Toxicology Letters[JOURNAL]
Sun
200 papers
Rotenone-induced cellular dysfunction in human blood platelets: Unraveling calcium dysregulation, mitochondrial impairment, oxidative stress, and apoptosis.
Beura SK, Yadav N, Maurya AK … +2 more , Kumari N, Singh SK
Toxicol Lett · 2026 Jan · PMID 41381019 · Publisher ↗
Rotenone, a naturally occurring pesticide and a well-established mitochondrial complex I inhibitor, disrupts electron transport chain activity, resulting in impaired energy metabolism, oxidative stress, and apoptosis. Ou...
Rotenone, a naturally occurring pesticide and a well-established mitochondrial complex I inhibitor, disrupts electron transport chain activity, resulting in impaired energy metabolism, oxidative stress, and apoptosis. Our recent findings revealed that rotenone suppresses agonist-induced platelet functional activity; however, the molecular mechanisms underlying this effect remain largely unclear. In this study, we demonstrate that rotenone exposure induces pronounced cytotoxic effects in human platelets, evident from decreased cell viability and phosphatidylserine externalization, a hallmark of apoptosis-like processes. At the mitochondrial level, rotenone markedly compromises organelle integrity by inducing mitochondrial membrane potential depolarization, excessive reactive oxygen species generation, and calcium dysregulation. These mitochondrial perturbations act as key upstream signals that trigger caspase activation and drive apoptosis-like cascades in platelets. Collectively, our findings identify mitochondrial dysfunction, oxidative stress, and calcium imbalance as central mediators of rotenone-induced, caspase-dependent platelet apoptosis. This study demonstrates that rotenone induces cytotoxicity and organelle dysfunction in human blood platelets, thereby providing mechanistic insight into altered platelet functions.
Dose-response to lead-induced alterations in right atrial and ventricular myocardial contractility in adult rats.
Gerzen O, Kuznetsov DA, Votinova V … +7 more , Tzybina A, Balakin A, Lisin R, Minigalieva I, Sutunkova M, Nikitina L, Protsenko YL
Toxicol Lett · 2026 Jan · PMID 41381018 · Publisher ↗
Lead is a widespread environmental xenobiotic known to adversely affect cardiovascular health. This study is the first to systematically assess the impact of subchronic lead acetate exposure (5.5, 11, and 22.88 mg/kg bod...
Lead is a widespread environmental xenobiotic known to adversely affect cardiovascular health. This study is the first to systematically assess the impact of subchronic lead acetate exposure (5.5, 11, and 22.88 mg/kg body weight, administered via intraperitoneal injections three times a week for six weeks) on the contractile properties of the right atrial and right ventricular myocardium in 12-month-old male rats, using both in vitro motility assays and physiological contraction measurements on myocardial strips from the same hearts. Lead exposure produced a dose-dependent decrease in thin filament sliding velocity over right atrial myosin, whereas the effects on right ventricular myosin were nonlinear. Higher doses of lead significantly reduced the fraction of motile filaments in the atrium, while lower doses affected the ventricle. Under physiological loading mode, right atrial myocardial strips generated approximately 20 % of the mechanical work produced by right ventricular strips. Increasing lead doses further reduced mechanical work in both chambers, with a more pronounced reduction in the atrium (≈65 %) than in the ventricle (≈17 %) at the highest dose. Maximum shortening velocity also declined with increasing lead concentration, particularly in the atrium at low afterloads. These findings demonstrate that the right atrial myocardium is more sensitive to subchronic lead intoxication than the right ventricular myocardium. Overall, this study provides the first comprehensive analysis of lead's differential effects on atrial and ventricular contractility under physiological loading conditions.
The role of FOXO1/PPARγ in atrazine-induced hepatic lipid metabolism disorders.
Yingchao H, Haoyan M, Zengchen W … +5 more , Haotang Z, Tong L, Ying Q, Xiaotong W, Yuezhu Z
Toxicol Lett · 2026 Jan · PMID 41354390 · Publisher ↗
As one of the most prevalently employed herbicides worldwide, atrazine (ATR) is widespread in the environment and is able to enter and impair the human body. Hepatic lipid metabolism disorders can be triggered by exposur...
As one of the most prevalently employed herbicides worldwide, atrazine (ATR) is widespread in the environment and is able to enter and impair the human body. Hepatic lipid metabolism disorders can be triggered by exposure to ATR. However, the underlying mechanism remains unclear. We performed a differential gene expression analysis using the NAFLD-related datasets GSE89632 and GSE160016 downloaded from the GEO database, both with the human liver as the samples. Then the GO and KEGG pathway enrichment analyses were performed. It was discovered that the FOXO1/PPARγ pathway might play a crucial role in hepatic lipid metabolism disorders. To confirm the hypothesis, forty 8-week-old male Wistar rats were randomly average exposed to different concentrations of ATR (0, 0.5, 5 and 50 mg/kg/d) by intragastric administration for 90 days. Then the liver tissue were isolated for histopathological observation; the levels of lipids were assessed by colorimetry; the expression of mRNA and protein was identified by Real-Time PCR and western blot. The findings demonstrated that the ATR-treated groups had higher levels of TC and TG in the liver; TC level in the serum was increased but TG level decreased. Besides, the expression of FOXO1, PPARγ, FASN, FABP4 and CD36 was also elevated. A correlation was observed between the lipid metabolism levels and the expression of FOXO1/PPARγ pathway genes. These results suggested that ATR can induce hepatic lipids accumulation by upregulating the expression of FOXO1/PPARγ. This study can offer insightful information for preventing and controlling risks related to agricultural residues.
Lopinavir/ritonavir induces hepatotoxicity in HepG2 cells through inhibition of the Nrf2 pathway, resulting in oxidative stress, endoplasmic reticulum stress, and cell cycle arrest.
Zhou W, Dan Wang, Tu J … +8 more , Li J, Xu J, Tan W, Mo D, Liang P, Guo Y, Hu M, Ye L
Toxicol Lett · 2026 Jan · PMID 41354389 · Publisher ↗
Lopinavir/ritonavir (LPV/r), a clinically used protease inhibitor for treating human immunodeficiency virus, is associated with liver injury. In this study, we demonstrated that LPV/r significantly suppressed HepG2 cell...
Lopinavir/ritonavir (LPV/r), a clinically used protease inhibitor for treating human immunodeficiency virus, is associated with liver injury. In this study, we demonstrated that LPV/r significantly suppressed HepG2 cell viability and increased the secretion of ALT, AST and LDH in the cell supernatant. Flow cytometry analysis revealed that LPV/r induced cell cycle arrest at the G0/G1 phase and triggered apoptosis in HepG2 cells. Furthermore, LPV/r significantly induced oxidative stress and endoplasmic reticulum (ER) stress, evidenced by elevated intracellular reactive oxygen species (ROS) levels, ER vesicular dilation, and alterations in the expression of related proteins. Additionally, LPV/r markedly increased the expression of apoptosis-related proteins. Mechanistically, activation of Nrf2 with tBHQ or overexpression of Nrf2 protein can effectively reverse the suppression of Nrf2/HO-1 expression by LPV/r, thereby reducing ROS accumulation and alleviating LPV/r-induced hepatocyte injury. Collectively, our findings demonstrate that LPV/r suppresses Nrf2 and HO-1 protein, promotes ROS accumulation, which induces oxidative stress and ER stress, ultimately leading to cell apoptosis and G0/G1 phase cell cycle arrest. This research provides novel mechanistic insights into the hepatotoxic effects of LPV/r.
Subtotal removal of the stratum corneum by brushing as a decontamination strategy after hydrofluoric-acid exposure of human skin.
Mini Vijayan S, Göen T, Kaifie A … +6 more , Kiesewetter F, Horch RE, Müller-Seubert W, Drexler H, Kilo S, Wolfschmidt A
Toxicol Lett · 2026 Jan · PMID 41344416 · Publisher ↗
Accidents with hydrofluoric acid (HF) can cause systemic poisoning by transdermal penetration of fluoride ions. Abrasive techniques, like mechanical brushing, are occasionally used as a method of decontamination, but the...
Accidents with hydrofluoric acid (HF) can cause systemic poisoning by transdermal penetration of fluoride ions. Abrasive techniques, like mechanical brushing, are occasionally used as a method of decontamination, but their efficacy in reducing systemic fluoride absorption remains unclear. In a modified Franz diffusion-cell model, human skin samples (0.9 mm thickness, n = 6 per group) were exposed to 30 % HF. After one minute of exposure, the supernatant fluid was removed with cotton swabs. With the exception of untreated controls, the skin was then decontaminated either with a water jet alone or combined with brushing, using an electric toothbrush. Samples were collected from the receptor solution at different timepoints during the 72 h post-exposure timeframe. Both strategies were effective when compared to a lack of decontamination. There was no significant difference in cumulative fluoride absorption between the combination of water jet plus brushing and the water jet alone. However, approximately 4-48 h after exposure, the fluoride flux (absorption per hour) was lower in the skin samples treated with the combination of water jet and brushing. This difference was significant at 12 h and 24 h post-exposure. Overall, our results suggest an additional efficacy of mechanical decontamination during the prolonged follow-up period after hydrofluoric-acid exposure. This might be especially relevant in exposure scenarios with a larger skin depot of fluoride, like exposure to higher HF-concentrations. However, future research is needed to place these findings on a broader data basis and to evaluate the safety and efficacy of mechanical decontamination in practice.
Relationship between urinary phthalate metabolites and liver function indicators in the elderly in Northeast China.
Liu T, Chen X, Chu Y … +2 more , Zhang R, Zhao Z
Toxicol Lett · 2026 Jan · PMID 41344415 · Publisher ↗
Phthalates are widespread environmental contaminants, yet their impact on liver function in older adults remains insufficiently understood. This cross-sectional study examined associations between urinary concentrations...
Phthalates are widespread environmental contaminants, yet their impact on liver function in older adults remains insufficiently understood. This cross-sectional study examined associations between urinary concentrations of 15 phthalate metabolites and serum liver biomarkers in elderly individuals. Metabolite levels were measured using liquid chromatography-tandem mass spectrometry and creatinine-adjusted. Multiple linear regression and Bayesian kernel machine regression (BKMR) models were applied to assess individual and combined effects. Several phthalate metabolites were positively associated with liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), and negatively associated with bilirubin (TBIL, DBIL), albumin, and total protein. BKMR analyses confirmed positive mixture effects on ALT, AST, ALP, and gamma-glutamyl transferase (GGT). Body mass index (BMI) modified these associations, suggesting a role of adipose tissue in phthalate accumulation and hepatic effects. These findings highlight potential subclinical liver dysfunction related to phthalate exposure in older adults, warranting further investigation in the context of environmental risk and healthy aging.
Integrated transcriptomic and metabolomic analyses reveal the pathogenesis of 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced liver injury in mice.
Zhang Z, Ji R, Ku A … +2 more , A R, Song B
Toxicol Lett · 2025 Dec · PMID 41337828 · Publisher ↗
The hepatotoxic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) has been widely utilized to establish various liver disease models. However, the molecular networks and metabolic regulatory mechanisms underlying...
The hepatotoxic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) has been widely utilized to establish various liver disease models. However, the molecular networks and metabolic regulatory mechanisms underlying DDC-induced liver injury remain to be fully elucidated. In this study, an integrated transcriptomic and metabolomic approach was employed to investigate the mechanisms of DDC-induced hepatotoxicity. C57BL/6 J mice were administered a 0.1 % DDC-supplemented diet for two weeks to induce liver injury, followed by collection of serum and liver tissue samples for analysis. The results demonstrated that DDC treatment significantly elevated markers of liver injury, cholestasis, and fibrosis. Histopathological examination revealed hepatocyte damage, inflammatory cell infiltration, and increased collagen deposition in DDC-treated mice. Liver transcriptomic analysis identified 814 differentially expressed genes, while serum metabolomic profiling detected 958 differentially expressed metabolites. Integrated pathway analysis revealed co-enrichment of 14 pathways in both transcriptomic and metabolomic datasets, including steroid hormone biosynthesis, glycerophospholipid metabolism, retrograde endocannabinoid signaling, and primary bile acid biosynthesis. Validation experiments using qRT-PCR and UPLC-MS/MS demonstrated that DDC treatment upregulated hepatic mRNA levels of Cyp27a1, Mrp2, and Mrp3, while downregulating Cyp8b1, Hsd3b7, Scp2, and Hsd17b4. Serum analysis showed significant increases in the concentrations of CA, TCA, GCA, TCDCA, α-MCA, β-MCA, Tβ-MCA, TUDCA, CDCA, UDCA, ω-MCA, and HDCA, along with decreased LCA levels. These findings indicate that DDC-induced liver injury involves multiple pathways and mechanisms, with disruption of bile acid homeostasis representing a central pathological feature.
Metabolic activation, hepatic protein covalent binding, and cytotoxicity of arctigenin.
Chen Y, Hu Z, Zhao G … +7 more , Li M, Jiang Z, Xu L, Zheng J, Li W, Peng Y, Zheng J
Toxicol Lett · 2025 Dec · PMID 41325899 · Publisher ↗
Arctigenin (ATG) is an important component isolated from the fruit of the medicinal plant Arctium lappa L., with anti-inflammatory, antiviral and anti-tumor properties. Although ATG has been reported to induce hepatotoxi...
Arctigenin (ATG) is an important component isolated from the fruit of the medicinal plant Arctium lappa L., with anti-inflammatory, antiviral and anti-tumor properties. Although ATG has been reported to induce hepatotoxicity in beagle dogs and SD rats, and the underlying mechanisms remained unclear. The aim of this study was to investigate the metabolic activation of ATG and to define the potential correlation between the metabolic activation of ATG and its hepatotoxicity. A quinone methide intermediate was identified in vitro and in vivo, and CYP3A dominated the metabolic activation. ATG was found to show significant cytotoxicity at 50 μM in cultured mouse primary hepatocytes. The ATG-derived quinone methide metabolite assaulted cysteine residue of hepatic protein to form protein covalent binding. The observed protein modification was most likely associated with the cytotoxicity of ATG observed.
Comprehensive estrogenicity assessment of 4-methylbenzophenone via in vivo, in vitro, and in silico approaches within an integrated testing strategy framework.
Ortiz DMD, Hoang NM, Lee H … +1 more , Park K
Toxicol Lett · 2025 Dec · PMID 41319934 · Publisher ↗
4-Methylbenzophenone (4-MBP) is extensively used as a photoinitiator in ultraviolet-cured printing inks and food packaging. This study comprehensively evaluated its estrogenic activity using an Integrated Testing Strateg...
4-Methylbenzophenone (4-MBP) is extensively used as a photoinitiator in ultraviolet-cured printing inks and food packaging. This study comprehensively evaluated its estrogenic activity using an Integrated Testing Strategy (ITS) incorporating in vivo, in vitro, and in silico methodologies. Repeated oral administration of 4-MBP at 300 mg/kg (lowest observed effect concentration, LOEC) in ovariectomized rats significantly increased relative uterine weight (0.11 ± 0.01 % vs. 0.05 ± 0.00 % in controls) and serum estradiol levels elevated serum estradiol levels (4-fold over vehicle control). Histological analysis confirmed estrogenic alterations, including epithelial thickening, glandular degeneration, and stromal inflammation. Although estrogen receptor α (ERα) expression remained unchanged, aromatase (CYP19) was significantly upregulated in uterine tissue, suggesting that enhanced estrogen biosynthesis plays a key role in the effects elicited by 4-MBP. In vitro assays showed that 4-MBP activated ER transcription in HeLa9903 cells with a maximum relative proliferative capacity (RPCmax) of about 200 % compared with 1 nM 17β-estradiol, and significantly induced MCF-7 cell proliferation at 10⁻⁵ M, coinciding with peak CYP19 mRNA expression. CYP19 expression was also increased at the mRNA and protein levels, and evidence of post-transcriptional regulation was observed at higher concentrations (10 µM). In silico molecular docking and dynamic simulations corroborated these findings demonstrating strong binding affinities of 4-MBP to ERα (docking score as low as -8.7 kcal/mol) and ERβ. Our results indicate that 4-MBP exerts estrogenic effects by elevating estrogen synthesis and inducing direct ER transcriptional activation. These findings highlight the utility of ITS for evaluating endocrine-disrupting chemicals and emphasize the need for regulatory consideration of 4-MBP and structurally related compounds in consumer products.
1-NP hijacks endocrine-metabolic checkpoints and disrupts testicular steroidogenesis by suppressing the cAMP-PKA-CREB-HMGCR axis.
Zhu XX, Zhang WW, Hao MY … +10 more , Chen ZY, Wan BF, Niu MH, Li XL, Wei JH, Liu SY, Mi SL, Wang H, Xu DX, Gao L
Toxicol Lett · 2025 Dec · PMID 41319933 · Publisher ↗
1-Nitropyrene (1-NP), a representative reproductive toxicant enriched in nitro-PAHs, is a known reproductive toxicant. Although our previous studies demonstrated that 1-NP impairs testosterone synthesis, its effects on o...
1-Nitropyrene (1-NP), a representative reproductive toxicant enriched in nitro-PAHs, is a known reproductive toxicant. Although our previous studies demonstrated that 1-NP impairs testosterone synthesis, its effects on other critical processes in testosterone biosynthesis, particularly cholesterol metabolism, remain unknown. Using in vivo and in vitro models, we investigated 1-NP's effects on cholesterol homeostasis and steroidogenesis. Mice were exposed to 1-NP (0, 1.25, 5 mg/kg), a mouse Leydig tumor cell line (MLTC-1) were treated with 0.1, 1 μM 1-NP along with hCG stimulation. IBMX was used for intervention experiment. Key assays included ELISA, qPCR, Western blot, filipin staining, and cholesterol/testosterone quantification. This study demonstrates that 1-NP exposure significantly depletes intracellular free cholesterol without altering total cholesterol, leading to testosterone reduction. Mechanistically, 1-NP decreases cAMP levels, impairing PKA nuclear translocation and CREB Ser133 phosphorylation, thereby downregulating the cholesterol synthesis rate-limiting enzyme HMGCR at both transcriptional and translational levels. Critically, phosphodiesterase inhibitor IBMX rescues cAMP levels, reverses HMGCR suppression, and restores free cholesterol pools and testosterone synthesis, establishing that 1-NP induces endocrine disruption via a novel cholesterol metabolic pathway. While limitations exist, this work redefines 1-NP toxicity as "metabolic sabotage" of specialized endocrine pathways, providing a framework for signal-pathway-targeted interventions against pollution-associated endocrine disruption.
Comparison of the serum levels of proteins involved in microtubule stabilization in patients with alcohol or heroin use disorder.
Kayadibi H, Cetin İ, Karadere ME … +1 more , Yazla E
Toxicol Lett · 2025 Dec · PMID 41318073 · Publisher ↗
AIM: In patients with alcohol or heroin use disorder, we aimed to examine the effects of alcohol or heroin use and treatment on the serum levels of microtubule stabilization proteins. METHOD: A total of 64 patients with...
AIM: In patients with alcohol or heroin use disorder, we aimed to examine the effects of alcohol or heroin use and treatment on the serum levels of microtubule stabilization proteins. METHOD: A total of 64 patients with 32 alcohol and 32 heroin use disorder, and age-gender matched healthy volunteers were included in this study. Fasting blood samples were taken from patients before and after three weeks of treatment, and from healthy volunteers on the first working day after first interview. RESULTS: Compared to healthy controls, there were statistically significant decreases for serum levels of microtubule associated protein-2, tau protein, phospho tau protein, glial fibrillary acidic protein, glial cell line derived neurotrophic factor and progranulin, while there was a statistically significant increase for serum levels of Nogo-A in patients with alcohol use disorder (P < 0.001, P < 0.001, P < 0.001, P < 0.001, P < 0.001, P = 0.002 and P < 0.001, respectively). In patients with heroin use disorder compared to healthy controls, there was a statistically significant increase only for serum level of Nogo-A (P < 0.001). Only post-treatment serum progranulin level of patients with alcohol use disorder was statistically significantly higher than pre-treatment levels (P = 0.040). CONCLUSION: It was considered that these proteins may be a potential biomarker in terms of reflecting molecular level of damage caused by alcohol or heroin use, as well as distinguishing patients with and without alcohol or heroin use disorder. Further studies with long term treatments may be performed to investigate the optimum therapy period, since three weeks of treatment may not be enough to repair this damage.
DBDPE inhibits myogenic differentiation of C2C12 cells through inhibiting mitochondrial function and PI3K/AKT/mTOR signaling pathway.
Tan X, Li J, Peng Y … +4 more , Huang G, Yu L, Hu G, Xu L
Toxicol Lett · 2025 Dec · PMID 41308956 · Publisher ↗
In recent years, decabromodiphenyl ethane (DBDPE), a type of brominated flame retardant, has gained popularity in industry as an alternative to decabromodiphenyl ether (BDEs). However, DBDPE exposure poses environmental...
In recent years, decabromodiphenyl ethane (DBDPE), a type of brominated flame retardant, has gained popularity in industry as an alternative to decabromodiphenyl ether (BDEs). However, DBDPE exposure poses environmental pollution and primarily impacts muscle contraction and the reproductive endocrine system. The cellular implications and underlying mechanisms of DBDPE's effects on muscle remain poorly understood. In the present study, we investigated the effect of DBDPE on myoblast differentiation, apoptosis, as well as the potential mechanisms involved. The results demonstrated that exposure to DBDPE disrupted the differentiation of myotubes, inhibited cell proliferation, and increased levels of reactive oxygen species (ROS), ultimately leading to cell death. In addition, the RNAseq analysis revealed that DBDPE mainly affected the biological processes in mitochondria related to oxidative phosphorylation, ATP synthesis coupled electron transport, etc. Then we demonstrated that DBDPE inhibited mitochondrial membrane potential and ATP production, implying DBDPE resulted in mitochondrial dysfunction in C2C12 cells. Mechanistically, we showed that PI3K/AKT/mTOR signaling pathway was inhibited by DBDPE in C2C12 cells. And the apoptosis rate was significantly increased by DBDPE as demonstrated by increased active caspase-3 and TUNEL signal. Taken together, these findings suggest that low-dose exposure to DBDPE hampers myogenic differentiation and mitochondrial function, and increased cellular apoptosis through PI3K/AKT/mTOR signaling pathway, providing important insights for understanding its environmental toxic effects and conducting risk assessments.
Microbiological toxicology of the new antibiotic aditoprim on human intestinal microbiota.
Wang J, Liu C, Gu F … +2 more , Gu Y, Hao H
Toxicol Lett · 2025 Dec · PMID 41285186 · Publisher ↗
Aditoprim (ADP) is a novel dihydrofolate reductase inhibitor. It has potent antibacterial activity, low toxicity, and no mutagenicity. These characteristics position it as a promising candidate for further research in cl...
Aditoprim (ADP) is a novel dihydrofolate reductase inhibitor. It has potent antibacterial activity, low toxicity, and no mutagenicity. These characteristics position it as a promising candidate for further research in clinical veterinary medicine and its effect on humans. Therefore, this research aimed to investigate the impact of ADP on human microbiota. ADP (0, 1, 16, and 128 mg/L) was added to chemostats containing human intestinal flora. Microflora communities, short-chain fatty acids (SCFAs), and the rate of antibiotic resistance were monitored at different time points before and after the administration of ADP. Salmonella Typhimurium inoculation was used to assess the gut microbiota's colonization barrier over a period of three days. The results indicate long-term exposure to higher levels of ADP (16 and 128 mg/L) disrupted the colonization barrier of intestinal flora and increased the proportion of resistant bacteria. 16S rRNA sequencing data indicate that high levels of ADP caused significant changes in gut microbiota, especially Bacteroides fragilis and Bacteroides uniformis. This study assessed the microbiological safety of ADP in vitro for the first time by simulating the human gut microbiota environment. The findings showed that 1 mg/L was the no observable adverse effect concentration, and the microbiological acceptable daily intake was determined to be 91.67 µg/kg.BW/day.
Co-exposure to low levels of DEHP, procymidone, Cd , Pb, and 1-nitropyrene may damage mouse ovary and uterus via Hippo pathway and circPVT1.
Li Y, Nie H, He S … +3 more , Zhang J, Fu H, Zhu Y
Toxicol Lett · 2025 Dec · PMID 41271002 · Publisher ↗
High doses of Di-(2-ethylhexyl) phthalate (DEHP), procymidone (PCM), Cd, Pb, and 1-nitropyrene (1-NP) induce reproductive toxicity in female experimental animals. However, evidence regarding female reproductive toxicity...
High doses of Di-(2-ethylhexyl) phthalate (DEHP), procymidone (PCM), Cd, Pb, and 1-nitropyrene (1-NP) induce reproductive toxicity in female experimental animals. However, evidence regarding female reproductive toxicity at low levels of combined exposure (co-exposure) to these substances is lacking. In this study, these environmental chemicals, which met or minimally exceeded the relevant standards, were administered simultaneously to 4-week-old female mice. After 21 days of exposure, the mice were kept feeding for 1 week and then sacrificed. Subsequently, their blood, ovaries, and uteri were taken. Co-exposure to concentrations ≥ 1/3 of the maximum allowable concentration (MAC) for each of these chemicals, as per relevant standards, was revealed to impair ovarian and uterine development in mice. This exposure activated the Hippo pathway, resulting in a decrease in ERα and circPVT1, and an elevation of miR-149. Co-exposure to these compounds in levels marginally lower than the MACs of each chemical also elevated cleaved CASPASE-3 levels. These changes showed a dose-response relationship. Joint exposure to these substances at values ≥ 1/3 of each average concentration in the blood could elicit similar biological effects in the ovaries and uteri cultured in vitro. Therefore, this study hypothesized that co-exposure to low levels of these environmental chemicals results in ovarian and uterine impairment in mice and that this damage may be linked to the activation of the Hippo pathway, downregulation of ERα and circPVT1, and upregulation of miR-149.
Long-term supplementation of taurine induces hepatic steatosis and disrupts bile acid homeostasis in male mice.
Shi T, Zhang SY
Toxicol Lett · 2025 Dec · PMID 41265536 · Publisher ↗
Taurine, a sulfur-containing amino acid, is widely used in energy drinks and nutraceuticals. However, the long-term effects of taurine supplementation on liver metabolism remain incompletely understood. Here, male C57BL/...
Taurine, a sulfur-containing amino acid, is widely used in energy drinks and nutraceuticals. However, the long-term effects of taurine supplementation on liver metabolism remain incompletely understood. Here, male C57BL/6 mice were administered 3 % taurine in drinking water for 32 weeks. Taurine treatment reduced body weight and abdominal fat, suggesting potential anti-obesity effects. However, hepatic lipid accumulation and steatosis were evident in taurine-treated mice. Serum levels of alanine aminotransferase, alkaline phosphatase, cholesterol, non-esterified fatty acids (NEFA), total bile acids, and hepatic triglycerides were markedly elevated. Taurine significantly upregulated hepatic expression of the fatty acid transporter Cd36, thereby enhancing hepatic fatty acid uptake and promoting lipid deposition, while increasing lipolytic enzymes Atgl and Hsl expression in white adipose tissue, contributing to increased circulating NEFA and subsequent hepatic lipid accumulation. Moreover, taurine disrupted the negative feedback regulation of bile acid biosynthesis in the enterohepatic circulation, increased bile acid synthesis and uptake, altered bile acid transport, and elevated both conjugated and unconjugated bile acid species. Histological and molecular analyses further revealed taurine-induced hepatic inflammation, characterized by perivascular immune cell infiltration and upregulation of pro-inflammatory cytokines and mediators. Importantly, taurine-induced metabolic alterations in lipid and bile acid homeostasis were evident as early as 5 weeks, preceding the onset of histological steatosis. Collectively, these findings demonstrate that prolonged taurine supplementation promotes hepatic steatosis and inflammation, accompanied by dysregulation of bile acid homeostasis. The study highlights the potential metabolic risks associated with chronic taurine intake and underscores the need for caution when considering taurine-based health supplements.
Reproductive effects of dibutyl phthalate (DBP) toxicity in the testes of mammalian and avian species.
Zakariah M, Molele RA, Mahdy MAA … +4 more , Harande IS, Musa EZ, Dasa JJ, McGaw LJ
Toxicol Lett · 2025 Dec · PMID 41265535 · Publisher ↗
Dibutyl phthalate (DBP), a widely used phthalic acid esters (PAEs), is a well-studied endocrine-disrupting chemical. It is one of the most and studied endocrine disruptors associated with reproductive disorders and infer...
Dibutyl phthalate (DBP), a widely used phthalic acid esters (PAEs), is a well-studied endocrine-disrupting chemical. It is one of the most and studied endocrine disruptors associated with reproductive disorders and infertility. Despite its prevalence, its exact mechanisms of action remain poorly understood. This review provides an overview of DBP's reproductive toxicity and explores its mechanisms in mammalian and avian species. Exposure to DBP during sexual differentiation disrupts the proliferation and maturation of Sertoli and Leydig cells, potentially leading to cryptorchidism, hypospadias, a shortened anogenital distance, and abnormal penile development in mammalian species. Additionally, it can cause atrophy of the seminiferous tubules and apoptosis of spermatogenic cells in both mammalian and avian species. Its effects are multifaceted, operating at hormonal levels by altering the release of hypothalamic, pituitary, and peripheral hormones, and at intracellular level by disrupting signalling cascades, nuclear and membrane receptors, altered steroidogenic gene expression, DNA disruption, and alteration of vimentin cytoskeleton proteins. It is important to note that the severity of reproductive toxicity varies between species at identical DBP concentrations, likely due to differences in metabolism. Nonetheless, existing data consistently implicate DBP in reproductive malformations that can lead to male infertility across species. This review highlights the need for further research into low-dose effects and species-specific responses to better understand and mitigate DBP's impact on reproductive health.
Transgenerational toxicity of tralomethrin in zebrafish: Parental exposure induces developmental defects in offspring.
Huang Y, Feng W, Zhang J … +3 more , Shi Y, Xiao P, Li W
Toxicol Lett · 2025 Dec · PMID 41260412 · Publisher ↗
Tralomethrin (TRA), a widely used type II pyrethroid insecticide, belongs to a class of pesticides frequently detected in aquatic environments, raising concerns about its potential chronic and transgenerational toxicity....
Tralomethrin (TRA), a widely used type II pyrethroid insecticide, belongs to a class of pesticides frequently detected in aquatic environments, raising concerns about its potential chronic and transgenerational toxicity. This study aimed to evaluate the long-term effects of environmentally relevant concentrations of TRA (0.05, 0.5, and 5 μg/L) on adult zebrafish and their offspring. Adult zebrafish were exposed to TRA for 150 days, during which phenotypic observations, histological assessments, biochemical assays, transcriptomic profiling, and developmental evaluations of F1 progeny were conducted. Following TRA exposure, male zebrafish exhibited increased body weight, and a significant decline in spawning rate was observed. Histological and biochemical analyses revealed gill and ovarian abnormalities, accompanied by oxidative stress and apoptosis in ovarian tissues. Transcriptomic analysis of TRA-exposed ovaries revealed gene enrichment in glutathione metabolism and signaling pathways including Hedgehog and Wnt, reflecting oxidative stress and developmental disruption. In the F1 generation, TRA exposure led to decreased survival and hatching rates, along with developmental abnormalities including pericardial edema, spinal curvature, and impaired swim bladder inflation. Gene expression analyses of swim bladder marker genes and regulatory pathways further corroborated TRA-induced disruption in organogenesis. Overall, these findings demonstrate that chronic TRA exposure can induce multi-level toxic effects in zebrafish, including reproductive impairment and transgenerational developmental defects. This study highlights the urgent need to assess the ecological risks of pyrethroid pesticides and to incorporate long-term and transgenerational endpoints into environmental risk assessment.
Hematological effects of chronic heavy metal exposure in children from marginalized occupational communities in Mexico.
Méndez-Rodríguez KB, Pérez-Vázquez FJ, Van Brussel E … +3 more , González-Palomo AK, Reyes-Zavala A, Saldaña-Villanueva K
Toxicol Lett · 2025 Dec · PMID 41242404 · Publisher ↗
Children engaged in precarious labor activities may experience exposure to environmental contaminants, including heavy metals, particularly in marginalized communities. Limited evidence exists regarding the potential hem...
Children engaged in precarious labor activities may experience exposure to environmental contaminants, including heavy metals, particularly in marginalized communities. Limited evidence exists regarding the potential hematological implications of such exposures in pediatric populations. A cross-sectional study was conducted among 50 children (<18 years) from three communities in San Luis Potosí, Mexico, engaged in informal recycling (Zone B), artisanal brickmaking (Zone C), or artisanal stone-carving (Zone A). Urinary concentrations of 15 metals were determined by ICP-MS, and hematological parameters were assessed using an automated analyzer. Associations were examined using nonparametric statistics, age-adjusted correlations, Bayesian Kendall's Tau analysis, and post hoc power evaluation. Distinct urinary metal profiles and hematological parameters were observed across the study zones. Zone B showed higher concentrations of Cr, Co, Ni, Al, and Sn, whereas As was elevated in Zone C. Hematological differences included higher WBC, lymphocyte, granulocyte counts, and MPV in Zone C. Age-adjusted correlations identified associations of As with WBC, lymphocyte, and granulocyte counts; Co with platelet indices; and negative correlations of Ni, Al, and Sn with several hematological variables. Bayesian analysis confirmed robust associations for Co with WBC, Al with granulocytes, and Sn with MPV. This study provides exploratory evidence of associations between urinary metal concentrations and hematological parameters in children engaged in precarious labor activities. While preliminary, the findings underscore the importance of child-focused public health strategies and support the need for larger, longitudinal studies to validate these associations and clarify their implications.
Chronicle of mixture effects: Sensitivity differences in multiple toxicity endpoints of transgenic C. elegans and assessment of combined toxicity interactions.
Huang P, Liu SS, Li J … +1 more , Wang D
Toxicol Lett · 2025 Dec · PMID 41242403 · Publisher ↗
The pesticide, as the typical emerging contaminants, has brought significant benefits to agricultural production due to its widespread use. However, the excessive residue of pesticides in environmental media poses potent...
The pesticide, as the typical emerging contaminants, has brought significant benefits to agricultural production due to its widespread use. However, the excessive residue of pesticides in environmental media poses potential risks to both the environment and human health. Therefore, this study focused on three typical pesticide residues (aldicarb (ALD)，methamidophos (MET) and triazophos (TAP)) that were commonly detected in fruits and vegetables, using the DAF-16 transgenic strain of Caenorhabditis elegans (C. elegans) as a model organism. Three binary and one ternary mixture systems were designed using the direct equipartition ray design and the uniform design ray method, resulting in a total of 20 mixture rays. These were used for multi-endpoint toxicity tests on C. elegans. The results indicated that all mixture rays exhibited higher sensitivity at the endpoints of lifespan and reproduction inhibition compared to the mortality endpoint. Furthermore, the sensitivity to lifespan and reproduction inhibition varied across the different mixture rays. The mixture toxicity interaction assessment results indicated that with increasing toxicity effects, a concentration ratio-dependent phenomenon was observed in the toxicity interactions. Furthermore, when the effect level exceeded 30 %, opposite toxicity interaction outcomes (i.e., the shift from antagonism to synergism or vice versa) emerged across different toxicological endpoints. These findings pose significant challenges for the assessment of mixture combined toxicity.
Neurovascular toxicity of dichlorvos: Crosstalk between endothelial dysfunction and neurodegeneration.
Dimeji IY, Murtala N, Ayodeji AS … +1 more , Jabba HL
Toxicol Lett · 2025 Dec · PMID 41241090 · Publisher ↗
O,O-Dimethyl O-(2,2-dichlorovinyl) phosphate (DDVP), commonly referred to as dichlorvos, is one of the most widely used organophosphorus insecticides for agricultural and domestic pest control, especially in low- and mid...
O,O-Dimethyl O-(2,2-dichlorovinyl) phosphate (DDVP), commonly referred to as dichlorvos, is one of the most widely used organophosphorus insecticides for agricultural and domestic pest control, especially in low- and middle-income countries, due to its low cost and effectiveness. While acute neurotoxicity through the irreversible inhibition of AChE and subsequent cholinergic overstimulation is well documented, there is growing evidence that DDVP exerts broader chronic effects, particularly those involving the neurovascular system. Specifically, endothelial dysfunction and disruption of the bloodbrain barrier have been shown to be early events that link vascular injury to neurodegeneration. These databases included PubMed, Scopus, Web of Science, ScienceDirect, EMBASE, and the Toxicology Data Network. The terms used in the search included "dichlorvos," "DDVP," "organophosphate pesticide," "neurotoxicity," "endothelial dysfunction," "bloodbrain barrier," "neurodegeneration," "oxidative stress," and "crosstalk." The inclusion criterion was peer-reviewed studies published in English between 2000 and 2025, which involved in vivo and in vitro experimental studies that reported DDVP-induced neurovascular toxicity. Studies not related to DDVP, publications in languages other than English, and non-peer-reviewed sources were excluded. Studies suggest that DDVP impairs endothelial integrity through disrupting the homeostasis of oxidative stress, nitric oxide, and inflammatory signalling. This type of endothelial insult impairs selectivity in BBB permeability, enabling the infiltration of circulating toxins and cytokines into the central nervous system, thus promoting neuronal apoptosis, mitochondrial dysfunction, and neuroinflammation. These findings suggest that the neurotoxicity of DDVP extends beyond synaptic cholinergic mechanisms but includes neurovascular-crosstalk-driven degeneration. This review synthesizes current mechanistic insights into DDVP-induced neurovascular toxicity and recognizes the neurovascular unit as a critical target in organophosphate poisoning. Elucidation of the interplay between endothelial dysfunction and neuronal injury opens new avenues for risk assessment, preventive strategies, and therapeutic interventions for pesticide-related neurodegenerative disorders.
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