Toxicology Letters[JOURNAL]
Sun
200 papers
Exposure to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine under hypoxic conditions (%O =2 %) alters differential gene expression and mitigates decreased invasion capacity, compared to normoxic conditions (%O ≥ 21 %) in HTR-8/SVneo cells.
Stein FH, Le NH, Elkin ER
Toxicol Lett · 2025 Dec · PMID 41232580 · Full text
Trichloroethylene (TCE) is a volatile organic compound used as an industrial solvent until the recent EPA phaseout. Despite regulatory restrictions, legacy TCE pollution persists in soil and groundwater and poses a risk...
Trichloroethylene (TCE) is a volatile organic compound used as an industrial solvent until the recent EPA phaseout. Despite regulatory restrictions, legacy TCE pollution persists in soil and groundwater and poses a risk to human health. This chemical exerts its toxic effects through its metabolites including the glutathione conjugation metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC). Although a known nephrotoxicant, limited research has explored its effects on placental development - despite a reported epidemiological association between maternal exposure and elevated risk of restricted fetal growth. The placenta plays a critical role in the first trimester, functioning under hypoxic conditions to support fetal growth. Extravillous trophoblasts (EVTs), essential for placental development, are sensitive to environmental stressors. In this study, effects of human-relevant DCVC concentrations on cytotoxicity, differential gene expression, and invasion capacity were evaluated and compared under normoxic and hypoxic conditions using the placental EVT cell line HTR-8/SVneo. Differential gene expression between normoxic and hypoxic controls was also evaluated to characterize the simulated hypoxic experimental conditions. DCVC exposure induced significant cytotoxicity at concentrations as low as 10 μM under both normoxic and hypoxic conditions. DCVC also caused differential gene expression under both conditions, with a more robust response under normoxia. Similar biological pathways were altered under both conditions, including those involved in oxidative balance, cell migration, and apoptotic signaling. Invasion capacity significantly decreased with 10 and 20 μM DCVC under normoxia but was partially rescued under hypoxia, indicating a possible protective effect. Overall, HTR-8/SVneo cell responses to DCVC were similar under both oxygen conditions, with some evidence of hypoxia offering mild protection. This study builds on previous literature and offers new evaluation of exposure under different simulated oxygen conditions mimicking those experienced during the first trimester of pregnancy.
Chlormequat chloride inhibited thyroid hormone in the pregnant rats by regulating sodium/iodide symporter.
Celigeer, Tian W, Wu Z … +3 more , Huang Y, Huang X, Xiagedeer B
Toxicol Lett · 2025 Dec · PMID 41207543 · Publisher ↗
Chlormequat chloride can increase agricultural production by making the stem of the crops shorter and stronger, so it has become one of the most popular growth regulators in the world and humans are widely exposed to it....
Chlormequat chloride can increase agricultural production by making the stem of the crops shorter and stronger, so it has become one of the most popular growth regulators in the world and humans are widely exposed to it. However, besides its regulatory effects on the growth of the plants, our previous studies have demonstrated that chlormequat chloride can also affect maternal and embryonic homeostasis in the rats. To better understand the regulatory effect of chlormequat during pregnancy, in this study, pregnant rats were orally exposed to chlormequat chloride at 0, 0.05, 0.5 and 5 mg/kg.bw from gestation day (GD) 0-20, we found that levels of maternal thyroid hormones (THs) were inhibited on GD11 and the brain weight of the pups was affected on postnatal day (PD) 10. To understand the mechanisms of the decreases in THs, we found that the sodium/iodide symporter (NIS), which is responsible for the uptake of iodide by thyrocytes in the biosynthesis of THs, was inhibited in pregnant rats by chlormequat chloride dose-dependently. Furthermore, the thyrotropin (TSH) induced cAMP dependent protein kinase A (PKA) signaling pathway, which is the up-stream regulating pathway of NIS, was also inhibited by chlormequat chloride in the pregnant rats. However, the TSH-PKA-NIS pathway was not affected by chlormequat chloride in the non-pregnant female rats. To summarize, chlormequat chloride caused down-regulation of NIS and thus inhibited synthesis of maternal THs during embryonic development, and leads to altered postnatal brain weight.
Impact of microplastics and nanoplastics on human health: Mechanistic insights and exposure pathways.
Rehman MFU, Khan MM, Khan MM
Toxicol Lett · 2025 Dec · PMID 41203090 · Publisher ↗
Microplastics (MPs) and nanoplastics (NPs) have emerged as critical environmental contaminants with potential adverse effects on human health. This review examines the various ways MPs and NPs can be spread in the enviro...
Microplastics (MPs) and nanoplastics (NPs) have emerged as critical environmental contaminants with potential adverse effects on human health. This review examines the various ways MPs and NPs can be spread in the environment and their potential impact on humans. They can be introduced into the environment through multiple sources, like synthetic textiles, cosmetics, packaging, and industrial processes. These particles enter the human body through ingestion, inhalation, and skin contact, and they deposit in various tissues, including the lungs, kidneys, and gastrointestinal tract. Additionally, they can cross embryonic layers and reach the placenta. They can cause inflammation, oxidative stress, metabolic disorders, genotoxicity, and immunotoxic effects upon interaction, as confirmed by in-vivo and in-vitro studies. Furthermore, long-term exposure to MPs and NPs causes various complications to the human body, including metabolic disorders or even the development of cancers. Despite the presence of much evidence, a significant gap remains in fully understanding the mechanism of toxicity posed by MPs and NPs exposure and its long-term health outcomes. There is an urgent need for extensive investigations and improvement in standardized methods to evaluate the human health impact of MPs and NPs. This review explores current evidence on exposure pathways, bioaccumulation mechanisms, and health outcomes and identifies critical knowledge gaps.
Recommendations for the calculation of inhalation exposure to cosmetic spray products: A comprehensive review.
Steiling W, Vandecasteele HA, Boisleve F … +6 more , Burke T, Keller D, Pappa G, Gurjanov A, Giusti A, Bowden AM
Toxicol Lett · 2025 Dec · PMID 41197689 · Publisher ↗
Consumer products such as cosmetic spray products must be safe. Strict rules to ensure this for cosmetic spray products are established by the EU Cosmetic Products Regulation, as well as by scientific advisory panels. In...
Consumer products such as cosmetic spray products must be safe. Strict rules to ensure this for cosmetic spray products are established by the EU Cosmetic Products Regulation, as well as by scientific advisory panels. In this article several default values are proposed from the literature to improve the consistency and accuracy of inhalation exposure assessments performed for cosmetic spray products. The use of these default values is given for the most relevant spray product types currently on the EU market. The use of well-known exposure calculation models (e.g. one-box and two-box models) are discussed for their applicability to estimate consumer inhalation exposure to certain spray product types. The availability of measured data from experimental studies is limited due to the complication caused by parameters such as technical product information relating to droplet/particle sizing of the airborne product. In some cases, there is reliance on conservative, worst-case input values (e.g., spray time and the amount released from the product container) for exposure assessment of individual product uses. Where the authors have identified data gaps for certain parameters for specific product types during the literature review, recommendations are provided for additional consolidated default values to promote the safety assessment.
Corrigendum to "TLR2-ERK signaling pathway regulates expression of galectin-3 in a murine model of OVA-induced allergic airway inflammation" [Toxicol. Lett. 397 (2024) 55-66].
Lv Y, Jiang G, Jiang Y … +2 more , Peng C, Li W
Toxicol Lett · 2025 Dec · PMID 41184169 · Publisher ↗
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Environmental relevant concentrations of TBBPA cause complex toxicological mechanisms.
Liao Y, Wang Y, Dong H … +11 more , Lin Y, Xiao Y, Jaman R, Mohan M, Azim F, Lu R, Zhao T, Zhu J, Chen G, Zhang C, Zhou J
Toxicol Lett · 2025 Dec · PMID 41177314 · Publisher ↗
Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant recognized for its environmental persistence, bioaccumulation and toxicological potential, raising concerns about its hazardous effects on both ec...
Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant recognized for its environmental persistence, bioaccumulation and toxicological potential, raising concerns about its hazardous effects on both ecological systems and human health. Our research investigated the hepatotoxicity of TBBPA at environmentally relevant concentrations (1-100 nM) using transformed human liver epithelial-2 (THLE-2) cells. Results demonstrated that TBBPA exposure induced cell alterations in cell density, nuclear irregularities and fibrosis-like extensions. Transcriptomic analysis revealed significant perturbations in pathways related to metabolism, cellular stress responses, inflammatory responses, cell proliferation, substance transport and degradation. Further investigations revealed the most obvious gene expression profile changes at 1 nM TBBPA exposure, however, higher concentrations (10 nM and 100 nM) of TBBPA appeared to cause more severe hepatotoxicity. RT-qPCR and molecular docking experiments confirmed the changed gene expression and TBBPA-Protein binding. These findings elucidate complex mechanisms of TBBPA-induced effects in hepatocytes, highlighting the environmental health risks of TBBPA.
Corrigendum to "Ibuprofen induces hepatic Cyp7a1 expression in mice via the intestinal FXR-FGF15 signaling" [Toxicology Letters 398 (2024) 1-12].
Li H, Xiong H, Wang X … +4 more , Xu T, Zhang C, Zhang W, Zhang Y
Toxicol Lett · 2025 Dec · PMID 41175709 · Publisher ↗
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Investigating the application of 3D skin models in micronucleus assay and comet assay.
Lin T, Luo H, Sun J … +4 more , Dong C, Hong X, Xiao P, Tao G
Toxicol Lett · 2025 Dec · PMID 41138959 · Publisher ↗
Conventional two-dimensional (2D) cell culture models for genotoxicity testing often yield false-positive results due to their limited metabolic capacity and lack of tissue architecture. Three-dimensional (3D) reconstruc...
Conventional two-dimensional (2D) cell culture models for genotoxicity testing often yield false-positive results due to their limited metabolic capacity and lack of tissue architecture. Three-dimensional (3D) reconstructed human skin models offer a more physiologically relevant alternative for evaluating genotoxicity. In this study, the reproducibility, dose-response, and predictive performance of the micronucleus test (MNT) and comet assay were systematically assessed using 3D skin models EpiSkin-MNT and T-Skin. A panel of reference chemicals, including both genotoxic and non-genotoxic agents, was tested. Cytotoxicity was measured using ATP and adenylate kinase (AK) assays; genotoxicity endpoints included micronucleus frequency and comet assay parameters such as tail intensity and tail moment. Both assays exhibited clear dose-dependent increases in genotoxic markers for positive controls, while negative controls showed no significant response. Use of the DNA repair inhibitor aphidicolin in the comet assay enhanced the sensitivity of DNA damage detection. The integration of 3D skin models with MNT and comet assays provides a robust, reproducible, and physiologically relevant platform for genotoxicity assessment, supporting the transition from animal-based methods and aligning with regulatory trends.
Epigenetic effects of cadmium and lead in asthma: Cadmium-specific associations with ADRB2 methylation and miRNA-146a expression in Egyptian Adults.
Aboubakr HM, Alsaeed SA, Eltokhy RAA … +7 more , Magdy S, Helmy NM, Shalby AB, Kassem SM, Mabrouk MI, Khalil WKB, Elrewieny NM
Toxicol Lett · 2025 Dec · PMID 41138958 · Publisher ↗
BACKGROUND: Asthma is a prevalent health condition with significant global impact. Heavy metals, especially lead and cadmium, have been markedly linked to asthma etiology, however, studying their epigenetic mechanisms re...
BACKGROUND: Asthma is a prevalent health condition with significant global impact. Heavy metals, especially lead and cadmium, have been markedly linked to asthma etiology, however, studying their epigenetic mechanisms remains limited. AIM: to study the association between exposure to lead and cadmium, the methylation of the ADRB2 gene, and the expression of miRNA-146a in adult asthma patients. METHODS: A case-control study included 35 adult asthma patients and 35 sex and age-matched healthy controls. Blood lead, cadmium, ADRB2 5'-UTR methylation and miRNA-146a expression levels were measured for all participants. RESULTS: Blood cadmium and ADRB2 5'-UTR methylation levels showed significantly higher values, blood lead levels showed higher, but nonsignificant, values, miRNA-146a expression levels showed significantly lower values in asthma patients, compared to controls. Blood cadmium positively correlated with ADRB2 5'-UTR methylation and negatively correlated with miRNA-146a expression. Regression analysis found that blood cadmium, ADRB2 5'-UTR methylation, and miRNA-146a expression levels were associated with asthma occurrence, showing significant odds ratios (95 % CI). Significant novel cutoff values for differentiating between healthy and asthmatic patients were set by ROC curve analysis. CONCLUSION: Blood cadmium is significantly linked to asthma, with increased ADRB2 5'-UTR methylation, and reduced miRNA-146a expression. The significant odds ratios and the novel cut off values demonstrate potential clinical applicability, offering promising epigenetic biomarkers for asthma prediction and diagnosis in Egyptian adults. Measures to minimize heavy metals' environmental exposure are recommended.
Urinary metal mixtures and cataract: Findings from a U.S. population-based study and network pharmacology analysis.
Yang R, Li J, Liu R … +4 more , Ren T, Wang N, Xu L, Ma J
Toxicol Lett · 2025 Dec · PMID 41135724 · Publisher ↗
AIM: To analyze the effects of various urinary metals on cataract using National Health and Nutrition Examination Survey data. METHODS: Multivariate logistic regression was used to analyze the relationship between nine u...
AIM: To analyze the effects of various urinary metals on cataract using National Health and Nutrition Examination Survey data. METHODS: Multivariate logistic regression was used to analyze the relationship between nine urinary metals and cataract. Weighted quantile sum (WQS) was used to analyze the positive and negative effects of various metals on cataract. The global and independent effects were analyzed using Bayesian kernel machine regression (BKMR). Network pharmacological analysis was used to explore the mechanism of metals on cataract. RESULTS: A total of 2207 participants were participated in the study. After excluding the influence of covariates, it was found that the concentrations of Ba, Sb, and Tl were significantly correlated with the prevalence of cataract. WQS showed that Cd, Pb, and Ba had the strongest negative effects on cataracts, while Tu and Co had the strongest positive effects. BKMR showed that the overall effect of nine urinary metals had no significant relationship with cataract, there was a significant positive correlation between Co and cataract, and a significant negative correlation between Pb and cataract under certain conditions. Co and cataract interact through various pathways, including Interleukin-4 and Interleukin-13 signaling. AKT1 may be the key protein in the correlation. CONCLUSION: Urinary metal concentrations may be associated with the risk of ocular outcomes. While our findings suggest potential links between Co and cataract, these results should be interpreted with caution due to the cross-sectional nature of the data. Further longitudinal studies are needed to confirm these associations and to explore possible threshold levels for clinical or public health monitoring.
A chemoproteomic strategy for identifying protein covalent binding targets of clozapine: An approach for advancing clozapine toxicity research.
Lockhart S, Tabana Y, Tabatabaei Dakhili SA … +8 more , Babu D, Tran NH, Eldalal O, West FG, Ussher JR, Barakat KH, Fahlman RP, Siraki AG
Toxicol Lett · 2025 Dec · PMID 41130544 · Publisher ↗
Schizophrenia affects a significant proportion of individuals, wherein a subset of patients is described as treatment-resistant. Clozapine (CLOZ) is an atypical antipsychotic, which is reserved for these patients and is...
Schizophrenia affects a significant proportion of individuals, wherein a subset of patients is described as treatment-resistant. Clozapine (CLOZ) is an atypical antipsychotic, which is reserved for these patients and is superior in its anti-suicidal activity. However, it carries numerous serious warnings and is well-known for its risk of drug-induced agranulocytosis. The mechanism of toxicity is unclear and could be due to CLOZ's protein covalent binding and off-target effects through its reactive metabolites produced from neutrophil myeloperoxidase (MPO) activity. We hypothesize that identifying and analyzing the protein-CLOZ adducts will contribute to our understanding of toxicity pathways. We have developed a novel clickable CLOZ (Click-CLOZ) derivative and have designed click chemistry protocols for protein identification. The HL-60 (human promyelocytic leukemia) cell line and isolated human neutrophils express MPO significantly and were used to identify the protein covalent targets of Click-CLOZ. In HL-60 cells, LC/MS analysis revealed many Click-CLOZ-bound proteins (compared to the vehicle control). Some captured proteins were known for their roles in DNA replication, immune responses and oxidative stress, such as cathepsin G, MPO, ribophorin I and P1-MCM3. In neutrophils, Click-CLOZ-bound proteins included MPO, S100, and DEFA1B, which are also associated with neutrophil-mediated oxidative stress and immune responses. In conclusion, the application of click chemistry proteomics has facilitated a novel approach to identify multiple CLOZ-bound protein targets that will be used to advance our understanding of the toxicity of CLOZ.
HRD1 promotes chronic alcoholic liver disease by mediating ACSL3 ubiquitination and degradation.
Meng L, Hu Y, Zhao X … +8 more , Wang Z, Wang Y, Zhang N, Guo S, Wang X, Gao D, Zhao Y, Yao J
Toxicol Lett · 2025 Dec · PMID 41130543 · Publisher ↗
BACKGROUND: Alcohol-associated liver disease (ALD), one of the most frequent chronic liver diseases globally, is characterized by steatosis. HMG-CoA reductase-degrading protein 1 (HRD1) participates in the endoplasmic re...
BACKGROUND: Alcohol-associated liver disease (ALD), one of the most frequent chronic liver diseases globally, is characterized by steatosis. HMG-CoA reductase-degrading protein 1 (HRD1) participates in the endoplasmic reticulum-associated protein degradation pathway through the recognition, translocation, and ubiquitination of substrate proteins. HRD1 is implicated in endoplasmic reticulum stress, oxidative stress and cell metabolism; however, the function of HRD1 in ALD remains unclear. AIMS: We aimed to explore the contribution and underlying molecular mechanism of HRD1 in alcoholic liver disease. METHODS: Mice were administered adeno-associated virus 9 encoding HRD1- or ACSL3-specific shRNA via intravenous injection, followed by feeding with a Lieber-DeCarli liquid diet containing 5 % ethanol. HepG2 cells were transfected with either HRD1 siRNA or HRD1 overexpression plasmids prior to ethanol exposure. RESULTS: Hepatic HRD1 expression was significantly increased under alcohol conditions. Hepatocyte-specific HRD1 knockdown markedly attenuated alcohol-induced hepatic injury, inflammation, oxidative stress and lipid metabolism disorders in vivo. Additionally, similar results were shown in vitro. Mechanistically, acyl-CoA synthetase long chain family member 3 (ACSL3), a key regulator known to ameliorate hepatic steatosis, was identified as a novel substrate of HRD1. HRD1 facilitates the ubiquitination and degradation of ACSL3. Interestingly, HRD1 knockdown significantly suppressed fatty acid synthesis and promoted fatty acid oxidation, which was reversed by ACSL3 silencing both in vivo and in vitro. CONCLUSION: In summary, HRD1 functions as a key mediator of ALD by ubiquitinating ACSL3, thereby promoting lipid dyshomeostasis, and aggravating ALD. Our findings reveal novel mechanistic insights into HRD1 and identify ACSL3 as a new downstream target of HRD1 to facilitate ALD treatment.
The single nucleotide polymorphism rs155787 on the autophagy gene of SQSTM1 is associated with silicosis susceptibility: A multi-stage study.
Jiang L, Wang F, Huai M … +10 more , Zhang W, Chen X, Li C, Zhang X, Liu B, Su Y, Chu M, Sun N, Jiao J, Wang W
Toxicol Lett · 2025 Dec · PMID 41110562 · Publisher ↗
OBJECTIVE: To investigate the association between single nucleotide polymorphisms (SNPs) in autophagy-related genes (ATGs) and susceptibility to silicosis. METHODS: Used silicosis genome-wide association study (GWAS) dat...
OBJECTIVE: To investigate the association between single nucleotide polymorphisms (SNPs) in autophagy-related genes (ATGs) and susceptibility to silicosis. METHODS: Used silicosis genome-wide association study (GWAS) data and multiple publicly available databases to identify autophagy-associated positive expression quantitative trait locus (eQTL)-SNPs. Candidate positive SNPs were subsequently validated for their association with silicosis susceptibility in an independent population. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to explore the expression of target genes. Finally, gene enrichment analysis was performed to preliminary explore the biological functions and potential pathways associated with the identified susceptibility genes. RESULTS: A total of 15 SNPs in 10 ATGs were finally obtained after screening. Validation phase results indicated a significant association between the mutant G allele of rs155787 on the Sequestosome 1 (SQSTM1) and an increased risk of silicosis (additive model: odds ratio (OR)= 1.55, 95 % confidence interval (95 % CI): 1.05-2.28, P = 0.027). Combining GWAS and validation phase data, the mutant G allele was correlated with heightened silicosis susceptibility (additive model: OR=1.70, 95 % CI: 1.22-2.36, P = 0.002). The eQTL results indicated that significantly higher SQSTM1 expression in AG and GG genotypes than in AA genotypes (P < 0.05). Bioinformatics analysis revealed that SQSTM1 may bind to a range of autophagy proteins and immunoproteins to activate the biological process of macroautophagy, which influences the development of silicosis. CONCLUSION: The rs155787 locus on the SQSTM1 may be associated with silicosis susceptibility, and the mutant G allele may serve as a potential risk factor. Furthermore, the A>G variation at this locus was observed to upregulate SQSTM1 gene expression. Additional large-scale studies are necessary to further validate our findings.
Embryo-fetal developmental toxicity and toxicokinetics studies of YWS20045 orally administered to pregnant rats.
Li H, Yue P, Shao Q … +1 more , Qiao H
Toxicol Lett · 2025 Nov · PMID 41110561 · Publisher ↗
This study aimed to explore the embryo-fetal developmental toxicity and concurrent toxicokinetic characteristics of YWS20045 in rats. Pregnant rats were divided into a solvent control group, three YWS20045 dose groups (4...
This study aimed to explore the embryo-fetal developmental toxicity and concurrent toxicokinetic characteristics of YWS20045 in rats. Pregnant rats were divided into a solvent control group, three YWS20045 dose groups (4, 16 and 32 mg/kg), and a positive control group (3.5 mg/kg cyclophosphamide). Oral administration was conducted from gestation day (GD) 6-17. Results showed that all dose groups exhibited loose stools, with the high dose group experiencing significant maternal toxicity, including perianal soiling, reduced food intake, weight loss, increased dead fetuses on GD and mortality. YWS20045 crossed the placental barrier and accumulated in fetuses at all doses. Doses of 4 mg/kg and above significantly increased fetal rib deformities, affecting fetal growth and development. Toxicokinetic analysis revealed non-proportional increases in C and AUC of YWS20045 and its metabolite with dose. The drug was primarily distributed in the liver and lungs, with maternal metabolite mainly in the lungs. Therefore, the relatively safe oral dose of YWS20045 for maternal rats in the embryonic-fetal developmental toxicity study was determined to be 16 mg/kg or lower, whereas doses of 4 mg/kg and above were found to adversely affect fetal growth and development. These findings provide a critical basis for evaluating the reproductive safety of YWS20045 in clinical use.
Toxicological evaluation of 4-methylimidazole: Research advances, health concerns and regulatory perspectives.
Shikha, Gautam K, Sharma M
Toxicol Lett · 2025 Nov · PMID 41106562 · Publisher ↗
This review provides a comprehensive analysis of the toxicology, mechanistic pathways, and regulatory evaluations of 4-methylimidazole (4-MI), a nitrogen-containing compound formed during caramel coloring production and...
This review provides a comprehensive analysis of the toxicology, mechanistic pathways, and regulatory evaluations of 4-methylimidazole (4-MI), a nitrogen-containing compound formed during caramel coloring production and industrial synthesis. The study aimed to consolidate evidence on health risks and clarify regulatory inconsistencies. Experimental models show that 4-MI induces hepatotoxicity via oxidative stress, mitochondrial dysfunction, and inflammation, leading to liver cell damage. Neurotoxicity includes behavioral changes, brain mitochondrial injury, and teratogenic effects. Reproductive toxicity has been observed in rodents and zebrafish, impairing sperm function, hormone production, and embryonic development. Although cytotoxic and genotoxic effects-such as DNA damage and chromosomal aberrations-have been reported, standard mutagenicity assays largely remain negative, contributing to regulatory uncertainty. California classifies 4-MI as a possible carcinogen with strict exposure limits, while EFSA finds genotoxic evidence insufficient. Emerging studies also link 4-MI to disruptions in glucose and lipid metabolism, raising concerns about chronic low-dose dietary exposure. Overall, these findings highlight significant public health risks and the urgent need for further toxicodynamic research to inform harmonized regulations and more accurate risk assessments.
Evaluating the role of glutathione reductase in aspartame-induced liver hepatocellular carcinoma: A molecular network and prognostic approach.
Sun W, Huo S, Li S … +4 more , Yang D, Wei C, Zheng J, Cai S
Toxicol Lett · 2025 Nov · PMID 41106561 · Publisher ↗
This study aims to elucidate the molecular mechanisms underlying aspartame-associated liver hepatocellular carcinoma (LIHC) by identifying glutathione reductase (GSR) as a key molecular target. Through a combination of n...
This study aims to elucidate the molecular mechanisms underlying aspartame-associated liver hepatocellular carcinoma (LIHC) by identifying glutathione reductase (GSR) as a key molecular target. Through a combination of network toxicology analysis and Mendelian randomization, GSR was implicated as a critical protein involved in the pathogenesis of aspartame-associated LIHC. Functional annotation using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that GSR is predominantly involved in energy metabolism, particularly lipid metabolism and glycolysis, both of which are central to tumorigenesis in LIHC. Elevated GSR expression was observed in LIHC tumor tissues, correlating with poor clinical outcomes including reduced overall survival (OS) and recurrence-free survival (RFS). Furthermore, genetic analyses revealed significant alterations in GSR, including mutations and copy number variations, in various cancer types, with specific relevance to immune regulatory gene networks. Molecular dynamics simulations demonstrated a robust binding affinity between aspartame and GSR, with favorable binding interactions, suggesting a stable protein-ligand complex. Additionally, functional assays confirmed that GSR modulates tumor cell proliferation via regulation of glycolytic enzyme activity, indicating its pivotal role in metabolic reprogramming during LIHC progression. These findings collectively highlight GSR as a promising biomarker and therapeutic target in the context of aspartame-associated hepatocellular carcinoma, with implications for targeted intervention in cancer treatment.
A systematic review on the effect of microplastics on the hypothalamus-pituitary-ovary axis based on animal studies.
Shahsavari S, Akbari-Adergani B, Shafaroodi H … +4 more , Akbari N, Basaran B, Sadighara M, Sadighara P
Toxicol Lett · 2025 Nov · PMID 41101573 · Publisher ↗
Humans are exposed to microplastics through three routes: oral, dermal, and respiratory. These tiny polymer particles enter the body and accumulate in various organs. One of the most sensitive organs to microplastics is...
Humans are exposed to microplastics through three routes: oral, dermal, and respiratory. These tiny polymer particles enter the body and accumulate in various organs. One of the most sensitive organs to microplastics is the female reproductive system. In this review, manuscripts that investigated the effects of various microplastics on the hypothalamic-pituitary-ovarian axis in laboratory animals were collected with relevant keywords. This axis plays an important role in the function of the female reproductive system. Effects on endpoints of this axis, including hormonal changes, gene expression, and histopathological changes, were assessed. The most studied microplastic was polystyrene. Hormone levels were measured in all studies. In almost all studies, 17β-estradiol was decreased. Apoptosis and oxidative stress-induced damage in the ovaries were also observed in some studies. The results summarized from the manuscript emphasize the adverse effects of microplastics, especially polystyrene microplastics, on the female reproductive system following exposure.
Prenatal exposure profiles to Benzophenones and their impacts on thyroid hormones.
Abderrezak K, Dana AA, Mohamed A
Toxicol Lett · 2025 Dec · PMID 41101572 · Publisher ↗
PURPOSE: Prenatal exposure to Benzophenones and their potential health impacts remain insufficiently studied, particularly among vulnerable populations such as pregnant women. The lack of research is concerning given the...
PURPOSE: Prenatal exposure to Benzophenones and their potential health impacts remain insufficiently studied, particularly among vulnerable populations such as pregnant women. The lack of research is concerning given the suspected risks these endocrine-disrupting chemicals (EDCs) may pose to neonatal health, especially in relation to thyroid hormone regulation. This study seeks to address this research gap by measuring prenatal exposure profiles to Benzophenones in women living in Algiers. Specifically, it aims to explore the associations between Benzophenone levels in umbilical cord blood and disruptions in thyroid hormone levels at the time of delivery. Additionally, the study investigates the possible link between women's exposure to specific sources and the resulting endogenous levels of Benzophenones. METHODS: This was a descriptive study carried out on 154 paired mother-newborns after gathering necessary information using a questionnaire. Umbilical cord blood was collected and TSH and thyroid hormones (FT3 and FT4) were measured by electrochemiluminescence while Benzophenones (BP-1, BP-2, and BP-3) were detected by LC-MS/MS. RESULTS: BP-1, BP-2, and BP-3 were detected in 29.87 %, 0 %, and 48.05 % of analyzed samples. Mean concentrations were 0.330 and 0.787 µg/g for BP-1 and BP-3, respectively. Significant negative association was found between levels of FT3 and concentrations of BP-3 in cord blood (β= -0.237), as well as a negative association between levels of FT4 and prenatal concentrations of BP-1 (β= -1.028). Notably, prenatal exposure to Benzophenones did not exhibit significant alterations on birth outcomes. A significant association linked lower levels of BP-1 with the tendency to read ingredient labels on cosmetic products by pregnant women (P = 0.024). CONCLUSION: In this Algerian population of parturient women, high exposure profiles to BP-1 and BP-3 through placental blood were associated with altered levels of thyroid hormones (FT4 and FT3, respectively). It appears these two compounds exert a diminishing effect on thyroid function. Such changes may involve adverse effects on maternal health and child development, especially on the nervous system.
Differentiating the in vitro toxicity of solid-surface composite dust: A comparison of material components and abrasive particles.
Mandler WK, McKinney W, Qi C … +5 more , Knepp A, Lee EG, Kang S, Keeley S, Qian Y
Toxicol Lett · 2025 Nov · PMID 41093157 · Full text
BACKGROUND: Workers fabricating solid-surface composite (SSC) materials like Corian® are exposed to airborne particulate matter (PM) containing aluminum trihydrate (ATH) and potentially abrasive particles from sanding to...
BACKGROUND: Workers fabricating solid-surface composite (SSC) materials like Corian® are exposed to airborne particulate matter (PM) containing aluminum trihydrate (ATH) and potentially abrasive particles from sanding tools, leading to concerns about respiratory health effects like pulmonary fibrosis. However, the relative toxicological contributions of the SSC material versus the sandpaper abrasives remain unclear. OBJECTIVE: This study aimed to compare the in vitro cellular responses induced by respirable dust generated from sanding SSC with different commercial sandpapers (aluminum oxide [Al2O3], ceramic, silicon carbide [SiC]) to the responses elicited by ATH and corresponding abrasive analogue particles. METHODS: Respirable dust (PM with an aerodynamic diameter less than 5 µm) was generated from sanding Corian® using the three sandpaper types via a fluidized bed generator coupled with a cyclone separator. Human monocytic THP-1 cells, differentiated into macrophage-like cells, were exposed for 48 h to suspensions of these SSC dusts, ATH, or Al2O3, ceramic, and SiC abrasive analogue particles (10 µg/well). Cytotoxicity (LDH release), apoptosis (Caspase 3/7 activity), necrosis (propidium iodide uptake), cell cycle distribution, and nuclear morphology (including mono-, bi-, multi-, and micronucleation) and the Nuclear Division Index were assessed. RESULTS: Exposure to SSC dusts generated with any sandpaper type, as well as ATH, resulted in significant increases in apoptosis compared to controls. However, these exposures did not cause significant LDH release or alterations in cell cycle progression or mitotic indices. Conversely, the Al2O3, ceramic, and SiC abrasive analogue particles induced significant disruptions in cell cycle (S phase population reduction) and mitosis (increased multinucleation, micronucleation, and NDI), alongside apoptosis (Al2O3, SiC) or necrosis (ceramic, SiC), but also caused minimal LDH release. CONCLUSION: Under these in vitro conditions, the apoptotic response to respirable SSC sanding dust appears primarily driven by components inherent to the SSC material itself, consistent with the effects of ATH. This response profile was distinct from the cell cycle arrest and mitotic disruption prominently caused by the abrasive analogue particles. These findings suggest the intrinsic properties of SSC material components are key drivers of initial macrophage responses in vitro, differing significantly from the effects of the abrasive materials alone.
Is lychee-associated encephalopathy in children a straightforward case of toxicity or a complex metabolic and environmental cascade?
Soni R, Das S, Sahni GS … +4 more , Goswami D, Verma D, Das B, Parmar P
Toxicol Lett · 2025 Nov · PMID 41067590 · Publisher ↗
Every year, annual outbreaks of AES occur in lychee-growing regions: previously healthy children suddenly succumb to Acute Encephalitis Syndrome (AES). Initial suspicions pointed towards the seemingly innocent lychee fru...
Every year, annual outbreaks of AES occur in lychee-growing regions: previously healthy children suddenly succumb to Acute Encephalitis Syndrome (AES). Initial suspicions pointed towards the seemingly innocent lychee fruit and its inherent toxins, Hypoglycin A and MCPG. However, the toxin-alone hypothesis is challenged by the fact that lychees are safely consumed globally. This discrepancy suggests that the development of severe illness is not caused by the toxins alone but requires specific host vulnerabilities, such as malnutrition, and co-factors like the consumption of unripe fruit on an empty stomach. This has prompted the consideration of alternative hypotheses. These include the role of pesticide contamination in orchards, potential bat-borne viral infections, and environmental stressors that may shift with seasons and geography. The striking differences in illness patterns observed in Bihar (India), Bangladesh, and Vietnam further complicate the picture. Moreover, documented reports of children falling ill with AES without any reported lychee consumption cast doubt on a singular explanation. This review delves into the heart of this enduring medical enigma, critically dissecting the compelling arguments and critical caveats surrounding each potential cause. This review critically evaluates the evidence for the multifaceted theories behind lychee-associated AES and challenges established assumptions. The analysis indicates a multifactorial etiology is responsible for this recurring childhood tragedy.
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