Toxicology Mechanisms and Methods最新文献

Human data on remains sparse and of varying quality and reproducibility. Ex vivo experiments and animal experiments currently is the most preferred way to predict the skin sensitization approved by the regulatory agencies across the world. However, there is a constant need and demand to reduce animal experiments and provide the scope of alternative methods to animal testing. In this study, we have compared the predictive performance of the published computational tools such as ProTox-II, SuperCYPsPred with the data obtained from ex-vivo experiments. From the results of the retrospective analysis, it can be observed that the computational predictions are in agreement with the experimental results. The computational models used here are generative models based on molecular structures and machine learning algorithms and can be applied also for the prediction of skin sensitization. Besides prediction of the toxicity endpoints, the models can also provide deeper insights into the molecular mechanisms and adverse outcome pathways (AOPs) associated with the chemicals used in cosmetic products.

Purpose: Arsenic has been reported to induce apoptosis in malignant tumor cells. Therefore, it has been investigated as a chemotherapy. From a mechanistic standpoint, the mitochondrial apoptosis pathway, mediated by GSK-3β, plays an important role in tumor cell apoptosis. Nonetheless, the regulation of GSK-3β by arsenic remains controversial. The study aimed to clarify the mechanism of GSK-3β in arsenic-induced apoptosis of tumor cells.

Materials and methods: We included 19 articles, which conducts the role of GSK-3β in the process of arsenic-induced tumor cell apoptosis by the meta-analysis.

Results: Compared with that of control group, the expression of GSK-3β (SMD= -0.92, 95% CI (-1.78, -0.06)), p-Akt (SMD= -5.46,95% CI (-8.67, -2.24)) were increased in the arsenic intervention group. Meanwhile, the combined treatment of arsenic and Akt agonists can inhibit p-GSK-3β. Using the dose and time subgroup analysis, it was shown that the low-dose (<5 μmol/L) and sub-chronic (>24 h) arsenic exposure could inhibit the expression of p-Akt (P < 0.05). In the subgroup analysis of GSK-3β sites, arsenic could inhibit p-Akt and GSK-3β (Ser9) (SMD = -0.95, 95% CI (-1.56, -0.33)). There was a positive dose-response relationship between arsenic and p-GSK-3β when the dose of arsenic was less than 8 μmol/L. The expression of Mcl-1 and pro-caspase-3 were decreased, while the loss of mitochondrial membrane potential and cleaved-caspase-3 increased significantly when arsenic stimulated GSK-3β (Ser9) (P < 0.05).

Conclusion: The study revealed that arsenic could induce tumor cell apoptosis, by inhibiting p-Akt/GSK-3β, and triggering the Mcl-1-dependent mitochondrial apoptosis pathway.

Pyridine is a basic heterocyclic organic compound. The pyridine ring is present in many important compounds, including agricultural chemicals, medicines and vitamins. Due to their widespread industrial use, bioaccumulation and non-target toxic effects are being considered as a great risk to human and environmental health. In this study, we aimed to evaluate the hematological, oxidative and genotoxic damage potentials by different concentrations (1, 1.5, and 2 g/L) of the ketone 3-Benzoylpyridine (3BP) on rainbow trout (Oncorhynchus mykiss). Alterations in the biomarker levels of oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG)), apoptosis (Caspase-3), malondialdehyde (MDA) as well as antioxidant enzyme activities including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), myeloperoxidase (MPO), paraoxonase (PON), and arylesterase (AR) were assessed in brain, liver, gill and blood tissues. Acetylcholinesterase (AChE) activity was also determined in brain tissue. In addition, we analyzed micronucleus (MN) rates and hematological indices of total erythrocyte count (RBC), total leukocyte count (WBC), hemoglobin (Hb), hematocrit (Hct), total platelet count (PLT), mean cell hemoglobin concentration (MCHC), mean cell hemoglobin (MCH), and mean cell volume (MCV) in blood. LC₅₀-96h value of 3BP was calculated as 5.2 g/L from the data obtained. A significant decrease in brain AChE activity was determined in clear time and dose dependent manners. While SOD, CAT, GPx, PON, and AR levels were decreased, MDA, MPO, 8-OHdG and Caspase-3 levels were increased in all tissues (p < 0.05). Again, the 3BP led to increases of MN formation at all applied concentrations in the rates of between 45.4 and 72.7%. Significant differences (p < 0.05) were found out in between all studied hematology parameters between 3BP-exposed and the control fish. In conclusion, ours study firstly indicated that the treatment doses of 3BP induced distinct hematological and oxidative alterations as well as genotoxic damage in rainbow trout.

As a pesticide extracted from plants, rotenone is widely used to control plant pests. In order to explore the safety of rotenone in the environment, we took 60 healthy male SD rats and randomly divided them into rotenone low-dose group, rotenone medium-dose group, rotenone high-dose group, dimethyl sulfoxide group (DMSO), and control group. After 28 days of oral administration, the rat liver tissue ultrastructure, liver function, oxidative stress indexs, mitochondrial function, and apoptosis-related factors were tested to evaluate the hepatotoxicity and toxicological mechanism of rotenone. The results showed that rotenone significantly increased the hepatic index of rats and the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum. Rotenone can reduce the number of endoplasmic reticulum of hepatocyte, concentrate chromatin and make the hepatocyte nuclears irregular. Rotenone weakened the ATP synthesis ability in mitochondria, decreased the activity of ATP enzyme in mitochondria, and increased the mitochondrial membrane potential in the high-dose group. And it induced oxidative stress damage to the mitochondria of rat liver cells. Rotenone can upregulate the expression of pro-apoptotic factors and downregulate the expression of anti-apoptotic factors. These results indicate that oral rotenone in rats induced hepatotoxicity in a dose-dependent manner. The mechanism of rotenone poisoning is that oxidative stress damages organelles of hepatocyte such as mitochondria and endoplasmic reticulum, resulting in their function being weakened or lost, leading to hepatocyte apoptosis.

Fumonisin B1 (FB1) is a possible carcinogenic molecule for humans as classified by the International Agency for Research on Cancer (IARC) in 2B group. In livestock, it is responsible for several mycotoxicoses and economic losses. Lactobacillus strains, inhabitants of a wide range of foodstuffs and the gastrointestinal tract, are generally recognized as safe (GRAS). Thus, the aim of this work was to evaluate the protective effect of Lactobacillus paracasei (LP) against FB1-induced reprotoxicities including testicular histopathology, sperm quality disturbance, and testosterone level reduction.Pubescent mice were divided randomly into four groups and treated for 10 days. Group 1: Control; Group 2: FB1 (100 μg/kg b.w); Group 3: LP (2 × 10⁹ CFU/kg b.w); Group 4: LP (2 × 10⁹ CFU/kg b.w) and FB1 (100 μg/kg b.w). After the end of the treatment, animals were sacrificed. Plasma, epididymis, and testis were collected for reproductive system studies.Our results showed that FB1 altered epididymal sperm quality, generated oxidative stress, and induced histological alterations. Interestingly, these deleterious effects have been counteracted by the LP administration in mice.In conclusion, LP was able to prevent FB1-reproductive system damage in BALB/c mice and could be validated as an anti-caking agent in an animal FB1-contaminated diet.

Naturalistic stimuli, such as movies, are being increasingly used to map brain function because of their high ecological validity. The pioneering studyforrest and other naturalistic neuroimaging projects have provided free access to multiple movie-watching functional magnetic resonance imaging (fMRI) datasets to prompt the community for naturalistic experimental paradigms. However, sluggish blood-oxygenation-level-dependent fMRI signals are incapable of resolving neuronal activity with the temporal resolution at which it unfolds. Instead, magnetoencephalography (MEG) measures changes in the magnetic field produced by neuronal activity and is able to capture rich dynamics of the brain at the millisecond level while watching naturalistic movies. Herein, we present the first public prolonged MEG dataset collected from 11 participants while watching the 2 h long audio-visual movie "Forrest Gump". Minimally preprocessed data was also provided to facilitate the use of the dataset. As a studyforrest extension, we envision that this dataset, together with fMRI data from the studyforrest project, will serve as a foundation for exploring the neural dynamics of various cognitive functions in real-world contexts.