Search Results (1,242)

Human exposure to mycotoxins is a global concern since several mycotoxins, such as enniatins and aflatoxins, have shown carcinogenic and neurotoxic effects, and the toxicologic mechanisms of most of them still need to be clarified. This study aims to investigate the metabolic pathways affected by mycotoxin exposure by evaluating metabolite alterations in urine. The participants were 540 women from the Spanish Childhood and Environment Project (INMA). For metabolite identification, a dilute and shoot extraction, followed by HPLC-Q-TOF-MS identification analysis, was performed. Data were processed using Agilent Mass Hunter Workstation with the METLIN database, Agilent Mass Profiler Professional 10.0, and Metaboanalyst 6.0. Over 2000 metabolites were obtained in each sample after feature extraction, and the most significant metabolites (p-value ≤ 0.05, fold change ≥ 2.0) were considered for pathway analysis. Enrichment analysis and topology showed that the most significantly affected pathway was the biosynthesis of unsaturated fatty acids (adjusted p-value = 0.007), with four metabolomic hits associated: linoleic acid, octadecanoic acid/stearic acid, an arachidonic acid metabolite, and (9Z)-octadecenoic acid/oleic acid. Other related pathways (unadjusted p-value ≤ 0.1) included fatty acid biosynthesis, glycerophospholipid metabolism, and ether lipid metabolism. The present study highlights the importance of metabolomics in increasing knowledge of the toxicity mechanisms and health effects of mycotoxins, especially emerging ones. Full article

Three people in England consumed fish steaks labeled as Red Snapper (Lutjanus bohar) originating from the Indian Ocean. Within 12 h, all three experienced sickness including nausea, vomiting, diarrhea, as well as myalgia and paresthesia. Three steaks from a single package of fish obtained from a grocery store were consumed, leaving one uneaten, which was submitted for analysis. Cytotoxicity testing via the mouse neuroblastoma assay confirmed the presence of sodium channel specific activity consistent with a ciguatoxin standard, and the levels detected were above established guidance limits for safe consumption. Chemical detection using liquid chromatography coupled with high-resolution mass spectrometry of both intact toxins and periodate oxidation products was used to confirm the presence of chromatographic peaks consistent with tri- and di-hydroxylated Pacific ciguatoxin 3C congeners. Taking the shared medical symptoms of patients, the recent dietary history, and the known potential for ciguatera poisoning to occur in snapper species, the subsequent evidence for CTX-like activity and CTXs in the same fish sample provides very strong evidence that the fish steaks consumed were similarly contaminated with CTXs. Furthermore, given the levels reported, such toxicity would be expected to cause intoxication in humans. Fish species identification based on DNA barcoding confirmed that the fish products were mislabeled, with the tissues instead being the Pinjalo snapper, Pinjalo pinjalo. This is the first confirmed ciguatera poisoning incident in both the UK and from the Pinjalo snapper and highlights the need for monitoring of these emerging toxins in reef fish imports to prevent future human intoxication. Full article

A hybrid method—combining liquid biomimetic chromatography techniques (immobilized artificial membrane chromatography and biopartitioning micellar chromatography) and Quantitative Structure–Activity Relationships—was used to derive helpful models for predicting selected biological properties such as penetration through the plant cuticle, the skin and the blood–brain barrier, and binding to human serum albumin of phenoxyacetic acid-derived congeners regarded as potential herbicides. Reliable, high-concept models were developed indicating the lipophilicity, polarizability, and sum of hydrogen bond donors and acceptors as properties that determine the biological efficacy of the title compounds. These models were validated by leave-one-out cross-validation. Modeling the toxicity of phenoxyacetic acid-derived congeners to red blood cells allowed the identification of the most toxic substances as well as those molecular descriptors that determine their hemolytic properties. Full article

Alzheimer’s disease (AD) is one of the most common and severe forms of dementia and neurodegenerative disease. As life expectancy increases in line with developments in medicine, the elderly population is projected to increase in the next few decades; therefore, an increase in the prevalence of some diseases, such as AD, is also expected. As a result, until a radical treatment becomes available, AD is expected to be more frequently recorded as one of the top causes of death worldwide. Given the current lack of a cure for AD, and the only treatments available being ones that alleviate major symptoms, the identification of contributing factors that influence disease incidence is crucial. In this context, genetic and/or epigenetic factors, mainly environmental, disease-related, dietary, or combinations/interactions of these factors, are assessed. In this review, we conducted a literature search focusing on environmental factors such as air pollution, toxic elements, pesticides, and infectious agents, as well as dietary factors including various diets, vitamin D deficiency, social factors (e.g., tobacco and alcohol use), and variables that are affected by both environmental and genetic factors, such as dietary behavior and gut microbiota. We also evaluated studies on the beneficial effects of antibiotics and diets, such as the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) and Mediterranean diets. Full article

Benzene, a well-known carcinogenic airborne pollutant, poses significant health risks, particularly in industries such as petroleum, shoemaking, and painting. Despite strict regulations, chronic occupational exposure persists, contributing to the onset of acute myeloid leukemia (AML) and other malignancies. Benzene’s carcinogenicity stems from its metabolic activation, leading to increased oxidative stress, DNA damage, and cancer transformation. While its toxicity is well-documented, the link between genetic and epigenetic alterations and cancer susceptibility in exposed workers remains underexplored. This study aims to identify early biomarkers of benzene exposure and AML risk by analyzing gene expression and DNA methylation datasets from GEO DataSets, integrated with molecular pathway analyses, as well as miRNA-target and protein-protein network evaluations. This multi-approach led to the identification of nine deregulated genes (CRK, CXCR6, GSPT1, KPNA1, MECP2, MELTF, NFKB1, TBC1D7, ZNF331) in workers exposed to benzene, with NFKB1 showing strong discriminatory potential. Also, dose-dependent DNA methylation changes were observed in CXCR6 and MELTF, while selected miRNAs such as let-7d-5p, miR-126-3p, and miR-361-5p emerged as key post-transcriptional regulators. Furthermore, functional enrichment linked these genes to immune response, inflammation, cell proliferation, and apoptosis pathways. While network analyses highlighted NFKB1, CRK, and CXCR6 as central to benzene-associated leukemogenesis. Altogether, these findings provide novel insights into an early biomarker fingerprint for benzene exposure and AML susceptibility, supporting the future development of biomolecular-based targeted occupational health monitoring and personalized preventive strategies for at-risk workers. Full article

Ulcerative colitis (UC) is a chronic inflammatory condition that affects the intestines. Research has shown that reducing the activity of DDR1 can help maintain intestinal barrier function in UC, making DDR1 a promising target for treatment. However, the development of DDR1 inhibitors as drugs has been hindered by issues such as toxicity and poor binding stability. As a result, there are currently no DDR1-targeting drugs available for clinical use, highlighting the need for new inhibitors. In a recent study, a dataset of 85 DDR1 inhibitors was analyzed to identify key characteristics for effective inhibition. A pharmacophore model was constructed and validated to screen a library of marine natural products for potential DDR1 inhibitors. Through high-throughput virtual screening and precise docking, 17 promising compounds were identified from a pool of over 52,000 molecules in the marine database. To improve binding affinity and reduce potential toxicity, scaffold hopping was employed to modify the 17 compounds, resulting in the generation of 1070 new compounds. These new compounds were further evaluated through docking and ADMET analysis, leading to the identification of three compounds—39713a, 34346a, and 34419a—with superior predicted activity and drug-like properties compared to the original 17 compounds. Further analysis showed that the binding free energy values of the three candidate compounds were less than −12.200 kcal/mol, which was similar to or better than −12.377 kcal/mol of the known positive compound VU6015929, and the drug-like properties were better than those of the positive compounds. Molecular dynamics simulations were then conducted on these three candidate compounds, confirming their stable interactions with the target protein. In conclusion, compounds 39713a, 34346a, and 34419a show promise as potential DDR1 inhibitors for the treatment of ulcerative colitis. Full article

Exportin 1 is responsible for the export of hundreds of proteins, several RNA species and ribosomal components from the nucleus to the cytoplasm. Several transported proteins are important for regulation of cell proliferation and survival both in normal and malignant cells. We review the biological importance and the possibility of therapeutic targeting of Exportin 1 in acute myeloid leukemia (AML). Exportin 1 levels can be increased in human primary AML cells, and even exportin inhibition as monotherapy seems to have an antileukemic effect. The results from Phase I/II studies also suggest that exportin inhibition can be combined with conventional chemotherapy, including intensive induction and consolidation therapy possibly followed by allogeneic stem cell transplantation as well as AML-stabilizing therapy in elderly/unfit patients with hypomethylating agents. However, the risk of severe toxicity needs to be further evaluated; hematological toxicity is common together with constitutional side effects, electrolyte disturbances, and gastrointestinal toxicity. A recent randomized study of intensive chemotherapy with and without the Exportin inhibitor selinexor in elderly patients showed reduced survival in the selinexor arm; this was due to a high frequency of relapse and severe infections during neutropenia. Experimental studies suggest that Exportin 1 inhibition can be combined with other forms of targeted therapy. Thus, Exportin 1 inhibition should still be regarded as a promising strategy for AML treatment, but future studies should focus on the risk of toxicity when combined with conventional chemotherapy, especially in elderly/unfit patients, combinations with targeted therapies, identification of patient subsets (AML is a heterogeneous disease) with high susceptibility, and the possible use of less toxic next-generation Exportin 1 inhibitors. Full article

There is a strong demand for new and efficient antiviral compounds. A series of 2-hydroxy-1,4-naphthoquinone Mannich bases were screened for their HIV-1-RNase H inhibitory activity. An HIV-1-RNase H assay was used to study the RNase H inhibition by the test compounds. Docking of active derivatives into the active site of the enzyme was carried out. Compounds 1e and 2k showed distinctly higher HIV-1-RNase H inhibitory activity (IC₅₀ = 2.8–3.1 µM) than the known inhibitors RDS1759 and compound 13. The binding mode and possible interactions of 1e and 2k with the HIV-1-RNase H active site were determined using molecular docking, which led to the identification of salient and concealed pharmacophoric features of these molecules. The docking analysis revealed that there are significant differences in the binding mode of these compounds within the active site of the target enzyme. A selection of HIV-1-RNase H-inhibitory Mannich bases was tested for antiviral activity against HIV-1, and compound 2k showed the highest activity at low toxicity to host cells. The lawsone Mannich bases 1e and 2k also underwent a preliminary screening for activity against SARS-CoV-2, and compound 1e was found to inhibit SARS-CoV-2 replication (IC₅₀ = 11.2 µM). Full article

The aim of the present study was to investigate the phenolic composition and the efficacy of an innovative formulation based on Mg, Vitamin B6, and water extracts from Vitex agnus-castus, Crocus sativus, Melissa officinalis, Betula pendula, and Betula pubescens developed as an effective tool to face neuroinflammation and depression symptoms occurring in premenstrual syndrome (PMS). The formulation was analyzed through colorimetric and liquid chromatography methods for determining the content in phenols and flavonoids. Additionally, scavenging/reducing properties were investigated via 2,2-diphenyl-1-picrylhydrazyl (DPPH,) 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and horseradish peroxidase assays. The biocompatible limits were determined via allelopathy, the brine shrimp lethality test, and Daphnia magna cardiotoxicity assay. The formulation was then assayed in an experimental model constituted by isolated mouse cortex specimens exposed to K⁺ 60 mM Krebs–Ringer buffer, a toxic depolarizing stimulus able to reproduce the burden of inflammation/oxidative stress and the increased serotonin (5-hydroxytryptamine, 5-HT) impoverishment occurring in different neurological and psychiatric conditions, including depression. The results of the phytochemical analysis showed that the formulation is rich in benzoic acids, namely gentisic acid (155.31 µg/mL) and phenylethanoid compounds, namely hydroxytyrosol (39.79 µg/mL) that support the antioxidant effects measured via DPPH (IC₅₀: 1.48 mg/mL), ABTS (IC₅₀: 0.42 mg/mL), and horseradish peroxidase (IC₅₀: 2.02 mg/mL) assays. The ecotoxicological models indicated the formulation as non-toxic, permitting the identification of a biocompatible concentration (1000 µg/mL) to be used in isolated mouse cortex exposed to K⁺ 60 mM Krebs–Ringer buffer. In this model, the gene expression of cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), estrogen receptor-1 (ESR1), prolactin receptor (PRLR), brain-derived neurotrophic factor (BDNF), and serotonin transporter (SERT) was determined by real-time PCR. In the isolated mouse cortex, the formula reduced COX-2, IL-6, SERT, ESR1, and PRLR gene expression and increased BDNF and IL-10 gene expression. Overall, the study corroborated the use of the formulation as an innovative tool to contrast inflammation, oxidative stress, and neurotransmitter impairment associated with PMS. Full article

Herbicides are synthetic chemicals that are extensively employed in agricultural practices with the objective of enhancing crop yield and quality. Despite their selectivity for plant systems and being generally regarded as non-toxic to animals, there is a paucity of understanding surrounding the sublethal effects on non-target organisms, including animals. This gap underscores the necessity for ecotoxicological research that prioritizes the identification of suitable models and develops reliable biomarkers for the early assessment of environmental impact. In this context, hemocytes—circulating immune cells found in invertebrates—have been identified as a crucial system for assessing sublethal toxicological effects, given their role in immune defense and overall organism health. Tenebrio molitor, a beetle pest of stored grain, was used as a model for the assessment of the effects of a metribuzin-based herbicide (MTB, Feinzin DF 70, 70% metribuzin, 0.25 kg ha⁻¹). Following a 96 h exposure to MTB, the males (7–10 days post-eclosion) were examined for multiple biomarkers in their hemocytes, including cell density, phagocytic activity, lysosomal membrane stability, and cytological changes. Although no mortality was observed, exposure to MTB resulted in a reduction in the phagocytic index and an increase in blast-like cells, indicating the potential for immunotoxicity. Lysosomal membrane stability was reduced, though no significant changes in hemocyte density or nuclear morphology were observed. These responses indicate potential immune system impairment, which could affect the beetle’s fitness and reproductive potential. This study highlights the potential of hemocytes for assessing sublethal herbicide effects, raising concerns about the ecological impact of herbicides in agroecosystems and their potential risks to both wildlife and human health. Full article

Normal tissue reactions vary significantly among patients receiving the same radiation treatment regimen, reflecting the multifactorial etiology of late radiation toxicity. Predicting late radiation toxicity is crucial, as it aids in the initial decision-making process regarding the treatment modalities. For patients undergoing radiotherapy, anticipating late toxicity allows for planning adjustments to optimize individualized care. Various dosimetric parameters have been shown to influence the incidence of late toxicity, and the literature available on this topic is extensive. This narrative review examines patient-related determinants of late toxicity following external beam radiotherapy for pelvic tumors, with a focus on prostate and cervical cancer patients. In Part I, we address various methods for quantifying radiation toxicity, providing context for interpreting toxicity data. Part II examines the current insights into the clinical risk factors for late toxicity. While certain factors—such as previous abdominal surgery, smoking behavior, and severe acute toxicity—have consistently been reported, most of the others show inconsistent associations. In Part III, we explore the influence of genetic factors and discuss promising predictive assays. Single-nucleotide polymorphisms (SNPs) likely elevate the risk in specific combinations. Advances in artificial intelligence now allow for the identification of SNP patterns from large datasets, supporting the development of polygenic risk scores. These innovations hold promise for improving personalized treatment strategies and reducing the burden of late toxicity in cancer survivors. Full article

Fusarium head blight, caused by Fusarium graminearum, continues to be one of the most important and devastating fungal diseases on cereal grains including wheat, barley, and oat crops. F. graminearum produces toxic secondary metabolites that include trichothecene type A and type B mycotoxins. There are many variants of these toxins that are produced, and in the early 2010s, a novel type A trichothecene mycotoxin known as 3ANX (7-α hydroxy,15-deacetylcalonectrin) and its deacetylated product NX (7-α hydroxy, 3,15-dideacetylcalonectrin) were identified in Minnesota, USA. In the current study, a total of 31,500 wheat spikes over a period of 6 years (2015–2020) within Manitoba, Canada, were screened for the F. graminearum pathogen, which accounted for 72.8% (2015), 98.3% (2016), 71.9% (2017), 74.4% (2018), 92.6% (2019), and 66.1% (2020) of isolations. A total of 303 F. graminearum isolates, confirmed through sequencing of the ribosomal intergenic spacer, were further investigated for variation in the gene Tri1, which was previously associated with the production of the NX toxin, as well as the accumulation of mycotoxins. A subset of these isolates, consisting of 73 isolates, which tested positive or negative for the NX-Tri1-F/R assay in this study, were cultured in vitro using rice media. Mycotoxins were quantified in these samples using mass spectrometry. Using the same rice culture, genomic DNA was isolated, and the Tri1 coding sequence along with its flanking regions (upstream and downstream of the Tri1 gene) was amplified and sequenced. Deoxynivalenol (DON) accumulated in 96% of the cultures from these isolates, while 3-acetyl deoxynivalenol (3ADON) and 3ANX mycotoxins accumulated in 66% and 63%, respectively. Nivalenol, 15-acetyl deoxynivalenol, and NX mycotoxins were detected in 62%, 36%, and 19% of samples, respectively. A significant correlation was observed between 3ADON and 3ANX (r² = 0.87), as well as between DON and 3ANX (r² = 0.89). This study highlights the first large identification of 3ANX- and NX-producing isolates of F. graminearum in Western Canada. In addition, it is the first identification of 15ADON chemotypes producing 3ANX in Western Canada and the first identification of 3ANX and NX-producing isolates in Manitoba, collected from wheat samples. Full article

Advancing our understanding of pancreatic toxicity and metabolic disorders caused by environmental exposures requires innovative approaches. The pancreas, a vital organ for glucose regulation, is increasingly recognized as a target of harm from environmental chemicals and dietary factors. Traditional toxicological methods, while foundational, often fail to address the mechanistic complexities of pancreatic dysfunction, particularly under real-world conditions involving multiple exposures. New Approach Methodologies (NAMs)—including high-throughput screening (HTS), OMICS technologies, computational modeling, and advanced in vitro systems—offer transformative tools to tackle these challenges. NAMs enable the identification of mechanistic pathways, improve testing efficiency, and reduce reliance on animal testing. This commentary explores the integration of NAMs into pancreatic toxicity screening, addresses critical gaps in evaluating the cumulative risks of chemical and dietary exposures, and proposes solutions for integrating the pancreas into toxicity screening through NAMs. By highlighting recent advancements and emphasizing their adoption in environmental toxicity assessment frameworks, this work demonstrates the potential of NAMs to revolutionize environmental health research, inspire interdisciplinary collaboration, and protect public health. Full article

Risk of lung damage from inhaled chemicals or substances has long been assessed using animal models. However, New Approach Methodologies (NAMs) that replace, reduce, and/or refine the use of animals in safety testing such as 2D and 3D cultures are increasingly being used to understand human-relevant toxicity responses and for the assessment of hazard identification. Here we review 2D and 3D lung models in terms of their application for inhalation toxicity assessment. We highlight a key case study for the Organization for Economic Cooperation and Development (OECD), in which a 3D model was used to assess human toxicity and replace the requirement for a 90-day inhalation toxicity study in rats. Finally, we consider the regulatory guidelines for the application of NAMs and potential use of different lung models for aerosol toxicity studies depending on the regulatory requirement/context of use. Full article

Carbon monoxide (CO) is a toxic gas, and faulty gas appliances or solid fuel burning with incomplete combustion are possible CO sources in households. Evaluating household CO exposure models and measurement studies is key to understanding where CO exposures may result in adverse health outcomes. This assists the assessment of the burden of disease in high- and middle-income countries and informs public health interventions in higher-risk environments. We conducted a literature review to identify themes that characterise CO exposure in household dwellings. A keyword-structured search using literature databases was conducted to find studies published in the period of 1 January 2010–5 June 2024. We focused on studies from high- and middle-income countries, excluding animal and biomass studies, and narratively synthesised themes. We identified 5294 papers in the literature search and included 22 papers from thirteen countries in the review. Most measured CO levels were below the WHO or country guidance levels, with sporadic peaks of measured CO linked to fuel-burning activities. To understand CO exposure in households, we identified sixteen themes grouped into five main categories: dwelling characteristics, source characteristics, temporal variation, environmental characteristics, and socioeconomic status of occupants. Seasonal variation (temporal variation), size of room and ventilation (dwelling characteristics), and cooking and outdoor CO levels (source characteristics) had the most evidence. These themes characterising CO exposure in household dwellings are important to aid the development of indoor exposure models and for understanding where CO exposures result in adverse health outcomes. These themes should be validated by household CO monitoring studies, which will enable the identification of higher-risk household dwellings and inform public health actions. Full article