Archives of Toxicology最新文献

Formaldehyde (FA) is a ubiquitous indoor air pollutant emitted from construction, consumer, and combustion-related products, and ozone-initiated reactions with reactive organic volatiles. The derivation of an indoor air quality guideline for FA by World Health Organization in 2010 did not find convincing evidence for bronchoconstriction-related reactions as detrimental lung function. Causal relationship between FA and asthma has since been advocated in meta-analyses of selected observational studies. In this review, findings from controlled human and animal exposure studies of the airways, data of FA retention in the respiratory tract, and observational studies of reported asthma applied in meta-analyses are analyzed together for coherence of direct association between FA and asthma. New information from both human and animal exposure studies are evaluated together with existing literature and assessed across findings from observational studies and associated meta-analyses thereof. Retention of FA in the upper airways is > 90% in agreement with mice exposure studies that only extreme FA concentrations can surpass trachea, travel to the lower airways, and cause mild bronchoconstriction. However, taken together, detrimental lung function effects in controlled human exposure studies have not been observed, even at FA concentrations up 4 ppm (5 mg/m³), and in agreement with controlled mice exposure studies. Typical indoor FA concentrations in public buildings and homes are far below a threshold for sensory irritation in the upper airways, based on controlled human exposure studies, to induce sensory-irritative sensitization nor inflammatory epithelial damage in the airways. Analysis of the observational heterogeneous studies applied in the meta-analyses suffers from several concomitant multifactorial co-exposures, which invalidates a direct association with asthma, thus the outcome of meta-analyses. The evidence of a direct causal relationship between FA and asthma is insufficient from an experimental viewpoint that includes retention data in the upper airways and controlled animal and human exposure studies. Taken together, a coherence of controlled experimental findings with individual observational studies and associated meta-analyses, which suffer from caveats, is absent. Further, lack of identified evidence of FA-IgE sensitization in both experimental studies and observational studies agrees with indoor FA concentrations far below threshold for sensory irritation. The assessment of experimental data with uncontrolled observational studies in meta-analyses is incompatible with a direct causal relationship between FA and asthma or exacerbation thereof due to lack of coherence and plausibility.

Exposomics is a field that studies environmental exposures and their impact on human health. The MRM-IDA-EPI method, which combines targeted and untargeted mass spectrometry methods, is useful for identifying and quantifying biomarkers in various biological matrices. The method's accuracy and precision in forensic toxicological screening suggest potential applications for detecting low-level environmental exposures. It can help detect and understand environmental exposures, explain their metabolic processes, and assess their impact on human health more effectively.

Femtosecond lasers represent a novel tool for tattoo removal as sources that can be operated at high power, potentially leading to different removal pathways and products. Consequently, the potential toxicity of its application also needs to be evaluated. In this framework, we present a comparative study of Ti:Sapphire femtosecond laser irradiation, as a function of laser power and exposure time, on water dispersions of Pigment Green 7 (PG7) and the green tattoo ink Green Concentrate (GC), which contains PG7 as its coloring agent. The treated samples were subsequently analyzed via UV‒Vis spectroscopy, gas chromatography‒mass spectrometry (GC‒MS), SEM imaging and associated statistical analysis. We found that, on average, the discoloration efficacy of femtosecond laser treatment was comparable to that of nanosecond lasers as were the decomposition products. In fact, two primary types of fragments are produced, both of which are potentially harmful, resulting either from the decomposition of chlorinated phthalocyanine (i.e., PG7) or from the active chlorination of naphthalene impurities. However, the outcomes for the PG7 and GC treatments differed significantly from each other from several points of view. The spectral intensity patterns of GC and PG7 were distinct, depending on the treatment conditions, and showed linearity with power only in the case of GC. Additionally, the relative ratios of the fragment products differed significantly, with the production rate showing a linear dependence on power only in the case of GC and no discernible trend for PG7. Shape and size distribution of the generated particles were highly dependent on the type of sample. Femtosecond laser irradiation of GCs primarily produces nanoparticles with a homogeneous size distribution, which are typically considered nontoxic. Large aggregates also formed, exhibiting a regular shape. In contrast, PG7 yielded rods and needles with aspect ratios similar to those of toxic fibers.

Human UDP-glucuronosyltransferases (UGTs) are pivotal phase II metabolic enzymes facilitating the transfer of glucuronic acid from UDP-glucuronic acid (UDPGA) to various substrates. UGTs are classic type I transmembrane glycoproteins, mainly localized in the endoplasmic reticulum (ER) membrane. This review comprehensively explores UGTs, encompassing gene expression, functional characteristics, substrate specificity, and metabolic mechanisms. A recent analysis of C-terminal structures, compared with original data, underscores the pivotal role of α3, α4, and β4 functional domains in selectively recognizing diverse glycosyl donors. Accumulating evidence suggests that UGTs function as homo- and heterodimers, with oligomers likely stabilizing UGTs and modulating their activity. The review sheds light on the implications of UGT oligomerization on substrate glucuronidation and the interplay between protein-protein interaction and glucuronidation activity. UGT-mediated drug resistance, often underestimated, emerges as a clinically relevant form of chemical resistance, with delineated outcomes in tumors and other diseases. This review provides a multifaceted exploration of the physiological significance of UGTs, spanning genetics, proteins, oligomerization, drug resistance, and more, offering insights into their metabolic mechanisms. Understanding interactions between UGT isoforms is crucial for predicting drug-drug interactions, preventing drug toxicity, and enabling precision treatment.

Chlorinated paraffins (CPs) are environmental pollutants extensively used in industries. While the use of short-chain chlorinated paraffins (SCCPs) has been restricted since 2017, the use of medium-chain chlorinated paraffins (MCCPs) has risen as their replacement. Due to lipophilic character, it can be expected that CPs enter the cells; however, the in vitro accumulation potential of CPs remains poorly understood. In this study, we aimed to explore the ability of SCCPs and MCCPs to accumulate in fat cells. We utilized an in vitro model of mouse 3T3-L1 preadipocytes and adipocytes. Using gas chromatography coupled with high-resolution mass spectrometry operated in negative chemical ionization mode, we determined the intracellular amounts of CPs. These compounds accumulated at rates of 8.5 ± 0.1 µg/g_cells/h for SCCPs and 7.8 ± 0.3 µg/g_cells/h for MCCPs when an initial concentration of 120 ng/ml was present in the medium. This rate increased approximately tenfold when the concentration of CPs was raised to 1200 ng/ml. CPs content in adipocytes steadily increased over 5 days, whereas preadipocytes accumulated 15-20 times less CPs. This highlights the importance of cellular lipid content, which was about 12 times higher in adipocytes. Furthermore, we found that the level of chlorine content in the CPs molecules significantly influenced their accumulation. Our results demonstrate that MCCPs exhibit a similar accumulation potential to SCCPs, with lipid content playing a crucial role. As with SCCPs, restrictions on the use of MCCPs in industry should be considered to mitigate their environmental and health impacts.

E-cigarettes (E.cigs) cause inflammation and damage to human organs, including the lungs and heart. In the gut, E.cig vaping promotes inflammation and gut leakiness. Further, E.cig vaping increases tumorigenesis in oral and lung epithelial cells by inducing mutations and suppressing host DNA repair enzymes. It is well known that cigarette (cig) smoking increases the risk of colorectal cancer (CRC). To date, it is unknown whether E.cig vaping impacts CRC development. A mouse model of human familial adenomatous polyposis (CPC-APC) was utilized wherein a mutation in the adenomatous polyposis coli (APC) gene, CDX2-Cre-APC^Min/+, leads to the development of colon adenomas within 11-16 weeks. Mice were exposed to air (controls), E.cig vaping, cig, or both (dual exposure). After 4 weeks of 2 h exposures per day (1 h of each for dual exposures), the colon was collected and assessed for polyp number and pathology scores by microscopy. Expression of inflammatory cytokines and cancer stem cell markers were quantified. DNA damage such as double-strand DNA breaks was evaluated by immunofluorescence, western blot, and gene-specific long amplicon qPCR. DNA repair enzyme levels (NEIL-2, NEIL-1, NTH1, and OGG1) were quantified by western blot. Proliferation markers were assessed by RT-qPCR and ELISA. CPC-APC mice exposed to E.cig, cig, and dual exposure developed a higher number of polyps compared to controls. Inflammatory proteins, DNA damage, and cancer stemness markers were higher in E-cig, cig, and dual-exposed mice as well. DNA damage was found to be associated with the suppression of DNA glycosylases, particularly with NEIL-2 and NTH1. E.cig and dual exposure both stimulated cancer cell stem markers (CD44, Lgr-5, DCLK1, and Ki67). The effect of E.cigs on polyp formation and CRC development was less than that of cigs, while dual exposure was more tumorigenic than either of the inhalants alone. E.cig vaping promotes CRC by stimulating inflammatory pathways, mediating DNA damage, and upregulating transcription of cancer stem cell markers. Critically, combining E.cig vaping with cig smoking leads to higher levels of tumorigenesis. Thus, while the chemical composition of these two inhalants, E.cigs and cigs, is highly disparate, they both drive the development of cancer and when combined, a highly common pattern of use, they can have additive or synergistic effects.

Testing for developmental toxicity is an integral part of chemical regulations. The applied tests are laborious and costly and require a large number of vertebrate test animals. To reduce animal numbers and associated costs, the zebrafish embryo was proposed as an alternative model. In this study, we investigated the potential of transcriptome analysis in the zebrafish embryo model to support the identification of potential biomarkers for key events in developmental toxicity, using the inhibition of angiogenesis as a proof of principle. Therefore, the effects on the zebrafish transcriptome after exposure to the tyrosine kinase inhibitors, sorafenib (1.3 µM and 2.4 µM) and SU4312 (1 µM, 2 µM, and 5 µM), and the putative vascular disruptor compound rotenone (25 nM and 50 nM) were analyzed. An early (2 hpf-hours post fertilization) and a late (24 hpf) exposure start with a time resolved transcriptome analysis was performed to compare the specificity and sensitivity of the responses with respect to anti-angiogenesis. We also showed that toxicodynamic responses were related to the course of the internal concentrations. To identify differentially expressed genes (DEGs) the time series data were compared by applying generalized additive models (GAMs). We observed mainly unspecific developmental toxicity in the early exposure scenario, while a specific repression of vascular related genes was only partially observed. In contrast, differential expression of vascular-related genes could be identified clearly in the late exposure scenario. Rotenone did not show angiogenesis-specific response on a transcriptomic level, indicating that the observed mild phenotype of angiogenesis inhibition may represent a secondary effect.

The potential risk of chemicals to the human eye is assessed by adopted test guidelines (TGs) for regulatory purposes to ensure consumer safety. Over the past decade, the Organization for Economic Co-operation and Development (OECD) has approved new approach methodologies (NAMs) to predict chemical eye damage. However, existing NAMs remain associated with limitations: First, no full replacement of the in vivo Draize eye test due to limited predictability of severe/mild damage was reached. Second, the existing NAMs do not allow reliable differentiation between reversible and irreversible eye damage. Especially the prediction of tissue recovery remains challenging in vitro. Existing in vitro NAMs are based on destructive analysis with no consideration of tissue recovery. In this study, we developed a standalone eye-irritation test method based on non-invasive impedance spectroscopy (ImAi) to discriminate between damaging and irritating chemicals. Tissue effects were analyzed via transepithelial electrical resistance (TEER) measurements of human in vitro epithelial models over 14 days. The TEER was performed using a developed impedance spectrometer. For development of the EIT, a chemical reference list of 329 chemicals was compiled. The applicability of the ImAi-test was exemplified by the discrimination of Cat. 1 vs. Cat. 2 for 23 reference chemicals. Correct classification was achieved for 90.9% of Cat. 1 and 83.3% of Cat. 2 chemicals. Our non-invasive in vitro test overcomes the limitations of Cat. 2 classification of the existing in vitro methods and provides for the first time a non-animal test method that can fully replace the Draize eye test.