Archives of Toxicology最新文献

Either melamine or cyanuric acid alone has low toxicity, but melamine-cyanuric acid crystals co-crystals melamine cyanurate (MC) is reported to cause renal toxicity and has latent effects on central nervous system. This study investigated the neurotoxic effects and mechanism of MC on hippocampus-dependent cognitive and synaptic function using a rat model administered MC during early postnatal stage. We tested the spatial learning and memory ability in Morris water maze (MWM) test and recorded hippocampal long-term potential (LTP) at CA1 synapses. Furthermore, we examined whether autophagy was involved in MC-induced cognitive, synaptic and oxidative damages. We found that MC given at a dose of 30 mg/kg/day for 28 consecutive days significantly impaired spatial performance without affecting locomotion or short-term memory ability. Hippocampal LTP at Shaffer-collateral-CA1 synapses was dramatically depressed while the presynaptic form of synaptic plasticity paired-pulse facilitation (PPF) and basal neurotransmission were not changed. Meanwhile, MC declined the expression postsynaptic GluN2A but not GluN2B subunits of N-methyl-D-aspartate (NMDA) receptors and the postsynaptic density protein 95 (PSD-95) level was also reduced. Autophagy in the hippocampus was down-regulated by MC, as indicated by reduction in the levels of Beclin-1and LC3-II, and the ratio of LC3II/LC3I. However, up-regulation of autophagy by rapamycin could effectively alleviate cognitive deficits and synaptic dysfunction. Meanwhile, retrieval of autophagic activity restored oxidation-antioxidation homeostasis, by elevating MC-declined superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and suppressing MC-enhanced superoxide anion radical, hydroxyl free radical and malondialdehyde (MDA). Additionally, MC elevated the caspase-3 activity and caused the apoptotic cell death, which was mitigated by rapamycin treatment. However, inhibition of autophagy further deteriorated MC-induced these impairments. Therefore, we demonstrate that MC induces cognitive impairments at least due to oxidative damage and synaptic dysfunction through postsynaptic actions, which can be further attributed to the down-regulation autophagy.

Enzymes from the cytochrome P450 (CYP) superfamily, especially from families CYP1, CYP2, and CYP3, play a decisive role in phase I of drug and xenobiotic metabolism in mammalian organisms. The enzymes are responsible for metabolic conversion and detoxification of a plethora of foreign molecules. Metabolic conversion of pro-carcinogenic compounds links CYP enzyme activities to cancer development, while in addition oncogenic pathways have been shown to regulate the expression of CYP genes, together with the well-known regulation by nuclear receptors acting as ligand-activated transcription factors triggered by exposure to xenobiotics. Specifically, the Wnt/β-catenin signaling pathway is among the recently established transcriptional regulators of CYP enzymes. β-Catenin is well-known as a key player in organism development and, when aberrantly activated, a major oncogenic driver of carcinogenesis. While the latter phenomena are rather well-described, new evidence suggests that CYP enzymes themselves may, under certain conditions, also affect the activity of the β-catenin pathway and thereby could impact on carcinogenesis in a way different from toxifying or detoxifying foreign compounds. This review focuses on the currently available knowledge about the regulation of β-catenin-dependent signaling by CYP enzymes. The synopsis of data reveals the possibility of a previously undervalued role of CYPs in the regulation of Wnt/β-catenin signaling, and possible molecular mechanisms are highlighted.

The in vitro micronucleus (MN) test (OECD TG 487) has become the gold standard in various regulatory silos for assessing compounds for their potential to cause clastogenicity. Its main advantages are the reproducibility and robustness, as well as the ability to investigate both structural and numerical chromosome damage, i.e. clastogenicity and aneuploidy. A disadvantage, however, can be seen in the resource-intensive microscopical evaluation. Consequently, faster, high-throughput methods, such as flow cytometry have been developed and integrated into the test guideline protocol. Regardless of the evaluation method applied, results must be consistent to justify the mutual acceptance of data established for OECD TG tests performed under GLP. This may be particularly challenging for substances of lower potency. Here, we present two case studies comparing the results of the MN test according to TG 487 with microscopic evaluation with those obtained using the MicroFlow kit (Litron Laboratories). The MN tests were performed with V79 cells without cytochalasin B, incubated for 4 h (with and without metabolic activation) or 24 h with 0.5, 1.0, 1.25, 1.375 and 1.5 mg/ml matrine or 0.5, 1.0, 1.5, and 2.0 mg/ml oxymatrine. These quinolizidine alkaloids, found in liquorice confectionary and organic green tea are suspected to be aneugenic or clastogenic. The MicroFlow test showed statistically significant increases in micronuclei formation from 1.0 mg/ml on, albeit with slightly reduced relative survival, the metric for cytotoxicity recommended for this method at the time of the assay implementation. Complementary testing using microscopical evaluation did not support these results due to excessive cytotoxicity observed at matrine concentrations of 1.0 mg/ml and higher. Additionally, mechanistic studies using the ToxTracker ACE assay indicated that matrine is not a direct clastogen. Herein, we illustrate and discuss the importance of appropriate metrics for cell proliferation and cytotoxicity which should account for the toxicological properties of the test compounds. The aim is to assure consistency between OECD TG-compliant evaluation methods and to avoid misleading positive findings when evaluating the biological relevance of increased micronuclei formation accompanied by cytotoxicity.

Disruption of the thyroid hormone (TH) system by environmental chemicals poses significant risks to human and wildlife health. Reliable in vitro assays are essential for assessing thyroid peroxidase (TPO) inhibition, which disrupts a key step in thyroid hormone (TH) synthesis, while adhering to 3R principles. This study aimed to compare the sensitivity and specificity of two types of in vitro assays, tyrosine iodination (Tyr-I) detected by HPLC-ICP-MS and Amplex UltraRed (AUR) and its modifications, using human HEK-TPOA7 cells and rat thyroid microsomes. It involved the evaluation of TPO inhibition by 21 chemicals (concentration range 0.002-200 µM) from diverse use categories, including industrial pollutants, pesticides, and pharmaceuticals. TPO-inhibition potential was indicated for 14 compounds. The Tyr-I assay, which measures the conversion of L-tyrosine to monoiodotyrosine, demonstrated superior sensitivity by capturing both the peroxidation and iodination steps of TPO activity, with effective concentrations for some human exposure-relevant chemicals (benzophenone 2, resorcinol) in the 15-74 nM range confirmed with both human and rat TPO sources. In contrast, the AUR assay detects only the peroxidation step, limiting its ability to fully assess TPO inhibition. The inclusion of sodium iodide (NaI) in the AUR assay significantly enhanced its sensitivity (though it was still lower than in Tyr-I assay), while adding L-tyrosine together with NaI did not. The study documents the advantages and limitations, as well as the application and interpretation potential of the different assays´ variants. It provides valuable information and scientifically sound methodology to support the development of efficient testing strategies for the assessment of thyroid hormone system-disrupting chemicals.

Chronic environmental arsenic exposure causes skin and lung cancers, but the molecular mechanisms are poorly understood. We identified that chronic trivalent inorganic arsenite (iAs) exposure at population relevant 100 nM concentration activates autophagy while suppressing downstream protein degradation. Here, we studied the mechanisms by which environmental iAs exposure uncouples autophagy activation from autophagic protein degradation across human skin and lung cell lines. During autophagy, zinc regulates the critical autophagosome-lysosome fusion (ALF) step connecting initiation to final protein degradation. iAs disrupts zinc dependent processes. Thus, we hypothesized that iAs suppresses autophagy by compromising ALF. We demonstrate that environmental 100 nM iAs exposure specifically targets the ALF step of autophagy to suppress autophagic protein degradation across multiple skin and lung cell line models. We show that iAs suppresses ALF in a zinc dependent manner. Physiological zinc supplementation (1 μM) prevented and rescued against iAs-induced suppression of ALF and autophagic protein degradation in the short and long-term. Our work provides a framework to understand and further investigate the precise molecular mechanisms by which chronic environmental iAs exposure disrupts global protein degradation, thereby inducing proteotoxicity across multiple target tissues and contributing to the observed proteome-wide differential expression patterns during multi-organ carcinogenesis.

Chikungunya virus (CHIKV) is a re-emerging mosquito-borne virus that has spread from Africa to Asia and the Americas, posing a growing global threat to public health. In China, following the first imported case in 2008 and subsequent local outbreaks, the largest nationwide epidemic occurred in 2025 with nearly 9,000 confirmed cases. Clinically, CHIKV infection is characterized by high fever, rash, and severe arthralgia, often leading to long-term joint pain and reduced quality of life. The virus is primarily transmitted by Aedes albopictus and Aedes aegypti, with transmission dynamics influenced by climate variability, rainfall patterns, and human mobility. As no licensed vaccine or specific antiviral therapy is currently available, this review summarizes recent advances in CHIKV epidemiology, pathogenesis, and prevention, emphasizing its potential public health threat and offering scientific insights to guide future surveillance and control efforts.

Lithium-ion batteries (LIBs) play a key role in the transformation of society away from fossil fuels. Despite extensive research on their behaviour and improvement, toxicological aspects are often neglected, in particular regarding the liquid organic electrolyte. This study aimed to investigate the genotoxic and mutagenic potential as well as cell cycle effects of LIB electrolytes including one of the three sulphur-containing additives 1,3‑propanesultone (PS), prop‑1‑ene‑1,3‑sultone (PES) and 1,3,2‑dioxathiolane‑2,2‑dioxide (DTD). These additives are used in LIB to improve performance. Genotoxicity was assessed in HepG2 cells by two different versions of the in vitro micronucleus assay, whereas for mutagenicity testing, the bacterial reverse mutation assay in Salmonella typhimurium strains was used. The study focussed mainly on the investigation of the electrolyte and its constituents in different electrochemical ageing stages. Pure additives and one suspected degradation product each were investigated as well. It was shown that the toxicity of the pristine electrolyte related to that of the present additive. However, ageing led to electrolyte decomposition and the formation of new species, which had a major influence on toxicity. In sum, the extent to which toxicity was reduced depended on the additive. The results suggested that for the application in LIBs, DTD should be preferred over PS and PES from a toxicological point of view.