Frontiers in toxicology最新文献

Microphysiological systems (MPS) and Organs-on-Chips (OoCs) hold significant potential for replicating complex human biological processes in vitro. However, their widespread adoption by industry and regulatory bodies depends on effective qualification to demonstrate that these models are fit for purpose. Many models developed in academia are not initially designed with qualification in mind, which limits their future implementation in end-user settings. Here, we explore to which extent aspects of qualification can already be performed during early development stages of MPS and OoCs. Through a case study of our blood-perfused Vessel-on-Chip model, we emphasize key elements such as defining a clear context-of-use, establishing relevant readouts, ensuring model robustness, and addressing inherent limitations. By considering qualification early in development, researchers can streamline the progression of MPS and OoCs, facilitating their adoption in biomedical, pharmaceutical, and toxicological research. In addition, all in vitro methods must be independent of animal-derived materials to be considered fully fit for purpose. Ultimately, early qualification efforts can enhance the availability, reliability, and regulatory as well as ethical acceptance of these emerging New Approach Methodologies.

Cefotaxime is a broad-spectrum antibiotic targeting Gram-negative bacteria used for diverse infections, but it can be toxic to the stomach, liver, and kidneys. This study explored the protective effects of geranium oil against cefotaxime-induced hepatotoxicity and nephrotoxicity in rats, employing biochemical, histopathological, and immunohistochemical evaluations. Thirty rats were divided into five groups of six animals each one. Group 1 received orally normal saline for 14 days, Group 2 was given orally 2.5% DMSO for 14 days, Group 3 received cefotaxime (200 mg/kg/day IM) for 14 days, Group 4 received with cefotaxime (200 mg/kg/day IM) and geranium oil (67 mg/kg b. w./day orally in DMSO) for 14 days, and Group 5 received geranium oil alone (67 mg/kg b. w./day orally in DMSO) for 14 days. Geranium oil significantly reduced cefotaxime-induced damage, evidenced by lower serum levels of liver enzymes (AST, ALT), renal markers (urea, creatinine), and other indicators (alkaline phosphatase, TNF-alpha, IL-1Beta, MAPK, nitric oxide, MDA). It also increased levels of protective tissue biomarkers such as NrF2, albumin, catalase, Beclin 1, and reduced glutathione (GSH). Histopathological and immunohistochemical analyses revealed significant protective effects in liver and renal tissues in rats treated with Geranium oil. These results suggest that Geranium oil is effective in mitigating cefotaxime-induced hepatotoxicity and renal toxicity.

Introduction: In 2015, the FDA released a Drug Safety Communication regarding a possible link between opioid exposure during early pregnancy and an increased risk of fetal neural tube defects (NTDs). At the time, the indications for opioid use during pregnancy were not changed due to incomplete maternal toxicity data and limitations in human and animal studies. To assess these knowledge gaps, largescale animal studies are ongoing; however, state-of-the-art technologies have emerged as promising tools to assess otherwise non-standard endpoints. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is a dynamic approach capable of generating 2D ion images to visualize the distribution of an analyte of interest across a tissue section.

Methods: Given the importance of lipid metabolism and neurotransmitters in the developing central nervous system, this study incorporates MALDI MSI to assess lipid distributions across mouse gestational day (GD) 18 fetuses, with and without observable NTDs following maternal exposure on GD 8 to morphine (400 mg/kg BW) or the NTD positive control valproic acid (VPA) (500 mg/kg BW).

Results: Analysis of whole-body mouse fetuses revealed differential lipid distributions localized mainly in the brain and spinal cord, which included several phosphatidylcholine (PC) species such as PCs 34:1, 34:0, and 36:2 localized to the cortex or hippocampus and lyso PC 16:0 across all brain regions. Overall, differential lipids increased in with maternal morphine and VPA exposure. Neurotransmitter distributions across the brain using FMP-10 derivatizing agent were also assessed, revealing morphine-specific changes.

Discussion: The observed differential glycerophospholipid distributions in relation to treatment and NTD development in mouse fetuses provide potential targets for further investigation of molecular mechanisms of opioid-related developmental effects. Overall, these findings support the feasibility of incorporating MALDI MSI to assess non-standard endpoints of opioid exposure during gestation.

Introduction: Modern oral nicotine pouch products (ONPs) are a category of oral nicotine products which contain pharmaceutical-grade nicotine, flavors, and other food-grade ingredients but no tobacco leaf. Recent reports indicate that ONPs in general do not contain (or only at minimal levels) the harmful and potentially harmful constituents (HPHCs) identified in cigarette smoke, suggesting their potential as alternative products for reducing harm from cigarette smoking.

Methods: We assessed in vitro toxicological effects of eight ONPs, designated as modern oral (MO) 1 to 8 along with an ONP, an oral tobacco (snus), and a combustible cigarette market comparator using established regulatory toxicological assays including Ames, in vitro micronucleus (ivMN), and neutral red uptake (NRU) assays.

Results: The MO test products 1-7 ZYN wintergreen, and General Snus white mint were negative for mutagenicity (Ames assay), genotoxicity (ivMN), and cytotoxicity (NRU). The combustible cigarette was positive in all three assays. The MO-8 test product was negative for mutagenicity; however, it was positive in the ivMN and NRU assays at concentrations either 42 to 135-fold based on the ivMN i to iv treatment schedule or 60-fold higher, respectively, when compared to combustible cigarettes.

Discussion: Thus, the MO test products are likely to be less harmful than combustible cigarettes and are alternatives to cigarettes. However, understanding of long-term effects of ONPs in general requires additional research.

Microplastics (MPs) have been detected in various aquatic environments and negatively affect organisms, including marine luminous bacteria. This study investigated the differences in bioluminescence patterns, cell viability, and biofilm formation of Photobacterium leiognathi strains (LB01 and LB09) when exposed to various concentrations of ground microplastics (GMPs; 0.25%, 0.50%, 1%, or 2% [w/v] per mL) at 22°C or 30°C for 3.1 days (75 h) and 7 days. The strains exhibited heterogenous responses, including variable bioluminescence patterns, cell viability, and biofilm formation, due to the GMPs having effects such as hormesis and bioluminescence quenching. Moreover, the bioluminescence and cell viability differed between the two strains, possibly involving distinct cellular mechanisms, suggesting that GMPs affect factors that influence quorum sensing. Furthermore, the biofilm formation of LB01 and LB09 was observed following exposure to GMPs. Both strains showed increased biofilm formation at higher GMP concentrations (1% and 2%) after 3.1 days at 30°C and 22°C. However, in the 7-day experiment, LB01 significantly (p < 0.05) increased biofilms at 22°C, while LB09 significantly (p < 0.05) produced biofilms at 30°C. These findings highlight the strain-specific responses of Phb. leiognathi to MP pollutants. Therefore, this study underscores the importance of evaluating MPs as environmental stressors on marine microorganisms and their role in the ecophysiological repercussions of plastic pollution in aquatic environments.

Micro and nanoplastics (MNPs) are ubiquitous in the environment and have been detected in most ecosystems, including remote regions. The class of contaminants under the MNP umbrella is quite broad and encompasses variable polymer types, shapes, and sizes. Fibers are the most frequently detected in the environment, followed by fragments, but still represent only a small fraction of laboratory studies. Many toxicity studies have been done using polystyrene microbeads which represent neither the polymer nor shape most present in the environment. Additionally, most of these studies are done using virgin particles when the majority of MNP pollution is from secondary microplastics which have weathered and broken down over time. To address these data gaps, we exposed the model fish Inland Silverside, Menidia beryllina, for 21-days to micro and nano cryo-milled tire particles, micro and nano polylactic acid, and polyester microfibers, both weathered and unweathered treatments were tested. We evaluated the impacts of these particles on growth, behavior, and gene expression to compare the relative toxicities of the different particles. We found that overall, the nanoparticles and weathered fibers had the greatest effect on behavior and gene expression. Gene ontology analysis revealed strong evidence suggesting MNP exposure affected pathways involved in muscle contraction and function. Unweathered microfibers decreased growth which may be a result of food dilution. Our results also suggest that under weathering conditions polyester microfibers breakdown into smaller sizes and induce toxicity similar to nanoparticles. This study highlights the variable effects of MNPs in fish and emphasizes the importance of considering particle shape and size in toxicity studies.

Chemical risk assessment plays a pivotal role in safeguarding public health and environmental safety by evaluating the potential hazards and risks associated with chemical exposures. In recent years, the convergence of artificial intelligence (AI), machine learning (ML), and omics technologies has revolutionized the field of chemical risk assessment, offering new insights into toxicity mechanisms, predictive modeling, and risk management strategies. This perspective review explores the synergistic potential of AI/ML and omics in deciphering clastogen-induced genomic instability for carcinogenic risk prediction. We provide an overview of key findings, challenges, and opportunities in integrating AI/ML and omics technologies for chemical risk assessment, highlighting successful applications and case studies across diverse sectors. From predicting genotoxicity and mutagenicity to elucidating molecular pathways underlying carcinogenesis, integrative approaches offer a comprehensive framework for understanding chemical exposures and mitigating associated health risks. Future perspectives for advancing chemical risk assessment and cancer prevention through data integration, advanced machine learning techniques, translational research, and policy implementation are discussed. By implementing the predictive capabilities of AI/ML and omics technologies, researchers and policymakers can enhance public health protection, inform regulatory decisions, and promote sustainable development for a healthier future.

[This retracts the article DOI: 10.3389/ftox.2024.1371131.].

Fetal Bovine Serum (FBS) is an important ingredient in cell culture media and the current standard for most cells in vitro. However, the use of FBS is controversial for several reasons, including ethical concerns, political, and societal pressure, as well as scientific problems due to the undefined and variable nature of FBS. Nevertheless, scientists hesitate to change the paradigm without solid data de-risking the switch of their assays to alternatives. In this study, HepG2 cells, a human hepatoblastoma cell line commonly used to study drug hepatotoxicity, were adapted to serum-free conditions by using different commercially available media and FBS replacements. After transition to these new culture conditions, the success of adaptation was determined based on cell morphology and growth characteristics. Long-term culturing capacity for each medium was defined as the number of passages HepG2 cells could be cultured without any alterations in morphology or growth behavior. Two media (Advanced DMEM/F12 from ThermoFisher and TCM^® Serum Replacement from MP Biomedicals) showed a long-term cultivation capacity comparable to media containing FBS and were selected for further analysis. Both media can be characterized as serum-free, however still contain animal-derived components: bovine serum albumin (both media) and bovine transferrin (only TCM^® serum replacement). To assess the functionality of the cells cultivated in either of the two media, HepG2 cells were treated with reference compounds, specifically selected for their known hepatotoxicity characteristics in man. Different toxicological assays focusing on viability, mitochondrial toxicity, oxidative stress, and intracellular drug response were performed. Throughout the different assays, response to reference compounds was comparable, with a slightly higher sensitivity of serum-free cultivated HepG2 cells when assessing viability/cell death and a lower sensitivity towards oxidative stress. Taken together, the two selected media were shown to support growth, morphology, and function of serum-free cultivated HepG2 cells in the early preclinical safety space. Therefore, these results can serve as a starting point to further optimize culture conditions with the goal to remove any remaining animal-derived components.

Scorpion envenoming is a relevant and neglected public health problem in some countries. The use of antivenom is widespread in many regions, targeting specific species of scorpions. However, the uncontrolled proliferation and adaptation of these animals to urban environments, combined with limited access to treatments in remote areas and delays in antivenom administration contribute to a significant number of fatalities from scorpion-related incidents. In recent decades, new research has revealed that the immune system plays an important role in triggering immunopathological reactions during scorpion envenoming, which places it as a therapeutic target; however, few clinical studies have been conducted. This work provides a review of the main immunopathological aspects of scorpion envenoming, as well as the clinical trials conducted to date on the use of corticosteroids for the treatment of scorpionism. We highlight emerging treatment perspectives as well as the need for further clinical trials. The use of corticosteroids in scorpionism, when appropriate, could significantly enhance access to treatment and help reduce fatalities associated with scorpion stings.