-20 μm) (pristine and after accelerated aging) over 7 days of exposure. At the end of the exposure period, we evaluated the ability of H. azteca to fragment the ABS particles, as well as the changes in its oxidative stress biomarkers (SOD, CAT, MDA, and GST) as the result of ABS exposure. H. azteca promoted a significant fragmentation of ABS particles. The ratio of this biofragmentation was more pronounced in pristine particles. Despite the absence of significant changes in the mortality of exposed organisms, alterations in the oxidative stress biomarkers were observed. The results demonstrate the ability of H. azteca to fragment pristine and aged ABS microplastics and, the consequent susceptibility of these organisms to the effects of microplastic exposure.

Deficiency of the V-domain immunoglobulin suppressor of T-cell activation (VISTA) accelerates disease progression in lupus-prone mice, and activation of VISTA shows therapeutic effects in mouse models of a lupus-like disease. Metabolic reprogramming of T cells in systemic lupus erythematosus (SLE) patients is important in regulating T-cell function and disease progression. However, the mechanism by which VISTA affects the immunometabolism in SLE remains unclear. Here, we demonstrated that the deficiency of VISTA promoted the synthesis of the metabolite lysophosphatidylcholine (LPC) using untargeted metabolomics and increased the protein expression of the CD40 ligand (CD40L). Furthermore, baloxavir marboxil (BXM), a small molecule agonist of VISTA, significantly ameliorated autoantibody production, renal damage, and imbalance of immune cell subpopulations in the models of a lupus-like disease in mice (chronic graft-versus-host disease and MRL/MpJ-Faslpr/J mice) possibly by inhibiting LPC synthesis to downregulate CD40L protein expression and inhibiting aberrant activation of noncanonical nuclear factor-κB pathway. Our results indicated that BXM targeting VISTA ameliorated lupus-like symptoms by altering lipid metabolism and CD40L expression, which offers novel mechanisms and a promising therapy for SLE.

Nicotine salt e-liquids are widely used in pod-style and disposable electronic nicotine delivery systems (ENDS). Studying the physical and chemical properties of their emissions can inform their toxicological impact. A prior companion study reported the harmful and potentially harmful constituents (HPHCs) and aerosol particle sizes produced from laboratory-made nicotine salt and freebase nicotine e-liquids to assess the effects of varying nicotine salts and nicotine protonation. This study reports the HPHCs and aerosol particle sizes for commercial brand nicotine salt and freebase nicotine formulations. Several tobacco, fruit, mint, and menthol flavored e-liquids of varying nicotine concentrations were tested with open and closed pod-style ENDS and a disposable ENDS. The nicotine yields showed a positive correlation with aerosol output, and the aerosol nicotine mass fractions reflected the e-liquid nicotine quantities. Benzene, crotonaldehyde, and 2,3-pentanedione were not detected or quantified in any of the aerosols, whereas acetaldehyde, acrolein, diacetyl, and formaldehyde were each quantified in at least one of the tested conditions. The aerosol particle number concentrations indicated that 97-99% of the aerosols for all the ENDS tested were composed of ultrafine (<0.1 μm) and fine (0.1-1.0 μm) aerosol particle sizes, and the mass median aerodynamic diameters ranged from 1.0 to 1.4 μm. The estimated regional deposition fractions and total respiratory depositions were calculated for all the ENDS conditions using a dosimetry modeling program. The calculations predicted depositions would predominantly occur in the pulmonary and head regions with a low total respiratory deposition (≤41%) calculated for all ENDS tested. This study broadens the availability of high-quality and reliable testing data of popular commercial nicotine salt-based ENDS for the scientific and regulatory communities. In conjunction with the previous work on the model e-liquids, these studies offer an extensive examination of the HPHCs and physical aerosol parameters of nicotine salt e-liquids.

UVA radiation and visible light can lead to indirect damage to DNA, proteins, and lipids through photosensitized reactions, where a molecule undergoes a photochemical alteration by the initial absorption of radiation by another molecular entity called photosensitizer (Sens). The chemical changes undergone by biomolecules in photosensitized reactions can trigger important adverse processes such as photoallergy, phototoxicity, and skin cancer, among others. Despite the knowledge about photosensitized reactions and the fact that many endogenous compounds present in the skin can act as Sens, UVA, and visible light are widely used in several devices for domestic and general use without a thorough evaluation of their possible harmful effects; one prominent example is UV-nail polish dryers. The information in the literature about the possible damage that can be caused by using this type of radiation source is controversial. In this work, we demonstrate that the radiation dose emitted by the nail polish dryer device during a typical gel nail manicure session effectively degrades molecules present in the skin under physiological and pathological conditions. Additionally, it may induce damage to biomolecules such as proteins and lipids due to the photosensitization process, leading to the loss of their biological functions.

The Toxic Substances Control Act (TSCA) requires the US EPA to evaluate the hazard and exposure of new and existing chemicals. New chemical notifications are typically data-poor and EPA has historically relied upon approaches including chemical categories to fill data gaps. As part of a multi-year Research Program, opportunities are being explored to leverage New Approach Methods (NAMs) in hazard and exposure assessments. Data from a battery of in vitro NAMs will be generated to form a case study for an adaptable approach to inform new chemical assessments. Herein, a cheminformatics workflow was developed to identify a set of ∼300 representative candidate chemicals for in vitro screening from the TSCA non-confidential active inventory. The freely available web application ClassyFire was used to categorize all discrete organic structures from the TSCA inventory into one of 68 primary structural categories. Large primary categories were subcategorized into smaller categories using hierarchical agglomerative clustering, ultimately yielding 180 structural terminal categories. The inventory was filtered to substances that lacked previous ToxCast bioactivity screening, were associated with physicochemical property predictions indicating non-volatile solids or liquids, and had a higher chance of procurement. Amenability predictions for liquid chromatography-mass spectrometry were also generated to provide an indication of which chemicals lent themselves to aqueous-based screening and analytical verification in solvated samples. Structures associated with transformation in solvent, potentially explosive or highly reactive, were excluded. Potential candidate substances were selected on the basis of being structurally representative of the terminal category and meeting other screenability conditions. A final set of 318 candidate chemicals were proposed to undergo analytical quality control and screening in a range of broad and targeted biological technologies for human health-relevant end points. Finally, in silico tools were applied to explore predicted hazard profiles of these candidate substances relative to the full inventory.

DNA interstrand cross-links (ICLs) are the sources of the cytotoxicity of many anticancer agents. Selenium compounds showed great potential as anticancer drugs. In this work, we synthesized a binaphthalene analog 1 containing phenyl selenide (-SePh) as the leaving group and investigated its photochemical reactivity toward DNA as well as its cytotoxicity and selectivity. DNA ICLs were not observed with binaphthalene phenyl selenide 1 without UV irradiation, while ∼15% DNA ICL products were detected with UV irradiation, indicating a photoresponsive property of 1. The trapping reactions with TEMPO and MeONH₂, respectively, suggested that free radicals and carbocations are involved in the DNA cross-linking process induced by the photoirradiation of 1. The photochemical reactivity of 1 toward DNA was sequence-dependent. DNA interstrand cross-linking occurred mainly at dG/dC base pairs, while monoalkylations occurred at dGs and dAs. Additionally, we have demonstrated that 1 alone without UV irradiation did not inhibit cancer cell growth even with a concentration of 100 μM, while the cytotoxicity of 1 toward cancer cells was significantly enhanced upon 350 nm irradiation with an IC₅₀ of 1.7 μM. No cytotoxicity was observed toward normal epithelial MCF 10A cells, regardless of UV exposure, in the presence or absence of 1. The alkaline comet assay suggested that the photoinduced cytotoxicity of 1 is correlated to cellular DNA damage. Normal cells showed higher levels of GSH than cancer cells and exhibited efficient DNA repair mechanisms, which can both prevent and repair potential DNA damage induced by 1, contributing to the selective cytotoxicity of the prodrug toward triple-negative breast cancer cells.

Dried Matrix Spot (DMS) is a cost-effective and stable sampling technique used in population-based studies, clinical research, and noninvasive chemical and biomarker screening. DMS is especially useful in developing countries like India, where collaborative initiatives are required for its improved applications.

During widespread applications of metal-organic frameworks (MOFs), the environmental hazards and risks of MOFs have aroused great concerns. In this study, we aimed to reveal the importance of the environmental stability of MOFs on their toxicity. Two Zn-MOFs, namely, ZIF-8 with high aqueous stability and Zn-BDC with low aqueous stability, were compared directly in the toxicological evaluations of a nitrogen-fixing bacterium Azotobacter vinelandii. Zn-BDC showed strong cytotoxicity at 100 mg/L and higher, inducing growth inhibition, cell apoptosis, structural changes, oxidative damage, and, consequently, loss of nitrogen fixation ability. In contrast, ZIF-8 was nearly nontoxic to A. vinelandii. The transcriptome analysis showed that Zn-BDC directly disturbed the ribosome pathway and lowered the expression level of nitrogen-fixing nif cluster genes. On the other hand, ZIF-8 stress could regulate the flagellar assembly, siderophore group nonribosomal peptide biosynthesis, bacterial chemotaxis, and amino sugar and nucleotide sugar metabolism pathways to promote the cell growth of A. vinelandii. Beyond that, the toxicity of Zn-MOFs to A. vinelandii was associated with the release of Zn²⁺, but Zn-MOFs were less toxic than the mixtures of their starting materials. Overall, our results suggested that the environmental stability of Zn-MOFs determined their environmental toxicity through different molecular pathways. Designing stable MOFs is preferred due to environment-friendly considerations.

Macrophages are professional phagocytic immune cells that, following activation, polarize on a spectrum between the proinflammatory M1 and the proresolution M2 states. Macrophages have further been demonstrated to retain plasticity, allowing for the reprogramming of their polarization states following exposure to new stimuli. Particulate matter (PM) has been repeatedly shown to modify macrophage function and polarization while also inducing worsening respiratory infection morbidity and mortality. However, limited work has considered the impact of the initial macrophage polarization state on subsequent responses to PM exposure. PM composition can demonstrate seasonality-specific compositional changes based on differences in seasonal weather patterns and energy needs, introducing the need to consider the seasonality-specific effects of airborne PM when investigating its impact on human health. This study sought to determine the impact of airborne PM collected during different seasons of the year in Xinxiang, China, on macrophage function in a polarization state-dependent manner. Macrophages were differentiated using the macrophage colony-stimulating factor (M-CSF) on CD14+CD16- monocytes isolated from the blood of healthy human volunteers. The resulting macrophages were polarized into indicated states using well-characterized polarization methods and assessed for phagocytic function, bioenergetic properties, and secretory profile following exposure to PM collected during a single day during each season of the year. Macrophages demonstrated clear polarization state-dependent phagocytic, bioenergetic, and secretory properties at the baseline and following PM exposure. Specific PM seasonality had a minimal impact on phagocytic function and a minor effect on bioenergetic properties but had clear impacts on the secretory profile as demonstrated by the enriched secretion of well-characterized mediator clusters by particle season. Together, these data suggest that both particle seasonality and macrophage polarization state must be considered when investigating the impact of PM on macrophage function. These factors may contribute to the negative outcomes linked to PM exposure during respiratory infections.