Toxicology最新文献

Cellulose nanofibrils (CNFs) are advanced biomaterials valued for their strength, lightweight nature, and low thermal expansion, making them suitable for diverse industrial applications. However, their potential inhalation risks necessitate thorough safety evaluations. This study investigates the pulmonary inflammatory effects and retention of CNFs following intratracheal instillation in rats. TEMPO-oxidized CNF (CNF1; 11.5 nm × 1.8 μm), mechanically fibrillated CNF (CNF2; 23.9 nm × 2.4 μm), and shorter-fibrillated CNF (CNF3; 21.6 nm × 1.2 μm) were administered at 2.0 mg/kg body weight. Endotoxin contamination was assessed using lipopolysaccharide (LPS) controls. Pulmonary inflammation was evaluated 28 days post-instillation, and lung retention of chemically stained CNFs was tracked for 90 days. Results indicated: (1) CNFs were taken up by alveolar macrophages, but no significant acute inflammation was observed; (2) CNF characteristics, particularly fiber diameter and length, play a key role in influencing lung inflammation responses and determining inflammation sites; (3) endotoxin levels in the CNF dispersions may have limited effects on inflammatory responses; and (4) CNFs persist in lung tissue for extended periods, indicating slow clearance. While immediate inflammatory responses were minimal, the prolonged retention of CNFs in the lungs could contribute to chronic low-grade inflammation. Given the variability in CNF properties influenced by raw materials and manufacturing processes, it is essential to test each CNF type individually, including toxicological endpoints beyond inflammation, to accurately assess their potential health risks.

Novel flame retardants (NFRs) have emerged as chemicals of environmental health concern due to their widespread use as an alternative to polybrominated diphenyl ethers (PBDE) in electrical and electronic devices. Humans and ecosystems are under threat because of e-waste recycling procedures that may emit NFRs and other anthropogenic chemicals into the e-waste workplace and the surrounding environment. The individual toxicity of NFRs including novel brominated flame retardants (NBFRs), their combined effects and the underlying mechanisms of toxicity have remained poorly understood. Exposure assessment as well as chemical safety testing should focus on prioritizing N(B)FRs for regulation and management. Here, the occurrence of N(B)FRs in the vicinity and surroundings of e-waste recycling sites are presented. Important knowledge gaps and prospects for a more integrated, harmonized, and mechanistically positioned risk assessment strategy for N(B)FRs as well as possible economically feasible and environmentally sustainable approaches for removing them from complex matrices are highlighted. Overall, data in the ng to µg-ranges of N(B)FR in soil, dust, sediment, water and fish were found. Dust and soil sample concentrations ranged from the low ng to low µg/g range while water concentrations were always in the low ng/L range (∼0.5 to ∼4 ng/L). Concentration in fish was usually in the range of 3- ∼300 ng/g with two substances in the low to medium-high µg/g range (DBDPE, BTBPE). From the 20 N(B)FR analysed in sediment samples only 10 were above detection limit. Most chemicals were found in a low ng/g range.

With the increasing use of lithium-ion batteries, the exposure and health effects of lithium nickel manganate cobalt (NMC), a popular cathode material for the battery, have attracted widespread attention. However, the main absorption routes and target organs of NMC are unknown. This study aims to systematically investigate the main absorption routes and target organs of NMC. Male adult C57BL/6 J mice were subjected to acute exposure to NMC particles (Ni: Mn: Co = 5: 3: 2, mass median geometric diameter 9.15 μm) by intragastric administration, transdermal drug delivery, and oropharyngeal aspiration (OPA). The OPA group showed a significant increase in NMC metal levels in organs and blood compared to the other exposure routes. After OPA treatment (0.5 or 2 mg, once per day, 3 days), significantly increased metal levels were found in the lung, liver and kidney, but there was no dose-response effect. In the lung, obvious inflammation, and significant elevation of white blood cells, neutrophils and eosinophils in bronchoalveolar lavage fluid were observed, all of which showed a dose-response effect. Reduced urine output and renal tubular cell loss, as well as dysregulated metabolic and immune functions as indicated by the hepatic transcriptome, were observed in NMC-exposed mice. Respiratory exposure is the main exposure route of NMC. Short-term respiratory exposure to NMC results in potential damage to the kidney and liver in addition to severe inflammation in the lung.

Genistein (GEN) is a phytoestrogen with oestrogen-like activity found in many plants. Classified as an endocrine disruptor, GEN is potentially hazardous, particularly during developmental stages. It induces alterations in anxious behaviour, fertility, and energy metabolism, alongside modifications in specific brain circuits. As the serotonin (5-HT) system is critically involved in many of these behaviours, we hypothesised that some of GEN's behavioural effects might results from disruptions in the development of the 5-HT system. To test this, we examined the impact of early postnatal exposure to GEN at a dose of 50 mg/kg body weight, mimicking the exposure level of infants consuming soy-based formulas, on anxiety-related behaviours and 5-HT neuronal populations in the raphe nucleus. Male and female CD1 mice were treated orally with GEN or a vehicle during the first 8 days of life. On postnatal day 60, one cohort underwent anxiety behaviour testing, while another was euthanised for immunohistochemical analysis. Behavioural testing revealed that male control mice exhibited higher anxiety levels than females, whereas GEN exposure produced sex-specific effects: anxiolytic in males and anxiogenic in females. Immunohistochemical analysis of the raphe nuclei demonstrated significant alterations in 5-HT neuronal numbers in GEN-treated animals. Specifically, GEN exposure affected dorsal and median raphe 5-HT neuronal populations in a sexually dimorphic manner, with females showing a reduction and males an increase in 5-HT neurones compared to controls. These findings indicate that the regulation of anxiety-related behaviours and the 5-HT system are key targets of early phytoestrogen exposure at levels comparable to those in soy-based infant formulas.

Asbestos minerals have been widely exploited due to their physical-chemical properties, and chrysotile asbestos has accounted for about 95% of all asbestos commercially employed worldwide. The exposure to chrysotile, classified like other five amphibole asbestos species as carcinogenic to humans, represents a serious occupational and environmental hazard. Nevertheless, this mineral is still largely employed in about 65% of the countries worldwide, which still allow its "safe use". The complex mechanisms through which the mineral fibres induce toxicity are not yet completely understood. In this regard, the morphometric parameters of asbestos fibres (e.g., length, width, aspect ratio) are known for their fundamental role in determining the degree of pathogenicity. In this context, the potential toxicity of short chrysotile fibres remains widely debated due to the contradictory results from countless studies. Thus, the present study investigated the different toxicity mechanisms of two representative batches of short (length ≤5 µm) and long (length >5 µm) chrysotile fibres obtained by cryogenic milling. The fibre doses were based upon equal mass and size, since due to chrysotile ability to form bundles, it was not possible to calculate the number of fibers applied per cell. The cytotoxic, genotoxic, and pro-inflammatory potential of the two size-separated chrysotile fractions was investigated on human THP-1-derived macrophages and HECV endothelial cells, both separately and in a co-culture setup, mimicking the alveolar pro-inflammatory microenvironment, in time course experiments up to 1 week. Both chrysotile fractions displayed cytotoxic, genotoxic, and pro-inflammatory effects, with results comparable to the well-known damaging effects of crocidolite asbestos, or higher, as in the case of the longer chrysotile fraction. Furthermore, in presence of HECV, fibre-treated macrophages showed prolonged inflammation, indicating an interesting crosstalk between these cells able to sustain a low-grade chronic inflammation in the lung. In conclusion, these results help to shed light on some important open questions on the mechanisms of toxicity of chrysotile asbestos fibres.

In the myocardium of control subjects and patients undergoing heart transplantation or left ventricular assist device implantation (LVAD), we analyzed concentrations of Al, As, Cd, Pb, and Ni using inductively coupled plasma mass spectrometry. Myocardial generation of oxidative-stress-induced lipid peroxidation was analyzed by quantifying concentration of 4-Hydroxynonenal (4-HNE) with ELISA and pro-apoptotic DAPK2 gene expression was determined with quantitative RT-PCR. Compared to six control hearts, myocardial samples of 128 individuals undergoing heart transplantation or LVAD implantation exhibited a moderate increase in deposition of five tested non-essential elements, which was significantly increased only for Cd and cumulative deposition of Al, As, Cd, and Pb. Patients with higher cumulative deposition of Al, As, Cd, and Pb, underwent heart transplantation or LVAD implantation at a younger age than those with lower cumulative deposition, which was not observed in individual elements. Also, Al, As, and Ni exhibited a positive correlation with DAPK2 expression. Moreover, Al, As, Cd, and Ni showed positive correlations and Pb negative correlations with several mitochondrial quality control (MQC) genes. None of the elements showed correlation with 4-HNE generation in the myocardium. There was no difference in tested non-essential element deposition between dilated and ischemic cardiomyopathy. In conclusion, patients with higher cumulative deposition of Al, As, Cd, and Pb in the myocardium underwent heart transplantation or LVAD implantation at a younger age, indicating that they may accelerate heart failure, which is associated with induction of DAPK2 expression. Deposition of Al, As, Cd, Ni, and Pb also altered the expression of several MQC genes.

The growing prevalence of environmental pollutants has raised concerns about their potential role in thyroid dysfunction and related disorders. Previous research suggests that various chemicals, including plasticizers like acetyl tributyl citrate (ATBC), may adversely affect thyroid health, yet the precise mechanisms remain poorly understood. The objective of this study was to elucidate the complex effects of acetyl tributyl citrate (ATBC) on the thyroid gland and to clarify the potential molecular mechanisms by which environmental pollutants influence the disease process. Through an exhaustive exploration of databases such as ChEMBL, STITCH, and GEO, we identified a comprehensive list of 19 potential targets closely associated with ATBC and the thyroid gland. After rigorous screening using the STRING platform and Cytoscape software, we narrowed this list to 15 candidate targets, ultimately identifying five core targets: CBX5, HADHB, TRIM33, TP53, and CUL4A, utilizing three well-established machine learning methods. In-depth Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses conducted in the DAVID database revealed that the primary pathways through which ATBC affects the thyroid gland involve key signaling cascades, including the FoxO signaling pathway and metabolic pathways such as fatty acid metabolism. Furthermore, molecular docking simulations using Molecular Operating Environment software confirmed strong binding interactions between ATBC and these core targets, enhancing our understanding of their interactions. Overall, our findings provide a theoretical framework for comprehending the intricate molecular mechanisms underlying ATBC's effects on thyroid damage and pave the way for the development of preventive and therapeutic strategies against thyroid disorders caused by exposure to ATBC-containing plastics or overexposure to ATBC.

Triclosan (TCS) is commonly used worldwide due to its bactericidal and antifungal properties. There are data suggesting the involvement of aryl hydrocarbon receptors (AhR) and peroxisome proliferator-activated receptors (PPARγ). Since the effect of TCS on mouse fibroblasts has not been described so far, we decided to investigate the mechanism of action of this compound in the mouse embryonic fibroblast cell line (3T3-L1). Our results showed that high µM concentrations of TCS increased caspase-3 activity and decreased cell viability after 24-h exposure. The molecular analysis confirmed that 1 µM TCS decreased Ki67 mRNA expression and PCNA protein expression with a similar tendency to that of AhR. The analyses of mRNA levels after treatment with αNF or βNF alone and αNF in combination with TCS showed an increase in Ki67 mRNA expression. TCS alone increased AhR mRNA but had different effects on Cyp1a1 and Cyp1b1 expression. These results suggest the involvement of the PPARγ pathway in the inhibition of Cyp1b1 by TCS. After the TCS exposure, we observed a decrease in PPARγ, and this effect was enhanced in the presence of an AhR agonist and antagonist. These results support the theory about the interaction between the AhR and PPARγ pathways. In the experiments, the strongest increase in PI3K protein expression was observed in the group treated simultaneously with TCS and βNF. Changes in the PI3K level were reflected in changes in the examined mTOR protein. TCS caused a decrease in both mTOR and Cyp1b1 after 24 hours, while opposite effects were observed after 48 hours. Given the crucial role of Cyp1b1, PPARγ, and mTOR in cellular metabolism, we can conclude that TCS is able to disrupt a number of cellular processes. Our data suggest that TCS reduces the metabolism of this xenobiotic in mouse preadipocytes.

The widespread use of plastic products worldwide has brought about serious environmental issues. In natural environments, it's difficult for plastic products to degrade completely, and so they exist in the form of micro/nanoplastics (M/NPs), which have become a new type of pollutant. Prolonged exposure to M/NPs can lead to a series of health problems in humans, particularly toxicity to the nervous system, with consequences including neurodevelopmental abnormalities, neuronal death, neurological inflammation, and neurodegenerative diseases. Although direct evidence from humans is still limited, model organisms and organoids serve as powerful tools to provide important insights. This article summarizes the effects of M/NPs on the nervous system, focusing on cognitive function, neural development, and neuronal death. Mechanisms such as neurotransmitter synthesis and release, inflammatory responses, oxidative stress, the gut-brain axis, and the liver-brain axis are covered. The neurotoxicity induced by M/NPs may exacerbate or directly trigger neurodegenerative diseases and neurodevelopmental disorders. We particularly emphasize potential therapeutic agents that may counteract the neurotoxic effects induced by M/NPs, highlighting a novel future research direction. In summary, this paper cites evidence and provides mechanistic perspectives on the effects of M/NPs on neurological health, providing clues for eliminating M/NP hazards to human health in the future.

Drug-induced gastrointestinal toxicity is a frequent clinical adverse event that needs to be carefully monitored and managed to ensure patient compliance. While preclinical assessment of drug-induced gastrointestinal toxicity mostly relies on animal experimentation, intestinal organoids have gained increasing attention to identify gastrointestinal toxicants in vitro. Nonetheless, current in vitro protocols primarily assess structural alterations induced by drugs, whereas gastrointestinal adverse events can often stem from functional disturbances. Disruption of serotonin signaling in the gastrointestinal tract is associated with impaired motility, as well as nausea and vomiting. We aimed to investigate alterations of serotonin homeostasis in organoids derived from the canine small intestine as a driver of drug-induced gastrointestinal toxicity. Treatment of the organoids with a compound (NVS-1) inducing acute gastrointestinal toxicity in dogs as well as with three tyrosine kinase inhibitors with known preclinical and clinical gastrointestinal adverse effects (afatinib, crizotinib and vandetanib) led to increased supernatant serotonin levels. Mechanistic assays showed that, while NVS-1 and afatinib stimulate serotonin release, crizotinib and vandetanib inhibit serotonin re-uptake via direct inhibition of the serotonin re-uptake transporter. Using a data mining approach, we further suggest that inhibition of serotonin re-uptake could contribute to gastrointestinal toxicity observed with multiple marketed drugs. In conclusion, we present the implementation of a novel in vitro gastrointestinal toxicity endpoint that could complement current methods and serve as a mechanistic and predictive/screening tool for drug-induced gastrointestinal toxicity.