Chemical Research in Toxicology最新文献

This study employed high-time-resolution systems to examine the transient properties of aerosols and gases emitted from electronic cigarette (EC) puffs. Using a fast aerosol sizer, we measured particle size distributions (PSDs) across various EC brands (JUUL, VUSE, VOOPOO), revealing sizes ranging from 5 to 1000 nm at concentrations of 10⁷ to 10¹⁰ cm^–3. Most aerosols were found to be in the ultrafine range (below 100 nm), with JUUL-, VUSE-, and VOOPOO-producing aerosols with geometric mean sizes of 19.9, 47.3, and 29.4 nm, respectively. Applying the International Commission on Radiological Protection (ICRP) deposition model and assuming no further evolution of aerosols in the respiratory system, we estimated particle deposition in different respiratory regions: 45–60% in the alveolar region, 10–25% in the tracheobronchial region, and 20–35% in the extrathoracic region. The highest single-puff deposition was observed with the VOOPOO device at 60 W, depositing 180.1 ± 7.6 μg in the alveolar region. The gas emissions (CO₂, NO_x, CO, and total hydrocarbons) were measured at different power settings of the VOOPOO EC. Single-puff NO_x and CO levels exceeded the permissible exposure limits of the Occupational Safety and Health Administration, indicating potential acute exposure risks. Higher power settings were correlated with increased gas mixing ratios, suggesting more e-liquid vaporization and possible chemical transformations at higher temperatures. These findings demonstrated significant health risks associated with ultrafine particles from high-power ECs and emphasize the need for advanced measurements to accurately assess their physicochemical properties and potential health implications.

Perfluorodecanoic acid (PFDA), a C10 fluorine-containing compound, is used widely and found to be present anywhere. However, whether it has reproductive toxicity for fetal Leydig cells and the underlying mechanisms remain unknown. PFDA was investigated for its effects on fetal Leydig cells (FLCs) following exposure to 0, 1, 2.5, and 5 mg/kg/days (gavage to dams) from day 14 to day 21 during gestation. The study showed that in utero medium-dose PFDA (1, 2.5 mg/kg/days) exposure increased fetal body weight. However, PFDA markedly reduced serum testosterone levels, downregulated FLC genes (Lhcgr, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Insl3), and decreased their protein levels in neonatal rat testes. PFDA at 5 mg/kg/day altered lipid metabolism with upregulation of Elovl1 and downregulation of Scd2, subsequently inducing endoplasmic reticulum stress. Additionally, PFDA exposure downregulated transcription factor Gli1, thereby inhibiting fetal Leydig cell differentiation. Meanwhile, PFDA reduced testosterone biosynthesis in R2C Leydig cells in vitro, and the endoplasmic reticulum stress inhibitor tauroursodeoxycholic acid (TUDCA) reversed this process. In conclusion, PFDA disrupts fetal rat testicular lipid metabolism, induces endoplasmic reticulum stress, and interferes with the steroidogenesis network, leading to fetal Leydig cell dysfunction. This study underscores the potential environmental risk of PFDA exposure on the development of male reproductive function development.

Cobalt is a crucial trace element that widely exists in natural environments and is necessary for normal physiological function. However, excessive cobalt exposure leads to various adverse health effects, especially hematological and endocrine dysfunctions. Here, we investigated the toxicity of cobalt on early erythropoiesis by using ex vivo cultured erythroid progenitor cells (EPCs). We exposed EPCs to cobalt chloride (CoCl₂) and observed that their proliferation was significantly reduced after treatment with 50 μM CoCl₂ for 3 days and 10 μM CoCl₂ for 4 days. Furthermore, CoCl₂ exposure reduced the proportion of S phase cells and induced apoptosis of EPCs in a dose-dependent manner (20–100 μM). Notably, further studies revealed that CoCl₂ exposure inhibited the expression and phosphorylation of the erythroid proliferation master gene c-Kit. During EPC differentiation, treatment with CoCl₂ hindered the enucleation of erythrocytes. Consistent with these findings, the RNA-seq results revealed that CoCl₂ treatment inhibited the expression of several genes related to both proliferation and differentiation. The gene responsible for nucleoprotein export during enucleation, Xpo7, was also downregulated. Gene ontology analysis revealed that CoCl₂ treatment inhibited a variety of biological processes, including DNA replication and ribosome synthesis. In summary, we demonstrated that sustained excessive CoCl₂ exposure impaired the function of the EPCs.

Apatinib, a commonly used tyrosine kinase inhibitor in cancer treatment, can cause adverse reactions such as hypertension. Hypertension, in turn, can increase the risk of certain cancers. The coexistence of these diseases makes the use of combination drugs more common in clinical practice, but the potential interactions and regulatory mechanisms in these drug combinations are poorly understood. We used the humanized CYP2D6 mouse model to predict the effect of apatinib on the pharmacokinetics and pharmacodynamics of metoprolol and investigated the interactional mechanism. The inhibitory effects and mechanisms of apatinib on metoprolol were investigated in vitro by using wild-type mouse liver microsomes (WT MLMs), humanized CYP2D6 mouse liver microsomes (hCYP2D6 MLMs), and human liver microsomes (HLMs). Molecular docking was utilized to explore the structural basis of the observed inhibitory mode. And in vivo interaction between apatinib and metoprolol was assessed by pharmacokinetics study using the humanized CYP2D6 mice. In vitro studies and molecular docking experiments indicated that apatinib competitively inhibited the metabolism of metoprolol. In vivo findings revealed that the administration of apatinib combined with metoprolol resulted in a significant increase in the AUC_(0-t), AUC_(0-∞) and C_max of metoprolol; additionally, there was a reduction in the CL_z/F and heart rate, indicating that apatinib strongly inhibited metoprolol metabolism. And the homologous CYP2D6 protein in WT mice was more sensitive to apatinib compared to the hCYP2D6 mice. Gender analysis revealed that metoprolol accumulation was more pronounced in male mice when combined with apatinib, indicating a higher susceptibility to cardiotoxicity in males.

We have assessed the human liver microsomal (HLM) metabolism of the chemical warfare nerve agents’ sarin (GB), cyclosarin (GF), and the Novichok agents A-230 and A-232. In HLM, GB showed drastically decreased stability (t_1/2 = 1.4 h). The addition of ethylenediaminetetraacetic acid (EDTA), which inhibits paraoxonase-1 (PON1), reduced the metabolism of GB in HLM suggesting at least a partial role in its metabolism (t_1/2 = 2.6 h). The absence of NADPH (a requirement for CYP activity) had a major impact on metabolism, suggesting a role of likely CYP-mediated metabolism, which was rescued with the later addition of NADPH at 4 h. GF was also metabolized readily in HLM (Control t_1/2 = 9.7 h; HLM t_1/2 = 0.5 h), and this metabolism was mitigated by the addition of EDTA (t_1/2 (fast) = 0.7 h, t_1/2 (slow) = 4.0 h), suggesting a PON1 role in the metabolism of GF. GF in HLMs also showed a reduced metabolism without NADPH, suggesting a CYP-mediated role. We have described for the first time the clearance of A-230 in HLM (t_1/2 (fast) = 0.9 h, t_1/2 (slow) = 26.5 h), with a significantly decreased stability from the control (t_1/2 = 48.3 h) and with the formation of the A-230 acid as the major metabolite. EDTA also reduced the metabolism of A-230 in HLMs (t_1/2 (fast) = 0.8 h, t_1/2 (slow) = 62 h). A-232 metabolism was also HLM-dependent (t_1/2 (fast) = 1.2 h, t_1/2 (slow) = 1190 h), although overall it was dramatically more stable in the control (t_1/2 = 2,300 h). The metabolism of A-232 in HLMs also showed some inhibition by EDTA (t_1/2 (fast) = 0.5 h, t_1/2 (slow) = 1480 h).

Novichok nerve agents, such as A-230, A-232, and A-234, were classified as Schedule 1 chemicals under the Chemical Weapons Convention (CWC) by the Organisation for the Prohibition of Chemical Weapons (OPCW) following poisoning incidents in 2018. As a result, the production, storage, and use of these chemicals are strictly prohibited by CWC signatory nations. The identification of biomarkers indicating Novichok exposure in humans is crucial for prompt detection and response to potential incidents involving these banned chemical weapons. In this study, BChE was isolated from human serum samples exposed to Novichok nerve agents in vitro using immunomagnetic capture, followed by enzymatic digestion with Pronase or proteinase K to generate new peptide biomarkers indicative of exposure. We identified nine previously unpublished Novichok-adducted peptides generated through enzymatic digestion with proteinase K and Pronase using liquid chromatography–high-resolution mass spectrometry. Two peptides, [Agent]-serine-alanine for proteinase K digestion and [Agent]-serine-alanine-glycine for Pronase digestion, were selected for optimization due to their abundance. The analysis was subsequently transferred to an LC-triple quadrupole system to enhance throughput and detect these new biomarkers at the limits of detection corresponding to BChE inhibition levels of 3.90% or less. These additional biomarkers can improve laboratory preparedness for OPCW-designated biomedical testing laboratories as well as other clinical and investigative laboratories tasked with responding to emergencies involving these highly toxic chemicals.

The widespread use of perfluorooctanesulfonic acid (PFOS) has raised concerns regarding its potential on pregnant women, particularly in relation to the development of pre-eclampsia (PE). This study investigates the impact of PFOS exposure on the LncRNA/Rnd3 axis in pregnant mice and its association with trophoblast cell functions in PE. Bioinformatics analysis revealed PFOS-related gene alterations in PE, with pathways enriched in apoptotic signaling and cytokine interactions. Experimental findings showed the downregulation of Oip5os1 and Rnd3, along with the upregulation of miR-155, affecting trophoblast behavior. Animal experiments confirmed that PFOS-induced gene expression changes are linked to PE progression. PFOS exposure impairs trophoblast proliferation and migration via the Oip5os1/miR-155/Rnd3 axis, contributing to PE development.

Defining the underlying toxicological mechanisms of various small molecules is of utmost importance in understanding the pathogenesis of chemical exposure-related human diseases and developing safe and effective therapeutics. Herein, we discuss the toxicological mechanisms of different small molecules utilizing the different tools of chemical biology.

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.