Toxicology[JOURNAL]
Sun
200 papers
In vitro and in vivo thyroid hormone system disruption by perfluorooctane sulfonate (PFOS) and tetrabromobisphenol A (TBBPA).
Stub M, Dahmen L, Niklas AA … +10 more , Mandrup K, Kuehn C, Arnold S, Liersch AL, Ford J, Gilbert M, Renko K, Axelstad M, Svingen T, Ramhøj L
Toxicology · 2026 Feb · PMID 41285219 · Publisher ↗
Thyroid hormone (TH) system-disrupting chemicals can cause adverse effects, including neurodevelopmental deficits. While current in vivo test methods reliably detect disruptions from potent antithyroid drugs such as prop...
Thyroid hormone (TH) system-disrupting chemicals can cause adverse effects, including neurodevelopmental deficits. While current in vivo test methods reliably detect disruptions from potent antithyroid drugs such as propylthiouracil (PTU) and methimazole (MMI) through thyroid gland histopathology, they may lack sensitivity for less potent chemicals or those acting through alternative mechanisms. A more systemic, mechanism-based approach may therefore be needed to identify TH system-disrupting capacity. Here, we assessed the effects of the environmental chemicals perfluorooctane sulfonate (PFOS) and tetrabromobisphenol A (TBBPA) on the TH system using in vitro and in vivo approaches. PFOS inhibited the TH transmembrane transporter monocarboxylate transporter 8 (MCT8) and the sodium-iodide symporter (NIS). TBBPA inhibited MCT8, the enzyme activity of all three iodothyronine deiodinases (DIO1/2/3), and thyroperoxidase (TPO). In time-mated rats, in utero and early postnatal exposure to PFOS (0.4 or 0.8 mg/kg bw/day) or TBBPA (250 or 500 mg/kg bw/day) reduced serum TH concentrations in dams and offspring, but neither chemical altered thyroid stimulating hormone (TSH) in offspring. We observed no, or only modest, effects on thyroid gland histology. Both chemicals altered TH metabolism by deiodinase and dehalogenase enzymes and reduced iodine content in the thyroid. In the fetal brain, PFOS increased T3, while TBBPA decreased T4 in the postnatal brain. These findings demonstrate distinct TH-disrupting profiles of PFOS and TBBPA, differing from classic antithyroid compounds PTU and MMI. Our results highlight the need for more comprehensive systems-approaches to capture TH disrupting chemicals acting through diverse mechanisms.
Retraction notice to "2,3,7,8-Tetrachlorodibenzo-p-dioxin induced autophagy in a bovine kidney cell line" [Toxicology 290 (2011) 258-270].
Fiorito F, Ciarcia R, Granato GE … +5 more , Marfe G, Iovane V, Florio S, De Martino L, Pagnini U
Toxicology · 2026 Feb · PMID 41271549 · Publisher ↗
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Impact of fluoride on antioxidant activity and mitochondrial homeostasis in fetal rat kidney.
Avila-Rojas SH, Montañez-Rodriguez E, Pantaleón-Gómez AK … +8 more , Tostado-Fernández IA, Pedraza-Chaverri J, Gerarduzzi C, Medina-Campos ON, Marquina-Castillo B, León-Contreras JC, Hernández-Pando R, Barbier OC
Toxicology · 2026 Feb · PMID 41270924 · Publisher ↗
Fluoride exposure harms human health. Additionally, recent attention has focused on understanding the impact of an adverse in utero environment on the programming of chronic kidney disease in adult offspring. A previous...
Fluoride exposure harms human health. Additionally, recent attention has focused on understanding the impact of an adverse in utero environment on the programming of chronic kidney disease in adult offspring. A previous study has described that fluoride alters kidney development, inducing oligonephronia and promoting the premature maturation of remnant nephrons. Therefore, it is essential to continue researching the potential mechanisms involved in fluoride-induced alterations. Female Wistar rats were administered two doses of fluoride (2.5 or 5.0 mg/kg body weight/day) for 20 days before and after mating. The results showed that fluoride diminished catalase and superoxide dismutase activities while increasing the markers of nuclear factor erythroid 2-related factor 2 (Nrf2) activation, mitochondrial dynamics, autophagy, and biogenesis. Morphometric analysis revealed an increase in mitochondrial size and content. Although the levels of Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) increased, the activity of caspase-3 and the immunodetection in the TUNEL assay decreased. Several of these changes were mainly observed with the high fluoride dose. In conclusion, the results suggest that fluoride alters the redox status and mitochondrial homeostasis while decreasing apoptosis. It is essential to recognize that, under normal conditions, apoptosis plays a crucial role in proper kidney development, and its occurrence decreases as the structures mature. Therefore, collectively, these alterations could lead to undesirable effects on postnatal life.
The combined exposure to AFB1 and DON induces the ferroptosis of porcine intestinal epithelial cells via down-regulating PI3K-AKT signal pathway.
Zhao W, Yang Q, Song Y … +1 more , Sun Y
Toxicology · 2026 Feb · PMID 41265777 · Publisher ↗
Aflatoxin B1 (AFB1) and deoxynivalenol (DON) are two highly hazardous mycotoxins often coexisting in feed, threating animal intestinal health. Ferroptosis, a regulated cell death linked to iron metabolism disorders, lipi...
Aflatoxin B1 (AFB1) and deoxynivalenol (DON) are two highly hazardous mycotoxins often coexisting in feed, threating animal intestinal health. Ferroptosis, a regulated cell death linked to iron metabolism disorders, lipid peroxidation, and amino acid metabolism abnormalities, may involve in mycotoxins' toxicity, but their interaction mechanism is unclear. This study used porcine intestinal epithelial cells (IPEC-J2) an in vitro model to explore ferroptosis mechanisms induced by AFB1 and DON alone or combined. The results showed that AFB1 and DON significantly reduced the viability of IPEC-J2 cells. Single and combined exposure to AFB1 and DON up-regulated the levels of MDA and ROS, while down-regulated the level of GSH. Meanwhile, they increased intracellular Fe content, accompanied by significantly down-regulated expressions of ferroptosis-related proteins including GPX4, SLC7A11 and FTH1, while markedly up-regulated the TFR1 protein level. Transmission electron microscopy (TEM) observation further confirmed that mitochondria suffered severe damage (shrinkage, cristae detachment and vacuolization). Mechanistically, single and combined exposure to AFB1 and DON down-regulated the protein levels of p-PI3K and p-AKT. Notably, the use of the PI3K activator 740Y-P significantly reversed aboved these changes. In addition, correlation analysis and molecular docking confirmed a strong positive correlation between PI3K/AKT signals and ferroptosis. In conclusion, single and combined exposure to AFB1 and DON induced IPEC-J2 ferroptosis by inhibiting PI3K-AKT, providing new insights for mycotoxin toxicity studies.
Combined exposure to polystyrene nanoplastics and bisphenol A results in mitochondrial damage and ferroptosis via the PI3K-AKT signaling pathway in mice kidneys.
Wang Q, Wang Y, Wang Y … +7 more , Li S, Yang X, Liu X, Yang J, Min Z, Liu S, Liu G
Toxicology · 2026 Feb · PMID 41260352 · Publisher ↗
Nanoplastics (NPs), a growing environmental concern, can act as carriers for co-pollutants like bisphenol A (BPA). Consequently, understanding the combined toxicity of these pollutants is critical, as mammals are often e...
Nanoplastics (NPs), a growing environmental concern, can act as carriers for co-pollutants like bisphenol A (BPA). Consequently, understanding the combined toxicity of these pollutants is critical, as mammals are often exposed to multiple environmental contaminants simultaneously, however, the potential adverse effects of NPs and/or BPA remain inadequately defined. Therefore, we conducted a six-week toxicity study in mice to evaluate the impacts of BPA, polystyrene nanoplastics (PS-NPs), and their combination. Our results demonstrated that simultaneous exposure to BPA and PS-NPs significantly worsened growth-related toxicity and induced renal damage compared to individual exposures or controls. Mechanistically, co-exposure to BPA and PS-NPs markedly elevated renal malondialdehyde concentrations while significantly reducing the activities of catalase, superoxide dismutase and glutathione peroxidase. This oxidative imbalance led to the dysregulation of the mitochondrial antioxidant system and disruption of ferroptosis kinetics via inhibition of the PI3K/AKT signaling pathway. In conclusion, this study demonstrated the significantly enhanced nephrotoxicity of co-exposure to PS-NPs and BPA in mice, providing crucial mechanistic insights into the toxicological interactions between NPs and endocrine disruptors in mammals. These findings highlight the potential health risks posed by multi-pollutant exposures in the real world.
Mechanistic insights into the structure-toxicity relationship of α-aminononanophenone derivatives: Role of CYP3A4 and oxidative stress.
Morikawa Y, Azuma N, Sakai Y … +7 more , Tsuchimura S, Miyazono H, Suenami K, Yanase E, Endo S, Ikari A, Matsunaga T
Toxicology · 2026 Jan · PMID 41242374 · Publisher ↗
Continuous abuse and overdose of aminophenone derivatives, a representative group of synthetic cathinones, are known to exhibit severe damage against neuronal cells, whereas little is known about their structure-toxicity...
Continuous abuse and overdose of aminophenone derivatives, a representative group of synthetic cathinones, are known to exhibit severe damage against neuronal cells, whereas little is known about their structure-toxicity relationship and cytotoxic mechanisms. Here, we newly synthesized eight α-aminononanophenone (ANP) derivatives bearing various N-alkyl side chains and measured sensitivity to toxicity elicited by treatment with the derivatives using six human cell lines. The sensitivity assay revealed a positive correlation between the length of substituted N-alkyl side chain and the strength of cytotoxicity of the ANP derivatives in all cell lines. In addition, treatment with butyl-ANP (B-ANP), one of the most potent cytotoxic ANP derivatives, markedly induced overproduction of reactive oxygen species (ROS) and 4-hydroxy-2-nonenal, mitochondrial membrane dysfunction and caspase-3/9 activation in neuronal SK-N-SH cells. Furthermore, the treatment resulted in the reductions of antioxidant capacity and 26S proteasome-based proteolytic activities and the significant formation of aggresome. These results indicate that exposure to the ANP derivatives provokes neuronal cell apoptosis through ROS overproduction and lowering of antioxidant properties. A measurement of ANP derivatives by liquid chromatography/mass spectrometry/mass spectrometry analysis revealed that cytochrome P450 (CYP) 3A4 metabolizes ANP derivatives with short N-alkyl chains (methyl and ethyl groups) in preference to ones with longer N-alkyl side chains (propyl and butyl groups) in liver HepG2 cells. Additionally, pretreatment with a CYP3A4 inhibitor augmented the cytotoxicity elicited by diethyl-ANP, not B-ANP. Therefore, it is inferred that CYP3A4-mediated metabolism is also a key factor involved in the reduction of neurotoxicity of ANP derivatives.
Hydramethylnon-induced autophagy and apoptosis in human bronchial epithelial cells by homeostatic changes.
Kang YH, Kim SH, Jeong HJ … +5 more , Song AY, Park HI, Kim EH, Jung YS, Park YJ
Toxicology · 2026 Feb · PMID 41240998 · Publisher ↗
Household chemicals are commonly used products worldwide; however, their effects on human respiratory health are poorly understood. In this study, we aimed to investigate the effects of hydramethylnon (HDM), an insectici...
Household chemicals are commonly used products worldwide; however, their effects on human respiratory health are poorly understood. In this study, we aimed to investigate the effects of hydramethylnon (HDM), an insecticide frequently found in household products, on human bronchial epithelial cells (BEAS-2B) using in vitro experiments. The cells were exposed to varying concentrations of HDM (range, 1-4 µg/mL) for 24 h, followed by the evaluation of cell viability, apoptotic markers, metabolite levels, and antioxidant levels. The results showed that HDM exposure significantly increased oxidative stress by elevating the levels of reactive oxygen species, leading to the autophagosome accumulation and impaired autophagic flux (manifested by increased LC3B and p62 levels) and apoptosis (detected by increased cleaved caspase-3 and Bax/Bcl-2 levels and cytochrome c release). Flow cytometry confirmed that dose-dependent apoptotic cell death was further enhanced by chloroquine, an autophagy inhibitor. HDM exposure also resulted in a dose-dependent decrease in the messenger RNA levels of antioxidant enzymes, including catalase and glutathione peroxidase, and notable disruptions in sulfur-containing metabolites, including decreased levels of S-adenosylmethionine, S-adenosylhomocysteine, taurine, and glutathione. These metabolic perturbations were significantly aggravated by autophagy inhibition, suggesting autophagy-lysosome pathway plays a protective role against HDM-induced oxidative damage. These results suggest that HDM exposure poses substantial risks to human respiratory health through the oxidative stress-mediated disruption of antioxidant defense systems and metabolic pathways, ultimately impaired autophagic flux and mitochondria-mediated apoptosis in bronchial epithelial cells. This study highlights the need for improved safety guidelines and risk assessments of human inhalation exposure to household insecticides, particularly HDM.
Mitochondrial dysfunction induced by E-cigarettes.
Sailis AB, Noh MABM, Leo BF … +3 more , Faruqu FN, Yee A, Sim MS
Toxicology · 2026 Jan · PMID 41240997 · Publisher ↗
E-cigarette use has been linked to mitochondrial dysfunction through exposure to reactive oxygen species (ROS), toxic aldehydes, metals, and flavoring agents. These constituents can damage mitochondrial DNA, impair oxida...
E-cigarette use has been linked to mitochondrial dysfunction through exposure to reactive oxygen species (ROS), toxic aldehydes, metals, and flavoring agents. These constituents can damage mitochondrial DNA, impair oxidative phosphorylation, and disrupt calcium homeostasis, resulting in oxidative stress, inflammation, and programmed cell death. Mitochondrial impairment contributes to many systemic disorders, including respiratory, cardiovascular, and metabolic conditions. Preclinical findings suggest altered mitochondrial morphology, reduced adenosine triphosphate (ATP) production, and increased ROS, all of which can contribute to mitochondrial dysfunction following e-cigarette exposure. Certain flavorings and metals intensify these effects. While early human data suggest systemic mitochondrial stress, most research remains in vitro or animal-based. This review identifies mitochondrial dysfunction as a key mechanism in e-cigarette toxicity and calls for longitudinal research to elucidate its long-term health consequences.
Ophthalmotoxicology of polyhalogenated compounds.
Louzon M, Chiquet C, Kamel M … +3 more , Aleya L, Blanc H, Blanc A
Toxicology · 2026 Feb · PMID 41240996 · Publisher ↗
Polyhalogenated compounds (PHCs), including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and per- and polyfluoroa...
Polyhalogenated compounds (PHCs), including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and per- and polyfluoroalkyl substances (PFAS), are persistent organic pollutants that bioaccumulate in tissues and are increasingly recognized as threats to human health. While their neurotoxic and endocrine-disrupting effects are often described, their potential impact on the ocular system remains underexplored. However, recent evidence suggests that chronic PHC exposure may contribute to a spectrum of ocular pathologies, such as retinal degeneration, cataracts and retinoblastoma. To clarify these emerging risks, this review synthesizes findings at the intersection of toxicology, ophthalmology, and environmental health, highlighting mechanistic insights into how PHCs impair ocular function. Epidemiological studies linking environmental contaminant exposure to visual deficits are discussed alongside experimental data from animal models and in vitro systems, with a particular focus on oxidative stress, mitochondrial dysfunction, endocrine disruption, and altered retinoid signaling as plausible pathways mediating PHC-induced visual toxicity. Given the widespread nature of PHC exposure and the increasing global burden of visual impairment, further research and regulatory oversight are urgently needed to bridge the gap between environmental toxicology and ocular health, ultimately aiming to better understand and mitigate the visual risks posed by these persistent pollutants.
An in vitro-in silico workflow for predicting renal clearance of environmental chemicals and drugs.
Sakolish C, Lin HC, Moyer HL … +9 more , Ford LC, Christen CH, Wetmore BA, DeVito MJ, Hewitt P, Ferguson SS, Raad F, Rusyn I, Chiu WA
Toxicology · 2026 Jan · PMID 41224188 · Full text
Accurate prediction of human renal clearance is essential for evaluating drug pharmacokinetics and environmental chemical risks, yet current methods often neglect rate-determining active transporter-mediated mechanisms....
Accurate prediction of human renal clearance is essential for evaluating drug pharmacokinetics and environmental chemical risks, yet current methods often neglect rate-determining active transporter-mediated mechanisms. This study aimed to expand and validate a unified in vitro-in silico workflow for predicting renal clearance of both pharmaceuticals and per- and polyfluoroalkyl substances (PFAS) with varied elimination half-life ranges. We hypothesized that robust predictions of human renal clearance across diverse chemical classes can be achieved by combining human proximal tubule cell-based permeability/uptake assays with computational models of renal physiology. Human RPTEC/TERT1 cells and their OAT1-overexpressing variant were cultured in 96-well plates and Transwells to measure uptake, directional transport, and intracellular accumulation of 36 chemicals (28 PFAS, 7 drugs, 1 cosmetic ingredient). Time-course concentration data were used for either two-compartment (96-well) or three-compartment (Transwell) kinetic models. Permeability parameters were integrated into a physiologically-based kidney model for in vitro-to-in vivo extrapolation (IVIVE). A follow-up validation study with PFAS used independent experiments to derive similar predictions. Transwell-based three-compartment modeling yielded the most accurate absolute renal clearance predictions for rapidly eliminated drugs. For slowly cleared PFAS, simpler 96-well two-compartment modeling provided high correlation with observed human clearance, accurately distinguishing low-, medium- and high-clearance compounds; model predictions were consistently human health-protective. The PFAS validation study confirmed reproducibility of the approach. The proposed workflow is a conservative, scalable, mechanistically-informed and empirically-benchmarked approach for predicting renal clearance in humans. Transwell assays best support drug clearance estimation, whereas high-throughput 96-well formats enable reliable relative clearance ranking for PFAS, supporting both pharmaceutical development and environmental chemical risk assessment.
Toxic effects of gadolinium on spermatogenesis are associated with inflammation, oxidative stress, apoptosis and autophagy.
Falvo S, Grillo G, Venditti M … +9 more , Chieffi Baccari G, Di Fiore MM, Cappello T, Maisano M, Petito G, Senese R, De Stefano C, Zaffino G, Santillo A
Toxicology · 2026 Jan · PMID 41218684 · Publisher ↗
The widespread use of gadolinium (Gd) in industrial and medical applications has raised concerns about its environmental persistence, particularly in water and soil. Once ingested, Gd may exert toxic effects on various o...
The widespread use of gadolinium (Gd) in industrial and medical applications has raised concerns about its environmental persistence, particularly in water and soil. Once ingested, Gd may exert toxic effects on various organs, but its impact on male reproductive health remains largely unexplored. This study investigated the effects of orally administered GdCl₃ or Gd₂O₃ on spermatogenesis and sperm quality in adult rats. To this purpose, male rats were allowed to drink GdCl or GdO (10-20-40 mg/Kg bw) for 4 weeks. Gd exposure triggered a strong inflammatory response, evidenced by NF-κB activation and increased TNFα and IL-6 levels in serum and testis. This was accompanied by oxidative stress, as indicated by elevated TBARS levels, as well as apoptosis and autophagy processes activation. Notably, Gd-treated animals exhibited a downregulation of spermatogenesis-related proteins (PCNA, p-H3, SYCP3, PRM2). Histological analysis revealed morphological and morphometric alterations in the seminiferous tubules, along with compromised sperm quality. To explore the cellular mechanisms, in vitro experiments were carried out using mouse GC-1 spermatogonial cells treated with GdCl₃ or Gd₂O₃ for 24 h. Gd exposure resulted in cytotoxicity and reduced cell proliferation, with decreased levels of p-ERK1/2 and PCNA. Gd exposure also disrupted oxidative homeostasis and induced autophagy and apoptosis, likely through the inhibition of the AKT signaling pathway. This study provides the first evidence that oral Gd exposure adversely affects spermatogenesis through inflammation, oxidative stress, and impairment of key cellular pathways, highlighting Gd as a potential environmental threat to male reproductive health.
Antiparasitic agent emodepside exerts cytotoxicity in human corneal stromal cells by blocking the interaction between mini-chromosome maintenance 6 protein (MCM6) and chromatin licensing and DNA replication factor 1 (CDT1).
Gao H, Gao H, Yin H
Toxicology · 2026 Jan · PMID 41203057 · Publisher ↗
Emodepside, a novel antiparasitic agent, exhibits remarkable efficacy against nematodes. Recent research from a phase 2b clinical trial has demonstrated that the most frequent adverse event in the emodepside treatment gr...
Emodepside, a novel antiparasitic agent, exhibits remarkable efficacy against nematodes. Recent research from a phase 2b clinical trial has demonstrated that the most frequent adverse event in the emodepside treatment group is blurred vision, but the mechanism of blurred vision remains largely unexplored. To provide references for secure medication and prospective therapeutic interventions of emodepside, we conducted an investigation into the cytotoxic effects of emodepside on the corneal stroma and its underlying mechanisms using an in vitro model of human corneal stromal (HCS) cells. The loading of the mini-chromosome maintenance 6 protein (MCM6) onto chromatin at replication origins by chromatin licensing and DNA replication factor 1 (CDT1) constitutes a crucial step in licensing DNA for replication. This study demonstrates that emodepside directly binds to the CDT1-binding domain (CBD) of MCM6, competitively blocking the MCM6-CDT1 interaction as confirmed by modified enzyme-linked immunosorbent assay and drug affinity responsive target stability assays. Molecular docking reveals that emodepside binds to CBD through hydrogen bonds with Lys754, Ile760, and Lys770. In HCS cells, this blockade results in the inhibition of DNA replication licensing and a decrease in DNA synthesis, as evidenced by the ethynyl-deoxyuridine incorporation assay, leading to cell cycle arrest at the G/G phase. Moreover, emodepside-induced cell cycle arrest in HCS cells leads to dose-dependent apoptosis and proliferation inhibition with the IC value being 32.3 μM. In conclusion, this study not only provides new insights into the mechanism of emodepside-induced vision blur but also offers a valuable molecular tool for the research of MCM6-CDT1 interaction.
Real-life organochlorine mixture-induced lipid dysregulation and oxidative stress in Leydig TM3 cells: Mechanistic insights into male reprotoxicity.
Virmani I, Sychrová E, Řehůřková E … +4 more , Gadara D, Spáčil Z, Novák J, Sovadinová I
Toxicology · 2026 Jan · PMID 41192750 · Publisher ↗
Persistent environmental pollutants such as organochlorines (OCs) remain a global concern due to their widespread distribution, bioaccumulative nature, and endocrine-disrupting potential. While associations with male rep...
Persistent environmental pollutants such as organochlorines (OCs) remain a global concern due to their widespread distribution, bioaccumulative nature, and endocrine-disrupting potential. While associations with male reproductive toxicity are well documented, the underlying mechanisms, particularly those involving lipid metabolism in testicular cells, are not fully understood. This study investigates the mechanistic basis of male reprotoxicity induced by a real-life OC mixture (OC-MIX), modeled after the contaminant profile of ringed seal blubber and comprising 20 environmentally relevant OCs, including pesticides (e.g., dichlorodiphenyltrichloroethane) and industrial compounds (e.g., polychlorinated biphenyls). We applied a mechanistic in vitro test battery that combines receptor-specific reporter gene assays with functional profiling in immature murine Leydig TM3 cells exposed to OC-MIX concentrations ranging from 0.04 to 50 µg/mL. OC-MIX exhibited strong antiandrogenic and dioxin-like activities. Functional assays revealed reduced testosterone and progesterone levels, increased oxidative stress, and impaired mitochondrial function. These effects were driven by broad lipid dysregulation, including enhanced fatty acid degradation and acylcarnitine depletion, which was evident even at the lowest tested concentration (2.5 µg/mL). These lipid alterations were not primarily mediated via androgen receptor antagonism or aryl hydrocarbon receptor agonism. Instead, the lipidomic signature closely resembled that of the lipotoxic drug amiodarone, rather than a non-cytotoxic fatty acid mixture. Our findings underscore the central role of lipid metabolism in testicular function and demonstrate that OC-MIX exerts reproductive toxicity via complex, non-classical endocrine mechanisms. This study highlights the value of integrating lipidomics with mechanistic in vitro models to assess the reproductive toxicity of environmental chemical mixtures.
Micro and nanoplastics in human carcinogenesis: Insights from in vitro studies.
Silva GCA, Fioretto MN, Lima MC … +2 more , Scarano WR, Delella FK
Toxicology · 2026 Jan · PMID 41177257 · Publisher ↗
Many types of cancer affecting humans have been investigated for centuries, underscoring their significance as a major global health challenge shaped by genetic, epigenetic, and environmental factors. In contrast, plasti...
Many types of cancer affecting humans have been investigated for centuries, underscoring their significance as a major global health challenge shaped by genetic, epigenetic, and environmental factors. In contrast, plastic production has only recently gained attention in healthcare, largely due to its degradation and the resulting formation of micronanoplastics (MNPs), which pose potential risks to both the environment and human health. In both contexts, experimental models are crucial for elucidating the mechanisms linking MNPs exposure to cancer, with in vitro studies serving as a key investigative approach. This narrative review compiles in vitro evidence on the effects of MNPs exposure across various tumor cell types. Current findings indicate that MNPs can bioaccumulate and disrupt organ-specific homeostasis, primarily through oxidative stress induction and interference with lipid peroxidation. Within tumor environments, the dose and physicochemical properties of MNPs play a decisive role in determining the severity of their effects. Overall, MNPs appear to activate signaling pathways that promote cell proliferation and tumor-specific invasiveness, thereby contributing to a tumor-promoting microenvironment. Based on available in vitro data, a possible correlation emerges between MNPs-induced carcinogenesis and the identification of potential biomarkers of plastic exposure and tumor progression. This review thus provides a critical foundation for future in vivo and clinical studies aimed at clarifying the role of MNPs in cancer development.
Toxicological evaluation of vape liquids circulating in Brazil: Evidence of emerging hazards.
Fragoso CLR, De Falco A, Santa-Helena E … +2 more , Gioda CR, Gioda A
Toxicology · 2026 Jan · PMID 41175964 · Publisher ↗
The increasing recreational use of Electronic Nicotine Delivery Device (ENDS) poses a serious public health threat, with clear evidence of adverse health effects. Studies over the past 15 years have confirmed the presenc...
The increasing recreational use of Electronic Nicotine Delivery Device (ENDS) poses a serious public health threat, with clear evidence of adverse health effects. Studies over the past 15 years have confirmed the presence of hazardous compounds in the emissions from e-cigarettes and e-liquids. In Brazil, where sales are banned but use is not, this is the first comprehensive study on ENDS in the country. E-liquids were collected through direct user donations and systematically categorized by their origin: Brazil, China, Europe, Paraguay, and the United States. Toxicity assessments were conducted using Saccharomyces cerevisiae and rat cardiomyoblasts. Our findings unequivocally establish that the toxicity of e-liquids escalates with increased concentrations across all samples and groups, with cytotoxic concentrations for 50 % growth inhibition (CC) values ranging (in percentage mass/volume) from 3.8 for the Paraguayan sample to 20.4 for the European sample. Cytotoxicity assessments in R9c2 cells demonstrate that toxicity intensifies with higher concentrations and the presence of additives, resulting in oxidative stress and apoptosis. Exposure (in percentage mass/volume) to 2.5 of e-liquids led to statistically significant changes compared to the unexposed group, with increased production of reactive oxygen species (ROS), release of lactate dehydrogenase (LDH), and inhibition of catalase enzyme activity. Significant toxicity was observed in products from both countries where sale is prohibited and countries where it is regulated. Evidence confirms e-liquids have distinct toxicity profiles based on their concentration and composition. Immediate action and increased public awareness are needed.
Polystyrene nanoplastics increase migration in normal lung cells while inducing differential cytotoxicity in lung cancer cells.
Kim Y, Park SJ, Oh JM
Toxicology · 2026 Jan · PMID 41175963 · Publisher ↗
Micro and nanoplastics, widely present in indoor and ambient air, are emerging inhalable contaminants that can accumulate in the respiratory tract. The potential health risks associated with their accumulation in the hum...
Micro and nanoplastics, widely present in indoor and ambient air, are emerging inhalable contaminants that can accumulate in the respiratory tract. The potential health risks associated with their accumulation in the human body are increasingly recognized. Polystyrene nanoplastics (PS-NPs)-induced toxicity has been studied; however, the different responses between normal and cancerous lung cells remain poorly understood. In this study, we exposed normal (IMR90, BEAS-2B) and cancerous (A549, HCC1833, NCI-H727, NCI-H1755) human lung cell lines to various sizes of PS-NPs (50-1000 nm) and evaluated cellular uptake, viability, gene expression, and cell migration. Confocal imaging revealed an efficient internalization of PS-NPs across all cell types, indicating that differences in downstream responses are not caused by uptake efficiency. Cancer cells in the lungs showed increased sensitivity to PS-NPs-induced cytotoxicity, accompanied by significant downregulation of the antioxidant enzyme superoxide dismutase 1, implicating redox imbalance as a possible mechanism of toxicity. However, the cells in the normal lung exhibited no significant change in viability but displayed increased cell migration following exposure to PS-NPs. Collectively, our findings highlight the distinct and cell-type-specific effects of PS-NPs on lung cells, suggesting that inhaled nanoplastics may contribute to pulmonary dysfunction and malignancy through multiple mechanisms, including oxidative stress and altered cell migration.
Premature aging and neuropathic behaviours induced by an acute low-dose exposure to a sarin surrogate.
Champault A, Leterrier S, Bel R … +8 more , Knoertzer J, Soyer A, Goutal S, Baati R, Francois S, Tournier N, Dal Bo G, Thibault K
Toxicology · 2026 Jan · PMID 41173233 · Publisher ↗
Acute poisoning from organophosphorus (OP) compounds induced a cholinergic toxidrome. Neurological complications may manifest weeks after the initial exposure, including muscle weakness and progressive loss of sensitivit...
Acute poisoning from organophosphorus (OP) compounds induced a cholinergic toxidrome. Neurological complications may manifest weeks after the initial exposure, including muscle weakness and progressive loss of sensitivity. These symptoms may be analogous to those observed in elderly individuals. However, the delayed neurological impact of OP exposure has received limited attention and remains an under-explored area of research. The present study investigated the long-term effects of OP exposure on the sensorimotor system using a mouse model exposed to a sublethal dose of a sarin surrogate. The mice received a 0.5 LD50 dose of 4-nitrophenyl isopropylmethylphosphonate (NIMP), and were observed for a period of six months. Our results demonstrate that NIMP exposure induced a mild intoxication severity in mice, without affecting weight evolution. Behavioral evaluation, using locomotor and sensory tests, revealed that mice exhibited persistent muscle weakness and an increase in mechanical sensitivity. Six months after NIMP exposure, acetylcholinesterase activity remained inhibited in specific regions of the cerebral cortex, while the spinal cord exhibited a return to normal values. Positron emission tomography scans and microcomputed tomography imaging revealed alterations in cerebral glucose metabolism and bone density. Luminex multiplex immunoassay analyses revealed an increase in specific biomarkers of aging. The present study demonstrates that a sublethal dose of NIMP triggered premature aging phenotype, resulting in long-term sensorimotor impairments, neurometabolic and cellular disturbances. These findings underscore the importance of identifying intoxication hallmarks, even in cases of asymptomatic OP exposure.
The effects of direct addition of lead(ii) acetate to a human in vitro model of hematopoiesis recapitulates exposure to lead in utero.
Zagorski JW, Cross KN, Goodyke A … +3 more , Siegwald E, Cordoba Munoz M, Kaminski NE
Toxicology · 2026 Jan · PMID 41173232 · Publisher ↗
Metal and heavy metal exposure during pregnancy and early immune system development is a known environmental health concern in the United States and worldwide. Michigan's aging infrastructure has led to disparities in he...
Metal and heavy metal exposure during pregnancy and early immune system development is a known environmental health concern in the United States and worldwide. Michigan's aging infrastructure has led to disparities in heath equity regarding exposure to lead. Flint, Michigan drew national attention for dangerous lead levels in the community's water sources. However, a 2016 report from the Michigan Department of Health and Human Services confirmed that no Michigan county has more lead-poisoned children than Kent County (Grand Rapids, MI), with a disproportionate number of lead-poisoned youth. Lead exposure during pregnancy has been associated with adverse obstetrical outcomes. Additionally, lead is a known immunotoxicant that easily crosses the placental barrier, and yet little is known about the effects of lead on the human developing immune system. Additionally, international regulatory agencies are moving to adopt new approach methodologies (NAM) for chemical safety assessments and regulatory decision-making. The purpose of the present study was to utilize a previously published NAM, which has been shown to develop cells from the myeloid and lymphoid immune lineages, to determine the effects of lead on human immune development, while confirming these findings with ex vivo human umbilical cord PBMCs exposed to lead in utero. Our results demonstrate that the in vitro approach recapitulates human exposure data and previously published rodent models.
Long-term low-dose N, N-dimethylformamide exposure disturbs hepatic lipid and glucose homeostasis in mice.
Hong SJ, Zhang MB, Qi LY … +3 more , Zhao TH, Wang P, Zeng T
Toxicology · 2026 Jan · PMID 41173231 · Publisher ↗
N, N-dimethylformamide (DMF) is a widely used industrial solvent with well-documented hepatotoxicity at high exposure levels. However, some epidemiological studies suggest that occupational exposure below the current occ...
N, N-dimethylformamide (DMF) is a widely used industrial solvent with well-documented hepatotoxicity at high exposure levels. However, some epidemiological studies suggest that occupational exposure below the current occupational exposure limits (OELs) may still have adverse effects on workers. This study was designed to investigate the hepatotoxicity of subacute (28 days) and chronic (6 months) DMF exposure at OEL-relevant levels in mice. Mice exposed to 75 mg/kg bw DMF (a dose equivalent to the OEL of 20 mg/m) for 28 days showed no signs of liver injury, while higher doses (150 and 300 mg/kg bw) led to increased serum aminotransferase activities, elevated liver weight/body weight ratio, and reduced hepatic lipid levels. However, 6 months of DMF exposure at 75 mg/kg bw caused a significant reduction in liver lipid content, activation of AMPK, and suppression of SREBP-1c, which were accompanied by elevated fasting blood glucose (FBG) levels, increased area under the curve (AUC) in glucose tolerance tests (GTTs), and enhanced lipolysis in white adipose tissue. Increased liver weight/body weight ratio, upregulation of AMPK and p-AMPK protein expression, white adipose tissue lipolysis, elevated FBG level, and increased AUC in GTTs were also observed in mice exposed to 37.5 mg/kg bw DMF. These results indicate that chronic DMF exposure at current OELs may disrupt hepatic metabolic homeostasis, highlighting the necessity to reestablish the OELs for DMF. Further validation of these results using an inhalation exposure model in both male and female mice, with dosimetry accurately bridging to human occupational exposure, is warranted.
Titanium nanoparticles provoke ferritinophagy-mediated ferroptosis via inhibition of the Nrf2-HO-1 signaling pathway in osteocytes.
Zhu R, Zhang Y, Wang Y … +4 more , Bao X, Zhang L, Fang J, Mao H
Toxicology · 2026 Jan · PMID 41167412 · Publisher ↗
Wear particles-induced osteolysis is the primary cause of aseptic loosening and subsequent joint replacement failure. Osteocytes, the most abundant cells in bone, are in direct contact with implants; however, the interac...
Wear particles-induced osteolysis is the primary cause of aseptic loosening and subsequent joint replacement failure. Osteocytes, the most abundant cells in bone, are in direct contact with implants; however, the interaction between osteocytes and wear particles remains largely unelucidated. In the present study, in vivo results showed that titanium (Ti) nanoparticles (with diameters of 40 nm and 800 nm) markedly triggered bone destruction and increased osteocytes death, and this effect was mitigated by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Our in vitro experiments revealed that Ti nanoparticles significantly inhibited the viability of osteocytes MLO-Y4, and induced cell death. Meanwhile, Ti nanoparticles remarkably promoted ferroptosis in MLO-Y4 cells, as evidenced by iron overload, lipid peroxidation accumulation, downregulated protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), and glutathione (GSH) depletion. Notably, this ferroptotic response was associated with enhanced ferritinophagy and degradation of ferritin heavy chain 1 (FTH1), since inhibition of ferritinophagy with 3-methyladenine (3-MA) alleviated Ti nanoparticles-induced ferroptosis. Additionally, Ti nanoparticles significantly suppressed the erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1(HO-1) pathway; the Nrf2-specific activator sulforaphane (SFN) reversed Ti nanoparticles-induced Fe²⁺ accumulation and lipid peroxidation, attenuated ferroptosis and ferritinophagy, and thereby restored the viability of MLO-Y4 cells. Collectively, these findings identify ferritinophagy-mediated ferroptosis as a novel mechanism underlying Ti nanoparticles-induced osteocytes death, and demonstrate that the Nrf2/HO-1 pathway is essential for regulating Ti nanoparticles-induced ferritinophagy and ferroptosis. These results further suggest that targeting the Nrf2/HO-1pathway may represent a promising therapeutic strategy for preventing or alleviating ferritinophagy-mediated ferroptosis in wear particles-related osteoclastogenesis and periprosthetic osteolysis.
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