Toxicology Letters[JOURNAL]
Sun
200 papers
In silico toxicity assessment and trace level quantification of potential genotoxic impurities in imipramine hydrochloride.
Nalawade VP, Kulkarni R, Sayyed FH … +3 more , Rathod N, Bandaru S, Mahule SR
Toxicol Lett · 2025 Oct · PMID 40774614 · Publisher ↗
Since the adoption of the ICH M7 guidelines in 2014, pharmaceutical industries have been mandated to screen all reagents and chemicals used in drug synthesis for genotoxicity. Genotoxic impurities (GTIs) have the potenti...
Since the adoption of the ICH M7 guidelines in 2014, pharmaceutical industries have been mandated to screen all reagents and chemicals used in drug synthesis for genotoxicity. Genotoxic impurities (GTIs) have the potential to induce mutations in DNA, which may lead to cancer. Unlike routine impurities, the threshold for controlling GTIs is extremely low. Imipramine hydrochloride (IH) is a commonly used antidepressant; however, the genotoxicity of both the drug and their impurities remain unknown. In this study, we systematically investigate the raw materials, intermediates, and known impurities involved in the synthesis pathway of IH for their potential genotoxicity. We employed in silico prediction tools to evaluate the toxicity of the impurities, intermediates, and raw materials used in the synthesis of IH, in accordance with ICH M7 guidelines. In silico prediction results revealed two specific impurities, 2,2-dinitro-1,2-diphenylethane (DNB) and 2,2-amino-1,2-diphenylethane (DAB), as potentially genotoxic. Furthermore, molecular docking and simulation studies were conducted to evaluate the specific interactions of these impurities with DNA. The results demonstrated consistent interactions of these impurities with the dG-rich region of the DNA duplex, particularly at the minor groove. Both in silico predictions and molecular docking studies corroborated the genotoxic nature of these impurities. As part of our risk assessment and control strategy, we developed and validated an HPLC-UV method in accordance with ICH guidelines to identify both GTIs in the final active pharmaceutical ingredient (API) of imipramine. This study will assist manufacturers of IH in controlling these genotoxic impurities to ensure its safe consumption.
Gentamicin aggravates renal injury by affecting mitochondrial dynamics, altering renal transporters expression, and exacerbating apoptosis.
Zhang M, Zhou Y, Wang X … +2 more , Li Y, Wu X
Toxicol Lett · 2025 Oct · PMID 40721128 · Publisher ↗
Drug-induced nephrotoxicity has developed as a prevalent trigger in patients with hospital-acquired AKI. Gentamicin, a broad-spectrum bactericidal aminoglycoside antibiotic, is used clinically in synergy with other antib...
Drug-induced nephrotoxicity has developed as a prevalent trigger in patients with hospital-acquired AKI. Gentamicin, a broad-spectrum bactericidal aminoglycoside antibiotic, is used clinically in synergy with other antibiotics. However, the presence of nephrotoxicity greatly limits their widespread clinical application. The kidney is one of the most energy intensive organs in the body, second to the heart in mitochondrial content and oxygen consumption. In particular, the mitochondria-rich proximal renal tubules are highly susceptible to be damaged by metabolic wastes or exogenous substances, and many studies have considered mitochondrial dysfunction as a targeted therapeutic strategy for the treatment of AKI. In this study, the results of in vitro experiments revealed that gentamicin could damage renal tubular epithelial cells in a dose- or time-dependent manner and resulted in impaired mitochondrial structure, decreased membrane potential, and reactive oxygen species (ROS) accumulation. Moreover, gentamicin aggravated renal injury by altering renal transporters expression, impairing mitochondrial homeostatic balance by affecting the expression of mitochondrial dynamics (e.g., OPA1, Mitofusin1/2, and DRP1), and promoting apoptosis through the Bax/Bcl2-Caspase3 pathway. It is worth noting that changes in serum creatinine or blood urea nitrogen (BUN) levels could not accurately identify early renal injury caused by gentamicin, and the road to finding an early diagnosis of kidney injury is still long. Our study provided a theoretical basis for gentamicin-induced renal injury and also contributed to the clinical application of gentamicin.
Deciphering the influence of heavy metals on adverse cardiovascular events using machine learning.
Li G, Zhang T, He K … +6 more , Zhang M, Hu J, Ge T, Wang M, Zou R, Fan X
Toxicol Lett · 2025 Aug · PMID 40714220 · Publisher ↗
This study investigates the association between chronic heavy metal exposure (lead [Pb], arsenic [As], cadmium [Cd]) and major adverse cardiovascular events (MACE) using data from 15,342 participants in the 2003-2018 NHA...
This study investigates the association between chronic heavy metal exposure (lead [Pb], arsenic [As], cadmium [Cd]) and major adverse cardiovascular events (MACE) using data from 15,342 participants in the 2003-2018 NHANES survey. Utilizing eight machine learning algorithms (including logistic regression, Random Forest, XGBoost, and LightGBM) combined with SHapley Additive exPlanations (SHAP) analysis, we evaluated the impact of these metals on angina, myocardial infarction (MI), and heart failure (HF), while adjusting for demographic and socioeconomic confounders. Results identified cadmium as the predominant risk factor across all cardiovascular outcomes: RandomForest achieved optimal angina prediction, XGBoost highlighted Cd's strongest association with MI, and LightGBM confirmed Cd's dominance in HF risk stratification. Multi-class modeling integrating logistic regression and RandomForest revealed Cd exposure significantly elevated overall MACE risk, surpassing Pb and As in feature importance. Mechanistic insights suggest Cd exacerbates cardiovascular pathology by disrupting myocardial calcium signaling, amplifying oxidative stress, and promoting inflammation, cardiomyocyte apoptosis, and fibrosis. These findings underscore cadmium's critical role in cardiovascular disease pathogenesis and advocate for prioritized public health interventions targeting environmental cadmium exposure mitigation. The integration of interpretable machine learning models with large-scale epidemiological data provides a robust framework for identifying environmental determinants of chronic diseases. This study identifies cadmium as the predominant heavy metal associated with increased risk of major adverse cardiovascular events, providing critical insights that inform public health interventions aimed at reducing environmental cadmium exposure.
Use of artificial intelligence in animal experimentation: A review.
Diogo Gonçalves S, Rodrigues M, Avidos M … +2 more , Morais AB, Caramelo A
Toxicol Lett · 2025 Aug · PMID 40712858 · Publisher ↗
Animal experimentation has historically supported biomedical and toxicological research; however, its limitations in accurately predicting human responses, combined with ethical and regulatory pressures, have driven the...
Animal experimentation has historically supported biomedical and toxicological research; however, its limitations in accurately predicting human responses, combined with ethical and regulatory pressures, have driven the development of alternative methods. Advances in artificial intelligence (AI) offer a promising opportunity to not only reduce animal use but also significantly enhance the reliability, efficiency, and human relevance of toxicity and safety assessments. This review examines AI-driven approaches - including in silico modelling, machine learning, and computational toxicology - used to predict toxicity, assess drug safety, and classify chemical hazards, with a focus on their contribution to the 3Rs principle and regulatory innovation. AI models, including deep learning algorithms, quantitative structure-activity relationship models, and integrated decision strategies, have demonstrated improved accuracy in predicting endpoints such as skin sensitization, carcinogenicity, and endocrine disruption. Moreover, hybrid methods combining in vitro data with AI-powered tools provide a scalable and reproducible framework for safety evaluation. While regulatory validation remains a challenge, the convergence of AI and toxicology holds immense potential to advance both predictive science and animal-free research. AI represents not only an ethical alternative but also a scientifically superior path toward safer and more human-relevant toxicity testing.
Nitric oxide plays a role in anxiety- and depression-like behaviors induced by sodium metabisulfite intake in rats.
Munzuroğlu M, Gökçek-Saraç Ç, Sinen AG … +1 more , Derin N
Toxicol Lett · 2025 Aug · PMID 40706911 · Publisher ↗
This study was carried out to investigate the effects of sulfite toxicity anxiety- and depression-like behaviors and elucidate the involvement of nitric oxide (NO) in this interaction. One hundred male Wistar rats were d...
This study was carried out to investigate the effects of sulfite toxicity anxiety- and depression-like behaviors and elucidate the involvement of nitric oxide (NO) in this interaction. One hundred male Wistar rats were divided into four groups. S25, S100, and S260 groups were given sulfite at doses of 25 mg/kg, 100 mg/kg, and 260 mg/kg, respectively, while the control (C) group received equal volumes of distilled water via gavage for 35 days. Fifteen rats from all groups were subjected to behavioral experiments. Five rats from each group were used for Long-Term Potentiation (LTP), and the other five rats were used for Long-Term Depression (LTD) recordings. The levels of nitrite/nitrate, neuronal nitric oxide synthase (nNOS), and inducible nitric oxide synthase (iNOS) were analyzed in the hippocampi. Behavioral experiments demonstrated that sulfite exposure may cause anxiety- and depression-like behaviors, especially at 100 mg/kg and 260 mg/kg doses. Moreover, sulfite exposure impaired LTP and facilitated LTD in the hippocampus. Besides, the levels of nitrite/nitrate, nNOS, and iNOS were significantly lower in the S100 and S260 groups compared to the C group. Overall, the results showed that sulfite toxicity in adults may induce anxiety- and depression-like behaviors. These findings suggest that sulfite-induced anxiety- and depression-like behaviors may be related to a reduction in NO production.
KCNQ1OT1/miR-140-5p/PTP4A3 axis is involved in endosulfan-induced vascular endothelial cell migration linking to atherosclerosis.
Zhang B, Li Q, Lu Y … +4 more , Wang W, Tian M, Guo J, Xu D
Toxicol Lett · 2025 Oct · PMID 40706910 · Publisher ↗
Endosulfan, an organochlorine pesticide, is implicated in human cardiovascular diseases. Protein-tyrosine phosphatase 4A3 (PTP4A3) has been identified to play a critical role in endothelial cell migration when exposure t...
Endosulfan, an organochlorine pesticide, is implicated in human cardiovascular diseases. Protein-tyrosine phosphatase 4A3 (PTP4A3) has been identified to play a critical role in endothelial cell migration when exposure to endosulfan. In the present study, we aim to explore the epigenetic mechanism by which endosulfan upregulates PTP4A3 expression to enhance cell migration in human umbilical vein endothelial cells (HUVECs). Bioinformatics analysis showed that there were complementary sequences in the 3'-UTR of PTP4A3 and lncRNA KCNQ1OT1 to the seed regions of miR-140-5p. Dual luciferase reporter assay confirmed that miR-140-5p had potential binding capacity to PTP4A3 and KCNQ1OT1. Endosulfan upregulated PTP4A3 and KCNQ1OT1, but downregulated miR-140-5p expression, promoting cell migration through the activation of MAPK/ERK and PI3K/AKT pathways in HUVECs, which were inhibited by miR-140-5p overexpression or KCNQ1OT1 silencing Anti-Ago2 RNA immunoprecipitation experiments confirmed the binding interaction between miR-140-5p and KCNQ1OT1. Transfection of miR-140-5p mimics downregulated PTP4A3 and KCNQ1OT1, while si-KCNQ1OT1 downregulated PTP4A3 and upregulated miR-140-5p in HUVECs. Either miR-140-5p mimic or si-KCNQ1OT1 attenuated cell migration and influenced MAPK/ERK and PI3K/AKT signaling pathways in HUVECs, which were counteracted by co-transfection with pEGFP-PTP4A3 or anti-miR-140-5p. We observed the upregulation of PTP4A3 and KCNQ1OT1, as well as the downregulation of miR-140-5p in the aorta of the ApoE atherosclerotic mice. These findings suggest the involvement of KCNQ1OT1/miR-140-5p/PTP4A3 axis in endosulfan-induced cell migration, providing new insights into the epigenetic mechanisms of endothelial dysfunction in cardiovascular diseases when exposure to endosulfan.
Protective effect of glucocorticoid receptor against lung inflammation induced by nicotine-derived nitrosamine ketone is mediated by suppression of the ROS-mediated cyclooxygenase-2/prostaglandin E2 pathway in human distal lung epithelial A549 cells.
Shim M, Lim W
Toxicol Lett · 2025 Oct · PMID 40706909 · Publisher ↗
Cigarette smoking is a significant risk factor for lung cancer. The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway is a well-established key player in inflammation and tumorigenesis, both of which are linked to...
Cigarette smoking is a significant risk factor for lung cancer. The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway is a well-established key player in inflammation and tumorigenesis, both of which are linked to cigarette smoking. Nevertheless, the function of glucocorticoid receptors (GR) in the context of the COX-2/PGE2 pathway induced by nicotine-derived nitrosamine ketones (NNK) remains to be elucidated. The NNK-induced increase in COX-2 expression and PGE2 production was inhibited by glucocorticoids, and this effect was antagonized by the GR antagonist, RU38486. Notably, the induction of COX-2 by NNK correlated with NNK's ability to increase reactive oxygen species (ROS). The ROS scavenger N-acetylcysteine inhibited the NNK-induced increase in COX-2 mRNA levels and promoter activity. Furthermore, dexamethasone significantly inhibited NNK-induced cell invasion. Conclusively, the data collectively indicate that NNK-induced ROS activates the COX-2/PGE2 pathway and cell invasion in lung cancer cells. These findings elucidate the pathophysiological connection between NNK, GR, inflammatory responses, and cell metastasis.
The role of endoplasmic reticulum stress in Atrazine-induced hepatic lipid accumulation.
Qian H, Ren S, Zhao H … +8 more , Shi J, Ge Z, Zhang J, Wang T, Zhang X, Jiang H, Zhang Y, Ye L
Toxicol Lett · 2025 Oct · PMID 40701419 · Publisher ↗
Atrazine (ATR) is an extensively applied triazine herbicide which belongs to the persistent environmental endocrine disruptors. ATR is capable of penetrating the body and disrupting lipid metabolism, but its underlying m...
Atrazine (ATR) is an extensively applied triazine herbicide which belongs to the persistent environmental endocrine disruptors. ATR is capable of penetrating the body and disrupting lipid metabolism, but its underlying mechanism is still unclear. L02 hepatocytes were exposed to ATR (0 (Con), 10, 50, 100 μM) and 0.02 % DMSO (VCon) for 24 h. Lipid levels were measured using colorimetry. The lipid droplet accumulation level and detection of Ca levels by fluorescent staining. Real-Time PCR and Western blot were used to measure mRNA and protein levels. The results showed that groups treated with ATR exhibited elevated levels of lipid. Both intracellular lipid droplet accumulation and Ca levels increased proportionally with higher ATR dosages. Additionally, the levels of genes linked to lipid metabolism (DGAT2, ACC1, PPARγ, and SCD1) were upregulated. Endoplasmic reticulum stress (ERS) was triggered, leading to augmented gene expression in the IRE1α/XBP1 signaling pathway, as well as enhanced expression of GRP78 and GRP94. ERS was inhibited by 4-phenylbutyric acid (4-PBA), IRE1α was silenced by lentivirus transfection. Notably, the upregulation of IRE1α, XBP1, GRP78, and GRP94, alongside the ATR-induced lipid elevations, were significantly reversed upon ERS inhibition or IRE1α gene silencing. This study demonstrated that ATR exposure caused ERS in L02 hepatocytes, and induced lipid metabolism disorders by activation the key ERS signal pathway IRE1α/XBP1, resulting in hepatic lipid accumulation.
Nano-assault on the heart: Molecular pathways of lead oxide nanoparticle cardiotoxicity.
Gerzen O, Nabiev S, Tzybina A … +6 more , Potoskueva I, Votinova V, Klinova S, Minigalieva I, Sutunkova M, Nikitina L
Toxicol Lett · 2025 Aug · PMID 40701418 · Publisher ↗
Lead is closely associated with increased cardiovascular risk. We investigated the molecular mechanisms underlying the impact of lead nanoparticle exposure (Pb) on the myocardium in different heart chambers, comparing th...
Lead is closely associated with increased cardiovascular risk. We investigated the molecular mechanisms underlying the impact of lead nanoparticle exposure (Pb) on the myocardium in different heart chambers, comparing the effects of Pb to those of its soluble form. Male rats received intraperitoneal injections of PbO nanoparticle suspension (2.5 mg/kg b.w.) or Pb(CHCOO)₂ solution (6.01 mg/kg b.w.) thrice a week for six weeks. We analyzed sliding velocity of actin, native, and reconstituted thin filaments over myosin, Hill cooperativity and calcium sensitivity of the "pCa-velocity" relationship, relative force by an in vitro motility assay. We determined the isoform content of myosin heavy (MHC) and light chains (MLC), and MLC 2 phosphorylation by gel electrophoresis. Both Pb and Pb(CHCOO) exposures decreased atrial, right, and left ventricular myosin kinetics, shifted ventricular MHC ratio toward β-MHC with lower kinetics, and reduced atrial MLC 2 phosphorylation; only Pb exposure reduced MLC 2 phosphorylation in ventricles. Despite a 2.4-fold lower lead dosage in the Pb, the magnitude of decline in myosin kinetics and MHC ratio shift was comparable between both exposure forms. Thus, Pb exposure may appear to be more toxic than its soluble counterpart. While certain mechanisms were common to both forms of exposure - decreased myosin kinetics, reduced atrial MLC 2 phosphorylation, shifts in ventricular MHC isoforms - the reduced ventricular MLC 2 phosphorylation emerged as a specific alteration unique to Pb exposure. Understanding the molecular mechanisms of influence of Pb exposure on specific heart chambers is essential for developing strategies for reducing cardiovascular morbidity and mortality.
Skin penetration and decontamination efficacy following in vitro human skin exposure to sulfur mustard.
Höjer Holmgren K, Wigenstam E, Öberg L … +2 more , Bucht A, Thors L
Toxicol Lett · 2025 Oct · PMID 40684891 · Publisher ↗
Sulfur mustard (HD) is a chemical warfare agent. Dermal injuries are most common following exposure and only supportive treatment exists. Consequently, skin decontamination is important to avoid severe injuries. In the p...
Sulfur mustard (HD) is a chemical warfare agent. Dermal injuries are most common following exposure and only supportive treatment exists. Consequently, skin decontamination is important to avoid severe injuries. In the present study, selected decontamination protocols were evaluated following in vitro human skin exposure to HD. The degradation kinetics of HD in receptor solution was also evaluated and a sample analysis method was developed. Rapid HD-degradation to thiodiglycol (TDG) was observed in the standard receptor solution (ethanol and water; 1:3). No intact HD was detected after 2 h. Low HD-degradation was detected in 100 % ethanol during 20 h (90 % intact agent). Subsequently, both HD and TDG was measured in all skin penetration samples. HD skin penetration experiments using the standard receptor solution or 100 % ethanol as receptor solution indicated that agent degradation primarily occurred in the receptor solution and not during agent penetration through skin. Reactive Skin Decontamination Lotion (RSDL) followed by wet decontamination displayed the highest decontamination efficacy following skin exposure to neat HD. Dry removal using an absorbent pad followed by wet decontamination and wet decontamination alone resulted in a significant efficacy, of which, wet decontamination alone resulted in the lowest efficacy. RSDL has displayed the highest decontamination efficacy following skin exposure to both HD and the nerve agent VX in experiments using the same skin penetration model. The present study supports previously reported benefits of dry removal prior to wet decontamination and should be recommended to enable rapidly initiated decontamination if specific resources are lacking.
Urinary phthalate metabolites associate with blood levels of estrogen quinone-derived hemoglobin adducts in Taiwanese pregnant women.
Wang SL, Chen DR, Hsu SY … +6 more , Liu CW, Lin C, Sun CW, Su PH, Tseng YC, Lin PH
Toxicol Lett · 2025 Oct · PMID 40684890 · Publisher ↗
In this study, we aimed to analyze the background levels of estrogen quinone-derived adducts in hemoglobin (Hb) obtained from pregnant women in Taiwan (n = 394) and to investigate the associations of these adducts with l...
In this study, we aimed to analyze the background levels of estrogen quinone-derived adducts in hemoglobin (Hb) obtained from pregnant women in Taiwan (n = 394) and to investigate the associations of these adducts with levels of urine metabolites of phthalates. Both 17β-estradiol-2,3-quinone (E-2,3-Q) and 17β-estradiol-3,4-quinone (E-3,4-Q) are reactive metabolites of estrogen that are thought to be responsible for the estrogen-induced genotoxicity and carcinogenicity. Results confirmed that levels of estrogen quinone-derived adducts in pregnant women, including E-3,4-Q-2-S-Hb and E-2,3-Q-4-S-Hb, were detected at concentrations comparable with those of non-pregnant women with mean levels at 165 (range 108-428) and 97.2 (range 34.9-251) pmol/g, respectively. Levels of E-3,4-Q-2-S-Hb correlated significantly with those of E-2,3-Q-4-S-Hb (correlation coefficient r = 0.543, p < 0.001). The ratios of primary (mono-2-ethylhexyl-phthalate) to secondary (mono (2-ethyl-5-hydroxyhexyl phthalate), mono (2-ethyl-5-oxohexy) phthalate) metabolites of di-2-ethylhexyl phthalate (DEHP), positively correlated with levels of E-2,3-Q-4-S-Hb and/or E-2,3-Q-4-S-Hb plus E-3,4-Q-2-S-Hb (p < 0.05). One of the urinary metabolites of phthalates, mono-isobutyl phthalate, a metabolite of diisobutyl phthalate (DiBP), positively correlated with those of E-3,4-Q-2-S-Hb (r = 0.110, p = 0.034) and E-2,3-Q-4-S-Hb plus E-3,4-Q-2-S-Hb (r = 0.13, p = 0.018). Overall, this evidence suggests that levels of these estrogen quinone-derived Hb adducts associate with environmental exposure to phthalates, in particular DEHP and DiBP. We hypothesized that environmental exposure to phthalates may enhance bioactivation of estrogen to quinones leading to accumulation of reactive quinonoid metabolites in pregnant.
Corrigendum to 'Multigenerational toxicity and transcriptomic changes induced by environmentally relevant concentrations of microcystin-LR and -RR in Caenorhabditis elegans' [Toxicol. Lett., 410 (2025) 58-66].
Wang X, Zhang J, Cao Z … +3 more , Dai L, Zhao Q, Du H
Toxicol Lett · 2025 Aug · PMID 40675828 · Publisher ↗
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Unveiling the m⁶A regulatory axis in cigarette smoke-induced carcinogenesis: A landmark analysis in toxicology letters.
Sheng R, Tao S, Jin C
Toxicol Lett · 2025 Aug · PMID 40675519 · Publisher ↗
This commentary highlights Nakano et al.'s significant study demonstrating that cigarette smoke extract (CSE) downregulates METTL3/METTL14, altering m⁶A RNA modification and establishing a novel regulatory axis where m⁶A...
This commentary highlights Nakano et al.'s significant study demonstrating that cigarette smoke extract (CSE) downregulates METTL3/METTL14, altering m⁶A RNA modification and establishing a novel regulatory axis where m⁶A dynamics control ARNT transcription via chromatin remodeling in A549 cells. The work provides important mechanistic insights linking environmental exposure to epitranscriptomic dysregulation relevant to carcinogenesis, particularly CYP1A1 induction. While technically rigorous and identifying m⁶A machinery as potential investigative targets, limitations include the A549 cell model, incomplete FTO characterization, dose-response, and CSE comparability to whole smoke. The findings underscore the need for follow-up studies to explore the therapeutic potential cautiously.
Folic acid alleviates gestational arsenic exposure-induced spatial learning and memory impairment in mice offspring via consuming SAM-mediated DNA hypomethylation in the developing brain.
Wu L, Wu X, Zhang X … +4 more , Wang J, Xia Y, Yang H, Lv J
Toxicol Lett · 2025 Aug · PMID 40669674 · Publisher ↗
Arsenic is ubiquitously distributed in the environment and substantially threatens human health; however, the mechanism underlying gestational arsenic exposure-induced impairment of neural development in offspring is unc...
Arsenic is ubiquitously distributed in the environment and substantially threatens human health; however, the mechanism underlying gestational arsenic exposure-induced impairment of neural development in offspring is unclear. Herein, the impact of arsenic exposure during pregnancy on spatial learning and memory was evaluated using a mouse model. The findings indicated that adult offspring exhibited cognitive disorders due to intrauterine arsenic exposure, which correlated with diminished S-adenosylmethionine (SAM) and folic acid (FA) levels in fetuses. Subsequent analysis confirmed that intrauterine arsenic exposure downregulated the DNA methylation, leading to a reduction in the expression of genes related to cognition in the fetal hippocampus, such as breast cancer susceptibility protein 1 (Brca1), c-Fos, activity-regulated cytoskeleton-associated protein (Arc), and Foxg1. We then established a mouse model with FA intervention and discovered that supplementing with FA prevented the arsenic-induced reduction of SAM and 5-methylcytosine (5mC) levels, and restored DNA methylation and genes associated with cognition, thereby mitigating spatial learning and memory impairments in adult offspring. This study demonstrates that FA supplementation alleviates gestational arsenic exposure-induced spatial learning and memory deficits, at least partially, by increasing SAM levels in the developing brain. Our findings identify potential targets and strategies for preventing cognitive impairments in offspring due to gestational arsenic exposure.
GSH promote renal cadmium efflux through ABCC1 of ABC family.
Jiang J, Gao H, Liu H … +7 more , Huang T, Yin Y, Wan S, Wang X, Zhao Q, Liu J, Huang S
Toxicol Lett · 2025 Aug · PMID 40659077 · Publisher ↗
Accumulation of cadmium in the kidneys can lead to toxicity; therefore, it is crucial to identify methods that promote cadmium excretion to mitigate nephrotoxicity. However, the mechanisms underlying cadmium excretion fr...
Accumulation of cadmium in the kidneys can lead to toxicity; therefore, it is crucial to identify methods that promote cadmium excretion to mitigate nephrotoxicity. However, the mechanisms underlying cadmium excretion from the kidneys remain unclear. The role of the ATP-binding cassette (ABC) transporter family in the renal excretion of cadmium was investigated in this study. We employed gene chip technology to identify alterations in gene and protein expression within the ABC transporter family, particularly focusing on ABCC1, in response to cadmium exposure. Utilizing CRISPR-Cas9 technology, we created NRK cells that overexpress ABCC1 (LV-OE), and observed that the overexpression of ABCC1 accelerated cadmium efflux in these cells. Conversely, the application of an ABCC1 inhibitor (MK571) to NRK cells suppressed ABCC1 expression and delayed cadmium efflux. Molecular docking studies, informed by computer-aided drug design, indicated that glutathione (GSH) exhibits a superior binding affinity to the ABCC1 protein structure. Furthermore, the addition of GSH enhanced cadmium efflux from renal tissue and NRK cells, suggesting that cadmium efflux may be mediated by the ABCC1 protein. These findings imply that ABCC1 plays a significant role in facilitating cadmium efflux in the kidneys, and that GSH can enhance this process via ABCC1. This research offers new targets and potential therapeutic strategies to address cadmium-induced nephrotoxicity.
Lysosomal changes caused by nicotine exposure in human epithelial tongue cells.
Uvsløkk S, Tanner T, Becher R … +2 more , Valen H, Samuelsen JT
Toxicol Lett · 2025 Aug · PMID 40623488 · Publisher ↗
Nicotine is an addictive substance and has been associated with several harmful effects on health. Many previous studies have focused on the receptor-mediated mechanisms of nicotine. However, non-receptor mediated effect...
Nicotine is an addictive substance and has been associated with several harmful effects on health. Many previous studies have focused on the receptor-mediated mechanisms of nicotine. However, non-receptor mediated effects of nicotine, such as effects on the lysosomes have also been reported. Well-functioning lysosomes are essential for cellular degradation pathways like the autophagic, phagocytic, and endocytic pathways. This study aimed to investigate nicotine's direct effect on lysosomes and lysosome-dependent activities in vitro. Cells from the immortalized human epithelial tongue cell line PE/CA-PJ49 were exposed to nicotine (5 mM) alone or in combination with bafilomycin A1 (10 nM; an inhibitor of lysosomal activity). Cell viability was measured using the MTT assay. Morphological changes were studied in a phase contrast microscope. Lysosomal activity was measured using flow cytometry and western blotting was used to quantify selected autophagy-related proteins. Only nicotine in combination with bafilomycin A1 resulted in decreased cell viability. However, morphological changes (vacuolization) were only observed in the cells exposed to nicotine. Apart from control, all exposures decreased lysosomal activity and increased the levels of the autophagy-related proteins p62/SQSTM1 and LC3-II. In conclusion, nicotine caused cellular vacuolization, reduced lysosomal activity, and increased levels of autophagy-related proteins indicating impaired autophagic flux.
Elucidating the impact of persistent organic pollutants on male reproductive health and testicular structure.
Ray SS, Gupta P, Mahapatra A … +2 more , Suman A, Singh RK
Toxicol Lett · 2025 Aug · PMID 40619073 · Publisher ↗
Persistent organic pollutants (POPs) are environmental contaminants that pose significant health risks due to their widespread distribution. This study examines the effects of POPs on male reproductive health using reali...
Persistent organic pollutants (POPs) are environmental contaminants that pose significant health risks due to their widespread distribution. This study examines the effects of POPs on male reproductive health using realistic human exposure scenarios. Male mice exposed to 28 ng of POPs for 35 days exhibited detrimental effects on sperm motility and count, significant changes in germ cell composition, and compromised steroidogenesis. Histopathological analyses revealed testicular architecture alterations and abnormal lipid accumulation in the interstitial space, potentially hindering steroidogenesis and Leydig cell function. Western blot and immunofluorescence studies showed reduced levels of steroidogenic markers. Flow cytometry indicated a decrease in round spermatids, suggesting impaired spermatogenesis. Molecular investigations revealed reduced mRNA expression of critical steroidogenic enzymes, while increased apoptotic markers and DNA fragmentation suggested apoptosis as a mechanism. This study highlights the need for stricter regulations and improved environmental health policies to mitigate the adverse effects of POPs on male reproductive health.
Spilled liquid mercury: Case studies, proposition of safety procedures with assessment of commercial cleanup kit and recommendations.
Niżnik Ł, Świdniak A, Toporowska-Kaźmierak J … +1 more , Jurowski K
Toxicol Lett · 2025 Aug · PMID 40614943 · Publisher ↗
Mercury, in its elemental form (Hg(0)), has intrigued humanity since antiquity, but its toxicological risks have become more apparent in recent times. Metallic mercury exposure primarily occurs through vapor inhalation,...
Mercury, in its elemental form (Hg(0)), has intrigued humanity since antiquity, but its toxicological risks have become more apparent in recent times. Metallic mercury exposure primarily occurs through vapor inhalation, affecting the central nervous system and causing symptoms such as tremors, cognitive impairments, and renal damage. Mercury contamination, often linked to artisanal gold mining and industrial spills, poses environmental and health challenges worldwide. Addressing these hazards requires effective mercury spill management practices. Guidelines from the EPA and WHO emphasize the need for immediate containment, avoiding vacuum cleaners or brooms, and using specialized spill kits. Best practices include isolating contaminated areas, increasing ventilation, and safely disposing of mercury. Large-scale spills may require professional decontamination, including chemical stabilization with sulphur. The manuscript underscores the importance of adopting comprehensive spill management strategies to mitigate both immediate and long-term health risks associated with mercury exposure, offering practical recommendations for handling spills in various environments.
Toxicological effects of micro/nano-plastics on human reproductive health: A review.
Talaie A, Alaee S, Hosseini E … +2 more , Rezania S, Tamadon A
Toxicol Lett · 2025 Oct · PMID 40609962 · Publisher ↗
Micro/Nano-plastics (MNPs), including microplastics (MPs; <5 mm) and nanoplastics (NPs; <100 nm), have become pervasive environmental pollutants due to extensive plastic production and insufficient recycling practices. T...
Micro/Nano-plastics (MNPs), including microplastics (MPs; <5 mm) and nanoplastics (NPs; <100 nm), have become pervasive environmental pollutants due to extensive plastic production and insufficient recycling practices. These particles originate from the degradation of larger plastic materials through processes such as photo-oxidation, thermo-oxidation, and incomplete biodegradation, resulting in chemically reactive fragments that persist in air, water, and food. Once released, MNPs enter the human body primarily via ingestion, inhalation, and dermal absorption, ultimately accumulating in various tissues, including reproductive organs. This review provides a comprehensive summary of current knowledge regarding the toxicological effects of MNPs on male and female reproductive health, with a focus on mammalian models and relevance to human exposure. In males, MNPs have been associated with testicular damage, impaired spermatogenesis, reduced sperm count and motility, and disruptions in the hypothalamic-pituitary-gonadal axis. In females, exposure has been linked to altered folliculogenesis, disrupted ovarian hormone levels, impaired oocyte quality, and placental dysfunction. These effects are largely driven by mechanisms involving oxidative stress, inflammation, endocrine disruption, mitochondrial dysfunction, and apoptosis. Furthermore, MNPs have been shown to disrupt gut microbiota composition, contributing to systemic inflammation and reproductive dysfunction through emerging pathways such as the gut-testis axis. Given their widespread presence and multifaceted modes of action, MNPs pose a serious threat to human reproductive health. Therefore, there is an urgent need for stricter environmental regulations, improved waste management, and further research to understand the long-term and transgenerational consequences of MNP exposure.
Neurotoxicity of food colorants: Gut dysbiosis and reduced short-chain fatty acids disrupt the enteric nervous system and lead to neurological disability.
Mohammed V, Arasu MV, Muthuramamoorthy M … +2 more , Karthick Raja Namasivayam S, Arockiaraj J
Toxicol Lett · 2025 Aug · PMID 40602696 · Publisher ↗
For centuries, the practice of adding color to food has become deeply ingrained in culinary traditions, evolving into an indispensable aspect of food production today. Major food manufacturing companies extensively use c...
For centuries, the practice of adding color to food has become deeply ingrained in culinary traditions, evolving into an indispensable aspect of food production today. Major food manufacturing companies extensively use colorants to enhance the visual appeal of their products. However, recent years have seen an increasing number of studies by researchers who have uncovered various health risks associated with food color additives. These studies have predominantly linked food colorants to severe health conditions such as cancer and allergies. Beyond these issues, further investigations have revealed that excessive use of food colorants can also lead to neurological disorders. Specifically, food colorants such as Tartrazine, Allura Red, Indigotine, Erythrosine, and Titanium Dioxide have been identified as significant contributors to bodily harm. Research indicates that these colorants do not directly affect the brain but impact the gut microbiome. They destroy beneficial gut bacteria, creating a pathway for neurological issues. While the direct mechanisms through which these colorants damage the gut and subsequently affect brain health are not yet fully understood, this paper aims to elucidate these pathways. Through comprehensive analysis, we demonstrate how these food colorants compromise gut health and lead to neurological impairments. By highlighting these interactions, this paper seeks to raise awareness and stimulate further research within the scientific community. Such research could pave the way for significant discoveries, providing deeper insights into the long-term effects of food colorants and leading to more informed regulatory decisions and safer food production practices in the future.
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