Frontiers in toxicology最新文献

Within occupational epidemiology, the establishment of associations between chemical exposures and health outcome, in particular of individual chemicals present in the exposome, is difficult. Epidemiological studies are valuable but may be prone to confounders, or lack detailed exposure characterisation. Rodent studies may suffer from interspecies differences in comparison to humans. Here, we explore if a data driven approach can leverage human relevant mechanistic information to inform presumed associations between chemical exposures and two common respiratory disorders: lung function decline (LFD) and allergic asthma (AA). Using public toxicogenomics datasets, we identified Gene Ontology Bioprocesses (GO BPs) enriched in human respiratory cells, exposed in vitro to either diesel ultrafine particles (UFP) or respiratory sensitisers. In addition, for LFD and AA, GO BPs were curated from Molecular Initiating Events (MIEs) and Key Events (KEs) extracted from the Adverse Outcome Pathway (AOP) Wiki, and DisGeNET, a gene-disease database. Considering the commonality in GO BPs, a clear overlap was observed between GO BPs derived from UFP and LFD (a.o. "negative -"/"positive" regulation of cell activation," "positive regulation of ion transport," "stem cell proliferation"). 20 GO BPs were overlapping between sensitisers in combination with AA (e.g., "responses to xenobiotic stimulus," "response to oxidative stress" and "regulation of response to cytokine stimulus"). For AA, sensitiser concentrations used in in vitro were generally higher compared to equivalent concentrations expected in vivo (from PBK modelling). Yet, the overlapping GO BPs discovered for these endpoints were plausible and aided in providing mechanistic insights. Currently, limitations exist in the approach to infer causality (e.g., data availability, coverage of AOPs, in vitro to in vivo dosimetry issues), however it can inform on the identification of chemicals within the occupational exposome and putative mechanistic linkage with occupational diseases. Finally, the annotated MIEs and KEs for LFD and AA may serve as valuable resource for further AOP developments.

Background: Plasticisers, widely present in daily life, have been linked to osteoporosis (OP), though the precise mechanisms remain unclear.

Methods: This study examined the association between mono (2-ethylhexyl) phthalate (MEHP) and OP using multivariate logistic regression based on NHANES data. Network toxicology identified key targets and pathways involved in MEHP-induced OP. Molecular docking and dynamics simulations validated the stability of MEHP-target interactions. The effects of MEHP on osteogenic differentiation were further assessed in mouse bone marrow stromal cells (BMSCs).

Results: All logistic regression models confirmed a significant positive correlation between MEHP levels and OP. Network toxicology analysis identified CTSD, SOAT1, and VCP as key targets and the apoptosis pathway as a key mechanism in MEHP-induced OP. Molecular simulations demonstrated stable MEHP binding to these targets. Cellular experiments revealed that MEHP significantly inhibited BMSC osteogenesis by downregulating CTSD and VCP, while SOAT1 showed a weaker correlation.

Conclusion: MEHP exposure is positively associated with OP risk, with CTSD, VCP, and the apoptosis pathway potentially playing key roles in impairing BMSC osteogenesis.

Background: The use of perfumes and cosmetic products is widespread, serving personal hygiene, aesthetic, and olfactory functions. However, concerns have been raised regarding the potential health impacts associated with long-term exposure to various ingredients used in these products.

Objectives: This narrative review aims to synthesize evidence on the health risks associated with perfumes and cosmetics, focusing on specific health concerns, including fertility, respiratory health, cancer risk, allergies, skin disorders, endocrine disruption, and neurological effects. It also discusses the presence of heavy metals in cosmetics, regulatory challenges, and the need for transparency in ingredient disclosure.

Methods: A comprehensive review of the literature that was published between 2005 and 2024 was conducted, examining findings from interdisciplinary studies relevant to the health impacts of cosmetic and fragrance products. The review highlights health concerns linked to specific chemical components, including synthetic chemicals such as phthalates, parabens, and volatile organic compounds (VOCs).

Results: The findings indicate that many synthetic chemicals in perfumes and cosmetics are associated with adverse health outcomes. These include allergies, respiratory issues, endocrine disruption, reproductive problems, and potentially cancer. Heavy metals in cosmetics also pose significant health risks. Despite regulatory guidelines, the cumulative and long-term effects of combined exposure to multiple cosmetic ingredients remain poorly understood and inadequately addressed.

Conclusion: There is a pressing need for stricter regulatory oversight and improved transparency in ingredient disclosure to safeguard consumer health. Further research is required to clarify the long-term health risks associated with the daily use of cosmetic products and to develop safer alternatives.

Background: Each year, approximately 100 million cases of bee and wasp stings are re-ported globally, with the majority resulting in mild reactions. However, in rarer instances, these stings can lead to severe and potentially fatal outcomes, including ischemic or hemorrhagic cerebral events. This article aims to synthesize and analyze the current evidence on the association between bee and wasp stings and the occurrence of ischemic and hemorrhagic strokes.

Methodology: A systematic review was conducted in accordance with PRISMA guidelines. Searches were performed in PubMed, Scopus, and Scielo databases, including studies published in English and Spanish without time restrictions. Studies that met the inclusion criteria, specifically focusing on "bee sting" or "wasp sting" and "stroke" or "cerebrovascular disease" in humans, were included.

Results: Out of the 83 articles initially identified, 28 met the inclusion criteria and were included in this systematic review, documenting a total of 29 cases of stroke associated with bee or wasp stings. The distribution of cases was nearly equal between bee and wasp stings. Ischemic stroke emerged as the most commonly reported type, with clinical manifestations primarily affecting the nervous system. Common symptoms included hemiparesis or hemiplegia, hypertension, dysarthria or aphasia, and loss of consciousness or syncope. This pattern underscores the significant neurological and systemic impact of envenomation, which, while rare, can lead to severe and potentially life-threatening complications.

Conclusion: While cerebrovascular events like ischemic and hemorrhagic strokes following bee or wasp stings are rare, the risk is significant and can be life-changing. The impact of a stroke extends beyond immediate symptoms, affecting long-term quality of life. Therefore, it is crucial that healthcare facilities establish protocols to recognize and manage these rare but severe complications. Further research is needed to better understand and mitigate this risk.

Introduction: Efficient preclinical prediction of cardiovascular side effects poses a pivotal challenge for the pharmaceutical industry. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are becoming increasingly important in this field due to inaccessibility of human native cardiac tissue. Current preclinical hiPSC-CMs models focus on functional changes such as electrophysiological abnormalities, however other parameters, such as structural toxicity, remain less understood.

Methods: This study utilized hiPSC-CMs from three independent donors, cultured in serum-free conditions, and treated with a library of 17 small molecules with stratified cardiac side effects. High-content imaging (HCI) targeting ten subcellular organelles, combined with multi-electrode array data, was employed to profile drug responses. Dimensionality reduction and clustering of the data were performed using principal component analysis (PCA) and sparse partial least squares discriminant analysis (sPLS-DA).

Results: Both supervised and unsupervised clustering revealed patterns associated with known clinical side effects. In supervised clustering, morphological features outperformed electrophysiological data alone, and the combined data set achieved a 76% accuracy in recapitulating known clinical cardiotoxicity classifications. RNA-sequencing of all drugs versus vehicle conditions was used to support the mechanistic insights derived from morphological profiling, validating the former as a valuable cardiotoxicity tool.

Conclusion: Results demonstrate that a combined approach of analyzing morphology and electrophysiology enhances in-vitro prediction and understanding of drug cardiotoxicity. Our integrative approach introduces a potential framework that is accessible, scalable and better aligned with clinical outcomes.

The CLARITY-BPA Core Study is the most comprehensive animal study of oral bisphenol A (BPA) exposure to date. Rats were exposed daily, in utero until postnatal day 21 or for the animals' lifetime. While the study authors concluded that several observations at the highest dose may be BPA treatment-related, a No-Observed-Adverse-Effect Level (NOAEL) has not been proposed in the published reports. Therefore, select endpoints deemed by the study authors to be potentially BPA treatment-related were further evaluated to determine a NOAEL. These include findings in the female reproductive tract and male pituitary gland at the highest dose level (25,000 μg/kg-bw/day). The data were examined for dose-response, relevance, and consistency of findings across study arms and timepoints, histopathological progression, and concordance with the estradiol positive control. Based on our evaluation, some of the female reproductive tract findings are possibly BPA treatment-related. However, there is a lack of consistency between study arms and/or timepoints, no significant dose-response, and a lack of progression to tumors for proliferative findings. Finally, the findings from the Core Study agree with previous high-quality guideline studies which determined that BPA did not pose adverse effects at doses below 25,000 μg/kg-bw/day in rodents. Altogether, some findings from the Core Study may be BPA treatment-related but they should not be considered adverse. Therefore, we hypothesize that the NOAEL from the Core Study is reasonably considered to be 25,000 μg/kg-bw/day.

Background: Unintentional pesticide poisoning is a global health concern, disproportionately affecting agricultural workers in developing countries due to inadequate regulations and limited access to protective equipment. While questionnaires offer a cost-effective alternative for assessing organophosphate (OP) pesticide exposure compared to urinary (e.g., Dialkyl Phosphates, DAPs) or blood biomarkers (e.g., acetylcholinesterase, AChE, and butyrylcholinesterase, BChE), these tools require validation against gold-standard methods. This study validated a questionnaire assessing occupational OP exposure among Chilean agricultural workers in the Maule region, contrasting its performance against DAP levels and AChE and BChE inhibition.

Methods: A longitudinal study was conducted with 51 agricultural workers. Urinary DAPs, measured via liquid chromatography-tandem mass spectrometry, AChE, and BChE activities, determined by Ellman's method, were measured before (T0) and during (T1) the spray season. The questionnaire was administered at T1. Sensitivity, specificity, predictive values, and Receiver Operating Characteristic (ROC) curve analyses were performed to assess the accuracy.

Results: Urinary DAP levels and AChE inhibition increased in T1 (from 6.54 ± 4.66 to 12.39 ± 9.88 μg/g creatinine, p = 0.004, and from 2.26E-3±6.53E-4 to 1.44E-3±2.73E-4 mmol/min^-1*mgProt^-1, p < 0.001, respectively), with AChE inhibition (30.99%) exceeding Chilean regulatory threshold. The questionnaire score correlated with AChE inhibition (p = 0.0063) but not with BChE inhibition or DAP levels. Sensitivity was 64%, and specificity improved from 56% to 71% when using a 20% AChE inhibition threshold instead of a 30%.

Conclusion: Agricultural workers in the Maule region are exposed to OP pesticides. The questionnaire shows potential as a screening tool for occupational exposure. These findings highlight the need to reassess the Chilean regulatory limits and refine the tool to enhance risk assessment and intervention planning.

Data from pre-clinical and clinical studies form part of an integrated assessment of the tobacco harm reduction (THR) potential of novel products that may act as cigarette alternatives for adult smokers. We report data from pre-clinical (emissions chemistry and in vitro toxicology) and clinical (nicotine pharmacokinetics and subjective effects) studies conducted with the iSENZIA™ heated herbal system (HHS; PULZE™ 2.0 device with iSENZIA™ sticks), which utilizes electronic heating of a tea-based substrate to generate an inhalable nicotine-containing aerosol. The aerosols from the iSENZIA™ HHS contained significantly lower levels, by up to 99.8%, of the nine World Health Organization Study Group on Tobacco Product Regulation (WHO TobReg) analytes compared with 1R6F reference cigarette smoke and elicited significantly lower in vitro cytotoxicity, genotoxicity, and mutagenicity responses. The clinical study demonstrated that the iSENZIA™ HHS delivers satisfactory levels of nicotine to users and has lower abuse liability than cigarettes. Overall, our data suggest that iSENZIA™ has the potential to offer substantially reduced toxicant exposure, as well as a reduction in toxicity, compared to cigarettes, while delivering satisfactory levels of nicotine. These findings support the THR potential of the iSENZIA™ HHS as a reduced-risk, acceptable alternative product for adult smokers.

Environmental exposure to complex metal mixtures plays a critical role in the onset and progression of diverse chronic diseases, in ways that the traditional toxicological framework fails to capture. A paradigm shift is underway, moving toward a more integrated understanding of combined metal effects through the interdisciplinary study of the metallome, the distribution of metal ions and metalloids within a biological system. In this perspective, we highlight the clinical importance of metallome to identify specific subpopulations in which disease onset or progression is primarily driven by environmental metal exposure rather than genetic predisposition. To achieve this goal, robust and sensitive analytical methods are required to overcome the limitations of conventional approaches and enable the detection of the full spectrum of metal species, including metals sequestered within mineral particles present in body fluids and tissues. We propose methodological innovations in sample preparation and analysis that expand the current scope of metallome-associated research. Together, these advances support a comprehensive framework for assessing metal mixture effects in environmental health, bridging toxicology with clinical practice and enabling more targeted, exposure-informed public health interventions.

Cell cultures form the backbone for scientific research and development, but also for clinical diagnostics and biotechnology. Supplying cells in vitro with growth factors, hormones, and other nutrients is achieved most often by supplementing culture media with fetal bovine serum (FBS). Despite its nearly ubiquitous use, there are major reproducibility, safety, and animal welfare issues arguing the need to replace FBS. Fortunately, numerous FBS replacements have been validated and are publicly or commercially available, making it possible to leave FBS behind. Successful serum-free, animal-component-free, and chemically defined media applications are highlighted in this review for the cultivation of stem cells and organoids, the development of organ-on-a-chip systems, the bioprinting of tissues, and the production of cultivated meat, antibodies, and vaccines, including the conduct of cytotoxicity tests and the cryopreservation of cells. Moreover, the use of fully animal-free models and methodologies is further discussed to promote their broader acceptance and adoption within the global scientific research and development community. In this regard, this review discusses novel avenues to address the scientific and practical hurdles that might limit a full transition from FBS to fully defined cell culture media and offers a brief perspective on potential future directions.