Toxicology Letters[JOURNAL]
Sun
200 papers
Preface.
Corsini E, Tsatsakis A
Toxicol Lett · 2025 Sep · PMID 40925710 · Publisher ↗
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Bisphenol A exposure promotes proliferation and invasion capabilities of bladder cancer cells: Insights from gene expression and pathway analysis.
Cong B, Liu H, Sun M … +4 more , Hu D, Li T, Wu W, Liu H
Toxicol Lett · 2025 Nov · PMID 40915513 · Publisher ↗
Bisphenol A (BPA), a synthetic organic compound widely used in plastic products, toys, water pipes, and flame retardants, has been linked to the onset and progression of various cancers. This study explores the associati...
Bisphenol A (BPA), a synthetic organic compound widely used in plastic products, toys, water pipes, and flame retardants, has been linked to the onset and progression of various cancers. This study explores the association between BPA and bladder cancer using bioinformatics approaches. We applied the ssGSEA algorithm to calculate BPA-related scores in TCGA-BLCA cohort and classify patients based on this. GO and KEGG pathway enrichment analyses identified key pathways associated with BPA-related genes. Prognostic genes were screened through differential expression, Cox regression, and Lasso regression, leading to the construction of a prognostic model. Pathway enrichment suggested that BPA exposure promotes bladder cancer progression by modulating the Epithelial-Mesenchymal Transition pathway. In vitro experiments demonstrated that exposure to 10⁻⁷ μM BPA significantly enhanced the proliferation and invasion of bladder cancer cells, with Western blot confirming that BPA induces the EMT phenotype in a dose-dependent manner. These findings suggest the involvement of the BPA-mediated regulatory network in bladder cancer progression, thereby providing novel insights into the molecular mechanisms underlying BPA-induced bladder cancer development upon environmental exposure.
Role of phthalates in breast cancer initiation, progression and drug rersistance: A scoping review and recommendations.
Benoit L, Tomkiewicz C, Bortoli S … +3 more , Bats AS, Coumoul X, Koual M
Toxicol Lett · 2025 Nov · PMID 40915512 · Publisher ↗
Phthalates are endocrine-disrupting chemicals (EDCs) with implications in breast cancer (BC). This review synthesizes epidemiological and experimental data to evaluate the role of phthalates in BC initiation, progression...
Phthalates are endocrine-disrupting chemicals (EDCs) with implications in breast cancer (BC). This review synthesizes epidemiological and experimental data to evaluate the role of phthalates in BC initiation, progression, and therapeutic resistance. We performed a scoping review using bibliographic citations from PubMed, Clinical Trials.gov, Embase, Cochrane Library, and Web of Science databases. MeSH terms for breast cancer and phthalates were combined and not restricted to the English language. The search was performed from 2010 to July 2024. The primary outcome was to determine the role of phthalates in BC. Two hundred and forty-seven articles were screened from 2010 to 2024. Of the 90 studies included, 23 were reviews, 24 were epidemiologic and 43 were experimental. Epidemiological evidence is mixed, with certain studies identifying a correlation between high cumulative exposure to specific phthalates, such as dibutyl phthalate, and increased BC risk, particularly in estrogen receptor-positive subtypes. Conversely, other studies reported no significant associations. Experimental investigations have demonstrated that phthalates disrupt estrogenic signaling, induce BC cell proliferation, and potentiate metastasis. Additionally, phthalates contribute to chemoresistance by modulating drug metabolism and altering gene expression. Given the persistent exposure to phthalates this review calls for public health interventions and recommendations.
Mouse model of prenatal valproic acid exposure: Effects on cortical morphogenesis and behavioral outcomes across environmental conditions.
Tanizaki M, Matsui T, Sugiyama R … +2 more , Kiriyama N, Komada M
Toxicol Lett · 2025 Nov · PMID 40915511 · Publisher ↗
Autism spectrum disorder is a developmental disability characterized by impaired social communication and repetitive behaviors, and environmental and genetic factors are involved in its onset. The use of the antiepilepti...
Autism spectrum disorder is a developmental disability characterized by impaired social communication and repetitive behaviors, and environmental and genetic factors are involved in its onset. The use of the antiepileptic drug valproic acid (VPA) during pregnancy is associated with neural tube defects and developmental disorders in the fetus. In this study, we aimed to identify abnormalities in cortical morphogenesis owing to prenatal VPA exposure and to elucidate the abnormalities in brain function associated with these abnormalities, particularly by comparing multiple and single environments. Pregnant mice were administered a single dose of 400 mg/kg/day of VPA on embryonic day 12, and the morphogenesis and behavioral characteristics of the fetal and newborn mouse brains were analyzed. Prenatal VPA exposure caused an increase in cell proliferation and morphological abnormalities in microglia. In the single-housing environment, a decrease in spontaneous locomotor activity and psychomotor activity, and an increase in anxiety-like behavior and abnormal social interactions, were observed. In the multiple-housing environment, no effect on spontaneous activity was detected, however, an effect on social interactions and social proximity was observed. These findings provide valuable insights into the effects of environmental factors during the fetal period on the risk of developmental disorders. Moreover, they indicate that developmental disorder-like behavior is also affected by the environment.
Clozapine-associated perturbation of arachidonic acid metabolism: A future direction for clozapine-induced cardiotoxicity.
Kingston E, Burns K, Tingle M
Toxicol Lett · 2025 Oct · PMID 40914282 · Publisher ↗
Clozapine is an effective antipsychotic medication utilised for treatment-resistant schizophrenia. However, clinical use of clozapine is limited due to the risk of cardiotoxicities, including clozapine-induced myocarditi...
Clozapine is an effective antipsychotic medication utilised for treatment-resistant schizophrenia. However, clinical use of clozapine is limited due to the risk of cardiotoxicities, including clozapine-induced myocarditis. Oxidation of clozapine and reduction of clozapine-N-oxide can be catalysed by the cardio-selective cytochrome P450 (CYP) isoforms CYP2J2, CYP1A1 and CYP1B1, which are also reported to metabolise arachidonic acid. Any interaction with CYP-catalysed arachidonic acid metabolism may perturb the balance of pro-inflammatory hydroxyeicosatetraenoic acids and anti-inflammatory epoxyeicosatrienoic acids, priming the heart to an inflammatory state. Thereby making it more susceptible to the damage that may induce clozapine-induced myocarditis. The purpose of this preliminary study was to investigate whether an interaction between arachidonic acid and clozapine or clozapine-N-oxide occurs at CYP2J2, CYP1A1 and CYP1B1, in comparison to the hepatic isoform CYP2C19. Our results demonstrated a clear perturbation of CYP1B1 catalysed arachidonic acid metabolism, with a concentration-dependent decrease in metabolite formation in the presence of clozapine and clozapine-N-oxide. Each isoform also had decreased N-desmethylclozapine formation relative to incubations with clozapine alone and impaired clozapine and clozapine-N-oxide REDOX cycling capacity. Although limited by analytical sensitivity, these data provide clear evidence of a metabolic interaction between arachidonic acid and clozapine. This offers a novel hypothesis to explain patient susceptibility and a feasible mechanism for the cardiac-selective inflammation observed in clozapine-induced myocarditis.
Characterization of formaldehyde-induced hepatotoxicity based on proteometabolomic analysis.
Paudel S, Sim H, Kang E … +7 more , Kim M, Park CW, Na AY, Min EK, Kim KT, Lee W, Lee S
Toxicol Lett · 2025 Oct · PMID 40907675 · Publisher ↗
Formaldehyde (FA) is a well-known environmental toxicant used in various industries, including biomedical, agriculture, and textiles, but poses significant health risks. Despite extensive research, the exact hepatotoxic...
Formaldehyde (FA) is a well-known environmental toxicant used in various industries, including biomedical, agriculture, and textiles, but poses significant health risks. Despite extensive research, the exact hepatotoxic mechanism of FA remains unclear. This study investigated FA-induced liver toxicity through an integrative analysis of proteomics and metabolomics in rat models, identifying 84 differentially expressed proteins and 66 metabolites. Using xMWAS and Reactome software, the study highlighted ferroptosis as a key pathway in FA-induced liver damage. STAT3/HO-1 were identified as crucial protein biomarkers, leading to ferroptosis via lipid peroxide accumulation through iron efflux. Validation through qPCR, western blot, and cell experiments confirmed the involvement of genes like Stat3, Hmox-1, and coagulation-related genes (Fga, Fgb, Fgg, Serpina1, and A2M). This research reveals a novel FA hepatotoxic mechanism involving ferroptosis and complement and coagulation pathways, offering potential for therapeutic interventions.
Skin-targeted AhR activation by microbial and synthetic indoles: Insights from the AhaRaCaT reporter cell line.
Vrzal R, Grycová A, Vrzalová A
Toxicol Lett · 2025 Oct · PMID 40907674 · Publisher ↗
Disruption of the epidermal barrier contributes to skin disorders such as atopic dermatitis and psoriasis. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, plays a key role in skin homeostasi...
Disruption of the epidermal barrier contributes to skin disorders such as atopic dermatitis and psoriasis. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, plays a key role in skin homeostasis and immune regulation. While traditionally associated with toxicity, AhR has emerged as a promising therapeutic target, particularly via tryptophan-derived indoles. To support AhR research in a dermatological context, we developed AhaRaCaT, a stable luciferase-based reporter cell line derived from human keratinocytes (HaCaT), enabling the assessment of AhR transcriptional activity in a skin-relevant model. We characterized the inducibility of AhaRaCaT in response to model AhR ligands (TCDD, BaP, FICZ) in dose- and time-dependent assays. Antagonist profiling with MNF, CH223191, GNF, carvone, and jasmone yielded IC50 values over 4- and 24-hour exposures. A panel of indoles previously studied in other models was evaluated for AhR activation, revealing a robust luciferase response at 4 h that declined at 24 h, consistent with trends observed in other cell types. Selected indoles also induced CYP1A1 mRNA expression and reversed cytokine-induced downregulation of filaggrin in HaCaT cells, highlighting their potential in mitigating inflammation-associated skin barrier defects. In summary, the AhaRaCaT cell line offers a sensitive and physiologically relevant tool for studying AhR signaling in skin, with broad applications in toxicology, dermatological research, and the development of AhR-targeted therapies for inflammatory skin diseases.
Establishing scientific confidence in a two-chamber co-culture system to evaluate androgenic response in the presence of hepatic metabolism.
van Tongeren TCA, Hall SJ, Madnick SJ … +13 more , Ip BC, Carmichael PL, Li H, Chen W, Breitweiser LA, Pence HE, Ames DM, Bowling AJ, Johnson KJ, Cubberley R, Sherf B, Morgan JR, Boekelheide K
Toxicol Lett · 2025 Oct · PMID 40902835 · Publisher ↗
For the in vitro determination of toxicity on target organs in the presence of physiologically relevant human metabolism, we recently developed a two-chamber liver-target organ co-culture system in a medium-throughput 96...
For the in vitro determination of toxicity on target organs in the presence of physiologically relevant human metabolism, we recently developed a two-chamber liver-target organ co-culture system in a medium-throughput 96-well format. Our proof-of-concept study using human HepaRG microtissues cultured in three-dimension (3D) and AR-CALUX reporter cells demonstrated the significantly reduced testosterone (T)-mediated androgen receptor (AR) responses in the presence of human liver metabolism. The present study further increased the scientific confidence in this two-chamber co-culture system as a flexible and robust tool to capture androgen-mediated responses by incorporating alternate AR reporter cell systems as the target and examining additional androgenic compounds. The system generated concordant metabolism-dependent changes in T- and 5α-dihydrotestosterone (DHT)-mediated AR responses using two different AR reporter cell systems (AR-CALUX, AR-INDIGO). The AR reporters had different sensitivity ranges and required media optimization. We demonstrated that this two-chamber co-culture system with integrated hepatic biotransformation can be used to evaluate endocrine activity with potential metabolism modulation of parent compounds.
Safety assessment of endotoxin related to drug products and medical devices: A review.
Liu F
Toxicol Lett · 2025 Oct · PMID 40886903 · Publisher ↗
Endotoxin, also known as LPS, is the main component of the outer membrane of Gram-negative bacteria. It is released into the environment during cell division and cell death. Contamination of drug products and medical dev...
Endotoxin, also known as LPS, is the main component of the outer membrane of Gram-negative bacteria. It is released into the environment during cell division and cell death. Contamination of drug products and medical devices by endotoxin has been reported. Although endotoxin has been studied for its therapeutic uses treating diseases via the tolerance mechanism, more overwhelming evidence points to its toxicity. Extensive literature has reported its acute and chronic health effects and association with a variety of human diseases due to its action on innate and adaptive immune systems. Endotoxin is tightly regulated by health agencies through the regulatory limits for drug products and medical devices. Safety insurance of endotoxin is critical by drug product and medical device industries to ensure product quality and patient safety. The current paper aims to provide a state-of-art review of the endotoxin structure, the mechanisms responsible for endotoxin bioactivity and toxicity, the health effects associated with endotoxin, the challenges of endotoxin to drug product and medical device developers, and the safety assessment status of endotoxin in relation to drug products and medical devices. Based on the historical record and recent data analysis of drug products and medical devices in relation to endotoxin, it has been proved that endotoxin has minimal safety risk to patients for these industries.
Human in vitro metabolism of an environmental mixture of polycyclic aromatic hydrocarbons (PAH) found at the Portland Harbor Superfund Site.
Gaither KA, Tyrrell K, Garcia W … +2 more , Anderson KA, Smith JN
Toxicol Lett · 2025 Oct · PMID 40854413 · Full text
Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that pose health risks to humans. Toxicity testing approaches of PAHs have evolved from traditional rodent models to New Approach Methodol...
Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that pose health risks to humans. Toxicity testing approaches of PAHs have evolved from traditional rodent models to New Approach Methodologies (NAMs), such as high-throughput screening in zebrafish, enabling rapid evaluation of chemical hazards. However, translating toxicity findings from laboratory systems to humans remains difficult due to complexity and species-specific differences. Chemical dosimetry modeling offers a quantitative framework to bridge this gap, but its accuracy depends on robust knowledge of PAH metabolism. The objective of this study was to measure human metabolism rates of Supermix-10, the ten most abundant PAHs found at the Portland Harbor Superfund Site, to support development of human pharmacokinetic models. We incubated individual PAHs from Supermix-10 in pooled human liver microsomes and quantified parent PAH disappearance using high-performance liquid chromatography (HPLC) with UV and florescent detection. To assess the potential of mixture interactions, we also measured metabolism of all 10 compounds in an equimolar mixture and compared rates of parent disappearance to those observed for individual PAHs. All Supermix-10 PAHs demonstrated rapid parent compound disappearance in human hepatic microsomes. PAHs grouped into three metabolism patterns: high metabolism rates and capacity (2-methylnaphthalene, acenaphthylene, fluorene, naphthalene), high affinity metabolism that rapidly achieves low-level saturation (benzo[a]anthracene, chrysene), and moderate metabolism rates and capacity (fluoranthene, pyrene, retene, phenanthrene). Smaller PAHs exhibited faster metabolism, and higher metabolism rates correlated inversely with molecular weight. When incubated in an equimolar mixture, Supermix-10 demonstrated significantly slower metabolism (47-89 %) compared to metabolism of individual PAHs at the same concentration. These findings enhance our understanding of PAH metabolism in humans and demonstrate significant mixture interactions under the conditions tested. Our findings offer insights into the metabolic behavior of Supermix-10 and provide critical metabolism rate data to support the development of physiological based pharmacokinetic (PBPK) models. Dosimetry models can translate PAH chemical dosimetry from high-throughput testing platforms, like zebrafish and cellular system assays, to human exposures enhancing the accuracy and reliability of PAH risk assessments.
Cyclin-dependent kinase inhibitor abemaciclib-induced cutaneous responses mediated by inflammation.
Boran T, Çamlı ÖP, Abudayyak M … +1 more , Özhan G
Toxicol Lett · 2025 Oct · PMID 40865691 · Publisher ↗
Abemaciclib is a cyclin-dependent kinase (CDK) enzyme inhibitor approved by the FDA for advanced and metastatic breast cancer therapy. Abemaciclib has caused someadverse reactions, such as dermatitis and skin reactions;...
Abemaciclib is a cyclin-dependent kinase (CDK) enzyme inhibitor approved by the FDA for advanced and metastatic breast cancer therapy. Abemaciclib has caused someadverse reactions, such as dermatitis and skin reactions; however, the underlying cellular mechanism is still not obvious. In the current study, human keratinocyte HaCaT cells were treated with 0-10 µM abemaciclib for 24 h. The cytotoxic, apoptosis/necrosis, oxidative stress, and inflammation-inducing potentials of abemaciclib were evaluated. Abemaciclib induced cytotoxicity and the half-maximal inhibitory concentration (IC) was computed to be ≥ 24.18 µM. It significantly induced apoptosis and oxidative damage in the lowest treatment group (0.1 µM). The time-dependent effects show that the highest effects were seen after 24 h. The study on low concentrations indicated that the maximum effects were seen in the 0.1 µM treatment group. There was a notable rise in the secretion of MCP-1, IL-6, and IL-8 at 0.1 µM, while it decreased at 1-10 µM. Similarly, the levels of other mediators were increased solely at 0.1 µM; however, no changes in the higher concentrations. The increase in TNF-α was significant at 5 µM; however, the increase diminished at the highest treatment concentration. It could be concluded that abemaciclib-induced toxicity could be via oxidative inflammation leading to cell death in human keratinocytes. No effect was detected in the higher concentrations, while the effect was observed in the lowest treatment group. These findings underscore the need for further comprehensive studies of the spectrum of activity and risk profile of abemaciclib and encourage future research in this area.
LncRNA SNHG15 sponges miR-3143/FOXO3 to regulate autophagy in ovarian dysfunction induced by benzene exposure.
Ye Z, Huang Q, Wu H … +11 more , Wang S, Li B, Zeng M, Jiang T, Ye B, Wei Y, Sun L, Wang S, Zeng Y, Chen Y, Tang H
Toxicol Lett · 2025 Oct · PMID 40854414 · Publisher ↗
Benzene, a recognized carcinogen, is utilized in synthesizing various chemicals. Epidemiological studies have established a positive correlation between benzene exposure and increased incidences of abnormal menstruation...
Benzene, a recognized carcinogen, is utilized in synthesizing various chemicals. Epidemiological studies have established a positive correlation between benzene exposure and increased incidences of abnormal menstruation and dysmenorrhea. This exposure might also pose risks to the fetal hematopoietic system. However, the precise molecular mechanisms underlying these effects are not fully understood. In this study, a chronic benzene exposure model was established through dynamic inhalation. We assessed the autophagy levels in mouse ovarian granulosa cells and human ovarian granulosa cells treated with 1,4-benzoquinone using molecular biology techniques such as qPCR, Western blot, and transmission electron microscopy (TEM), etc. The experimental results show that Benzene-exposed mice exhibited autophagy, a reduced number of ovarian granulosa cells, and vacuolar lesions in the fallopian tubes. Cell-based experiments demonstrated that benzene exposure significantly upregulated SNHG15 expression in human ovarian granulosa cells (P < 0.05). The upregulation of SNHG15 enhanced FOXO3 expression via the miR-3143/FOXO3 axis, which in turn increased the transcription of autophagy-related proteins such as Atg5 (P < 0.05), ultimately leading to excessive autophagy in granulosa cells and ovarian dysfunction. Benzene and its metabolite benzoquinone increase autophagy in ovarian granulosa cells. The lncRNA SNHG15 regulates this autophagy induced by benzene exposure through sponge-like binding to miR-3143/FOXO3, thus impairing ovarian function. Inhibiting SNHG15, miR-3143, and FOXO3 expression markedly reduced autophagy in granulosa cells and ameliorated ovarian dysfunction resulting from benzene exposure. These results suggest that the ceRNA axis involving SNHG15 may be a potential clinical therapeutic target.
Cluster-based read-across of ToxCast data identifies buprofezin as a partial PPARγ agonist with obesogenic potential.
Hwang S, Oh S, An S … +3 more , Park IG, Gong J, Noh M
Toxicol Lett · 2025 Oct · PMID 40848978 · Publisher ↗
The identification of environmental obesogens has become increasingly urgent amid rising rates of metabolic disorders linked to chemical exposures. Here, we employed a cluster-based read-across framework that integrates...
The identification of environmental obesogens has become increasingly urgent amid rising rates of metabolic disorders linked to chemical exposures. Here, we employed a cluster-based read-across framework that integrates structural descriptors with high-throughput screening (HTS) data from the ToxCast database to systematically identify potential obesogens. A total of 8971 chemicals were represented in a 2,217-dimensional structure-activity matrix, combining 1905 chemical fingerprints and 312 bioactivity endpoints, which were reduced and clustered into 135 distinct chemical groups. Among these, Cluster 14 was notably enriched with compounds affecting lipid metabolism pathways and included buprofezin, a thiadiazine insecticide not previously linked to obesogenic activity. Functional assays in human bone marrow-derived mesenchymal stem cells (hBM-MSCs) demonstrated that buprofezin promotes adipogenesis. Despite its classification as inactive in PPARγ-specific ToxCast assays, mechanistic studies revealed that buprofezin acts as a partial agonist of PPARγ (K = 14.8 µM), enhancing SRC1 coactivator recruitment. These findings underscore the limitations of current HTS data in capturing partial agonist activities and demonstrate the value of integrated read-across approaches in uncovering hidden chemical hazards. Given buprofezin's environmental persistence and widespread agricultural use, its potential metabolic health risks require further investigation.
Dose-dependent hepatotoxicity in Norway rat: Investigating the effects of methadone and morphine on liver gene expression and function.
Norioun H, Ghiasvand S
Toxicol Lett · 2025 Oct · PMID 40846171 · Publisher ↗
Methadone and morphine are two widely prescribed opioids for pain management and opioid substitution therapy. While both are pharmacologically effective, their long-term use may induce hepatotoxic effects. This study aim...
Methadone and morphine are two widely prescribed opioids for pain management and opioid substitution therapy. While both are pharmacologically effective, their long-term use may induce hepatotoxic effects. This study aimed to evaluate the hepatotoxic potential of methadone and morphine through an integrative approach combining experimental and bioinformatics analyses. Male Norway rats were administered methadone and morphine at doses of 3 and 7 mg/kg for 30 days. Liver tissues were analyzed using qRT-PCR to assess the expression of key metabolic genes (Cyp2b3, Cyp1a2, Cyp3a2, Cyp7a1, and Ugt2b), and serum liver enzyme levels (SGOT and SGPT) were measured as markers of liver injury. To further elucidate the molecular mechanisms underlying drug-induced liver injury, RNA sequencing (RNA-seq) data were analyzed to identify differentially expressed genes and enriched biological pathways. The bioinformatics data were sourced from the Gene Expression Omnibus (GEO) database with the accession number GSE250058. Bioinformatics analysis using DESeq2 revealed significant alterations in gene expression profiles, especially within immune regulation, oxidative stress, and metabolic detoxification pathways. KEGG and GO enrichment analyses highlighted the involvement of apoptosis, autophagy, and inflammation-related processes. These findings were supported by observed elevations in liver weight and liver enzymes, particularly in the high-dose methadone group. Overall, our results demonstrate that high-dose methadone induces more severe hepatic metabolic stress and gene dysregulation compared to morphine, indicating its greater hepatotoxic potential. This integrative study underscores the importance of combining experimental data with transcriptomic analyses to enhance our understanding of opioid-induced liver injury and inform future therapeutic strategies.
Associations of semen essential/non-essential elements with the risk of male infertility: A systematic review and meta-analysis.
Chen J, Tan W, Chen Z … +4 more , Zhang L, Yu Y, Zhu X, Xin B
Toxicol Lett · 2025 Oct · PMID 40829714 · Publisher ↗
BACKGROUND: Defective sperm function is the leading cause of male infertility, and epidemiological studies have revealed that various trace elements are linked to declining semen quality. However, differences in study qu...
BACKGROUND: Defective sperm function is the leading cause of male infertility, and epidemiological studies have revealed that various trace elements are linked to declining semen quality. However, differences in study quality and the heterogeneity of findings complicate the interpretation of the clinical significance of essential and non-essential elements in semen, especially ultra-trace elements. METHODS: Essential and non-essential elements in the semen of male infertility were systematically searched within eight databases (Embase, Cochrane, PubMed, MedLine, Web of Science, Chinese Knowledge Infrastructure (CNKI), China Science and Technology Journal Database, and Wanfang database) up to November 2024. RESULTS: A total of 38 studies involving 5070 patients (male fertility: 3061 vs. healthy control: 2009) were included. Thirty-eight studies measuring five essential elements (Zinc, Zn; Iron, Fe; Manganese, Mn; Selenium, Se; Copper, Cu) and four non-essential elements (Calcium, Ca; Magnesium, Mg; Lead, Pb; Cadmium, Cd) in the semen of men with infertility were included. Random-effect results indicated that the semen Cu (SMD = 0.505; 95 % CI: 0.246-0.764; P = 0.000) and Cd (SMD = 0.725; 95 % CI: 0.534-0.916; P = 0.000) levels in the male infertility group were higher than those of the control group. No significant differences in male infertility patient cases and healthy controls were found for Zn, Fe, Mn, Se, Ca, Mg, and Pb in semen. CONCLUSION: Elevations of Cu and Cd in semen were associated with the risk of male infertility. Investigation of essential and non-essential elements in semen may help to understand the pathogenesis of male infertility and could also be useful to plan treatment strategies in the future.
Cytokine profile and early immune response to SARS-CoV-2 in occupationally lead-exposed individuals: A cross-sectional study.
Jeziorska M, Kasperczyk S, Słota M … +8 more , Jakubowski J, Kasperczyk A, Czuba ZP, Matuszek P, Bellanti F, Badura-Brzoza K, Bułdak RJ, Dobrakowski M
Toxicol Lett · 2025 Oct · PMID 40825463 · Publisher ↗
BACKGROUND: The adaptive immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by the production of various antibodies, with immunoglobulin M (IgM) being the initial isotype syn...
BACKGROUND: The adaptive immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by the production of various antibodies, with immunoglobulin M (IgM) being the initial isotype synthesized. Lead (Pb), a toxic heavy metal, accumulates in biological systems and disrupts multiple biochemical processes, potentially modulating immune function through alterations in cytokine production and antibody levels. OBJECTIVE: This study aimed to elucidate the early immune response to SARS-CoV-2 in lead-exposed individuals by examining antibody profiles and associated immunological parameters. METHODS: A cohort of 277 male employees from a zinc and lead smelting facility in Poland was evaluated for SARS-CoV-2-specific IgM, IgG, and IgA antibodies prior to COVID-19 vaccination. Participants were stratified into IgM-positive (n = 13) and IgM/IgG/IgA-negative (n = 149) groups. Biomarkers of inflammation, hematological parameters, and oxidative stress were analyzed. RESULTS: The IgM-positive group exhibited significantly elevated levels of cytokines, including a proliferation-inducing ligand (APRIL), B cell activating factor (BAFF), interleukin-20 (IL-20), pentraxin-3 (PTX-3), and soluble tumor necrosis factor receptor 2 (sTNF-R2). A significantly higher level of IgM antibody levels was observed in individuals with higher zinc protoporphyrin (ZPP) concentrations. However, no significant differences in blood lead levels (PbB), oxidative stress markers, or hematological parameters were detected between the groups. CONCLUSION: Elevated levels of APRIL, BAFF, IL-20, sTNF-R2, and PTX-3 in lead-exposed individuals with recent SARS-CoV-2 infection may indicate robust dendritic cell and B cell activation and enhanced modulation of tumor necrosis factor-alpha (TNF-α) activity. These findings contribute to our understanding of the complex interplay between environmental lead exposure and the immune response to SARS-CoV-2 infection.
Zinc and titanium nanoparticles exposure intensifies the risk of skin issues by elevating cytokine gene expression despite following current international safety protocols.
Babaei V, Ashtarinezhad A, Torshabi M … +6 more , Teimourian S, Shahmirzaie M, Abolghasemi J, Gohardani HZ, Vernousfaderani EK, Shirazi FH
Toxicol Lett · 2025 Oct · PMID 40819699 · Publisher ↗
OBJECTIVES: The growing use of nanomaterials in daily life has raised concerns about their biological effects and potential toxicity. This study examines the impact of Zinc oxide (ZnO) and Titanium dioxide (TiO₂) nanopar...
OBJECTIVES: The growing use of nanomaterials in daily life has raised concerns about their biological effects and potential toxicity. This study examines the impact of Zinc oxide (ZnO) and Titanium dioxide (TiO₂) nanoparticles (NPs) on the expression of cytokine genes related to inflammation and their effects on skin abnormalities. METHODS: Conducted in Iran in November 2021, this study involved 110 factory workers, all adhering to international safety protocols when handling nanomaterials. Workers were classified by their years of experience in the warehouse and production lines. Skin complications were assessed by physicians, alongside measurements of inflammatory cytokines (IL-4, IL-6, IL-8, TNF-α) using RT-PCR, and CRP levels using a diagnostic kit. These workers were compared with a control group of administrative employees unexposed to nanoparticles. The concentrations of Zn and Ti nanoparticles in the workers were measured before and after their shifts. RESULTS: The concentrations of Zn and Ti nanomaterials in these individuals were measured before and after their daily work shifts. Results were modeled with skin manifestations in Network Pharmacology, drawing on previous studies. Blood nanoparticle measurements before and after work shifts indicated that current protective methods are inadequate to prevent NP penetration into the body. CONCLUSION: The results show a strong correlation between years of exposure to nanoparticles and increased inflammatory gene expression, CRP, and skin manifestations, with p values less than 0.0001. The results highlight the need for enhanced safety measures when using nanomaterials in industries like cosmetics, hygiene products, and food, to prevent potential health risks from prolonged exposure.
Cuproptosis is involved in small intestinal toxicity in the paraffins during pregnancy.
Tang J, Xu Z, Jiang M … +9 more , Luo C, Li X, Jiang Y, Qu Y, Ruan J, Wang X, Zheng M, Law WC, Zhao X
Toxicol Lett · 2025 Oct · PMID 40789379 · Publisher ↗
Short-chain chlorinated paraffins (SCCPs) is generally regarded as an emerging persistent organic pollutant. So far, small intestine injury in the progeny of adult mice exposed to SCCPs during pregnancy has not yet been...
Short-chain chlorinated paraffins (SCCPs) is generally regarded as an emerging persistent organic pollutant. So far, small intestine injury in the progeny of adult mice exposed to SCCPs during pregnancy has not yet been the subject of any research. To investigate potential intestinal injury in the progeny of adult mice exposed to SCCPs during pregnancy. There were no noticeable variations in litter size, sex ratio, or the birth weight of male and female mice. However, SCCPs gestational exposure significantly reduced the adult body weight of female and male mice. In addition, we discovered that SCCPs exposure resulted in histological alterations in the small intestines of both female and male newborns. Furthermore, the small intestines of SCCPs-treated female and male mice showed a significantly elevated superoxide dismutase (SOD) activity and reduced glutathione (GSH) activity compared to control group. Moreover, SCCPs exposure led to downregulation of FDX1 protein level and upregulation the protein levels of DLAT and SLC31A1, indicating initiation of coppers. Interestingly, the alterations in FDX1, DLAT, and LIAS mRNA expression levels varied between female and male progeny. Even while none of the phenotypes showed the typical dose-dependent effects, the findings suggest that female offspring are more susceptible to small intestine toxicity than male offspring. According to our findings, SCCPs exposure during pregnancy might develop sex-specific small intestine toxicity, which may lead to reactive oxygen species activation and following coppers. In summary, this study demonstrated that exposure to SCCPs during pregnancy had deleterious effects on the offspring's small intestine.
Exploring the impact of lysis conditions on the alkaline standard and Fpg-modified in vivo comet assay.
Collia M, Saenz-Martinez E, Vettorazzi A … +1 more , Azqueta A
Toxicol Lett · 2025 Oct · PMID 40783055 · Publisher ↗
The comet assay is a method used to detect DNA lesions. The protocol involves cell lysis and electrophoresis of the DNA once the cells are embedded in agarose. In this study, we investigated how lysis duration and pH aff...
The comet assay is a method used to detect DNA lesions. The protocol involves cell lysis and electrophoresis of the DNA once the cells are embedded in agarose. In this study, we investigated how lysis duration and pH affect Wistar rat tissues. A single oral dose of 200 mg/kg methyl methanesulfonate (MMS) to induce DNA strand breaks (SBs), or 5 mg/kg MMS or 400 mg/kg potassium bromate (KBrO) to induce Fpg-sensitive sites, was administered to male Wistar rats (n = 3 rats/group). The negative control rats received saline solution. After 3 h, the rats were sacrificed and different tissues were analysed after necropsy or snap-frozen in liquid nitrogen before analysis. The tested duration of lysis was from no lysis to overnight (pH 10). Different pH (i.e. 7 and 10) were tested in longer lysis (up to 1 week) in the case of the standard assay and in 1-hour lysis in the case of the Fpg- modified assay. No significant differences in SBs were found among the lysis lengths, including no lysis, but, after applying longer lysis in frozen samples, up to 1 -week, an increase in SBs was seen in the samples from treated rats. A neutral pH seems to slightly increase the % DNA in tail obtained. In the case of using Fpg a 5-min lysis was needed to detect Fpg-sensitive sites. The detection of Fpg-sensitive sites in MMS-treated rats was time and pH dependent. On the contrary, there were no differences in KBrO detected lesions.
Imidacloprid and its major metabolites blocks the alpha subunit of the human hERG (KV11.1) channel: Evidence from in-silico and fluorescence polarization studies.
Naik VU, Potnuri AG, Sharma S … +2 more , Mandla A, Arya DS
Toxicol Lett · 2025 Oct · PMID 40783054 · Publisher ↗
Neonicotinoids are high affinity agonists of insect Nicotinic Acetyl Choline Receptors (nAChRs) resulting in insect paralysis and death. Although they are assumed to have relatively low affinity towards mammalian and oth...
Neonicotinoids are high affinity agonists of insect Nicotinic Acetyl Choline Receptors (nAChRs) resulting in insect paralysis and death. Although they are assumed to have relatively low affinity towards mammalian and other non-insect nAChRs, studies have shown that they can cause neuro-endocrine toxicity, immunotoxicity and endocrine toxicity. Moreover, as a result of bioaccumulation the levels of neonicotinoids can be even traced in non-farming population at an significant level. KCHN2 gene encodes ERG1 or hERG or KV11.1 which is responsible for Ikr current. Multiple chemical molecules can block this KV11.1-alpha sub unit and can result in prolongation of QT interval causing Drug induced Long QT Syndrome (DI-LQTS). This could potentially trigger Torsades de Pointes (TdP), a unique form of the premature ventricular complex which are spontaneous in origin and often result in Sudden Cardiac Death (SCD). Imidacloprid (IMI) is highly bioavailable and undergoes biotransformation by cytochrome p450 monooxygenases (CYP) and aldehyde oxidases (AOX) forming Desnitro-Imidacloprid (DNI) and Imidacloprid-Olefin (IOL). Interestingly, acute poisoning with IMI can result in cardiac features such as ventricular tachyarrhythmias with severe hypotension. Nonetheless, despite of the evidence regarding the toxic bioaccumulation of neonicotinoids, a little is known about their cardiovascular toxicity. Henceforth, the current study aims to understand the effect of imidacloprid and its major metabolites on hERG (KV11.1) channel blockade using molecular docking studies. Findings of the study highlighted that IMI, DNI and IOL can potentially bind to residues like Tyr652 and Phe656 in the pore forming domain and can cause hERG (KV 11.1) blockade.
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