Drug and Chemical Toxicology最新文献

Per- and polyfluoroalkyl substances (PFAS) are widely used in various industries but pose significant ecological and human health risks, particularly to the nervous system. However, the underlying neurotoxic mechanisms remain poorly understood. This study combines network toxicology and machine learning to explore these mechanisms. Using ADMETLAB 3.0, we assessed the environmental toxicity of six common PFAS and identified their potential targets using online tools. A compound-target interaction network was built, followed by protein-protein interaction (PPI) and KEGG pathway analyses to investigate toxicological pathways. Core targets were selected through machine learning, and differential gene expression was analyzed using transcriptomic data. Molecular docking simulations predicted binding affinities between PFAS and their core targets, while molecular dynamics simulations on key complexes were performed using Gromacs 2023.2 and the Charmm36 force field. PFDS showed the highest bioconcentration factors (BCF), while PFOA demonstrated the greatest toxicity. We identified 62 intersecting targets, with PTGS2, MMP9, and ESR1 being central in the PPI network. Transcriptomic analysis revealed 1,077 differentially expressed genes (DEGs), highlighting associated biological processes and pathways. The random forest model identified 20 core genes, with 9 significantly differentially expressed in the PFAS-treated group. Molecular docking suggested potential interactions between the compounds and core targets, and molecular dynamics simulations further supported the stability of the complexes under physiological conditions. This study provides valuable insights into the neurotoxic mechanisms of PFAS, enhancing our understanding of their impact on the nervous system.

Sulfur mustard (SM), a chemical warfare agent, inflicts severe acute and chronic health effects. This study investigates the impact of SM-induced oxidative stress on telomere length (TL) and shelterin gene expression, which are crucial for telomere maintenance in exposed veterans. This study involved SM-exposed veterans and non-exposed controls. The SM-exposed group was divided into three subgroups based on exposure severity (severe, mild, and asymptomatic) and gender. Leukocyte TL, transcript of shelterin genes (TPP1, POT1, TIN2, TRF1, TRF2, RAP1), and plasma MDA were measured. TL was decreased in the SM-exposed group compared to the non-exposed group, while the MDA level was increased. The SM-exposed group showed lower expression of TIN2, TRF2, and the composite shelterin genes compared to the control group. In the SM-exposed subgroups, TL, TRF2 transcript, and composite shelterin gene expression were reduced compared to the non-exposed group, while the MDA levels were significantly increased. There are negative correlations between MDA and both TIN2/TRF2 expression and TL, and positive correlations between TL and composite shelterin gene expression. In the gender comparison, there were different effects of SM toxicity on TIN2, TPP1, TRF2, and the composite of shelterin gene expression between SM-exposed men and women. SM-exposed men had significantly higher MDA levels, while women showed no significant change. Also, there was no difference between non-exposed men and women. It is concluded that SM exposure increases lipid peroxidation, shortens telomeres, and alters shelterin genes in a gender-specific manner, suggesting accelerated biological aging as a delayed toxic effect.

The developmental neurotoxicity of lead, a result of its adverse effects on the developing nervous system, is associated with various mechanisms. One such mechanism involves the disturbance of the equilibrium between pro-oxidants and antioxidants within the developing brain which can be ameliorated with natural antioxidants. The aim of this study was to investigate the potential protective effects of Galbanic acid (GA) on lead acetate-induced developmental neurotoxicity in pre-pubertal rats. In this experimental study, 32 prepubertal immature male rats divided into 4 groups (n = 8); group 1 (control): rats received deionized drinking water, group 2 (Pb acetate): rat received deionized drinking water containing 0.3% lead acetate, group 3 (Pb acetate + GA): rats received deionized drinking water containing 0.3% lead acetate with 1 mg/kg of GA by gavage every other day, group 4 (GA): rats received deionized drinking water with a dose of 1 mg/kg of GA. Lead acetate exposure resulted in spatial memory deficits (p < 0.01), increase in lead concentration (p < 0.001), ROS levels by 150% (p < 0.001) and MDA levels by 200% (p < 0.001). Lead acetate also caused histopathological changes in the Cornu Ammonis 1 and 3 (CA1 and CA3) regions of hippocampus (p < 0.001), while also impairing mitochondrial function and inducing 15% mitochondrial membrane potential (MMP) collapse (p < 0.001). However, co-administration of GA alongside lead acetate significantly ameliorated these effects, demonstrating improvements in spatial memory (p < 0.01), ROS generation (p < 0.001), MDA levels (p < 0.001), and histological changes (p < 0.001). These findings highlight the antioxidant properties of GA and suggest its therapeutic potential in mitigating oxidative stress related damage.

The study focuses on the in vivo toxicity of two concentrations of Polyethylene Terephthalate (PET) microplastics (MPs) (average size 30.22 ± 10.21 µm; 1 mg/mL and 2 mg/mL in distilled water) in Swiss Albino mice after 14 days of exposure via their feeding bottles, followed by a depuration period of 7 days. After 14 days of exposure, PET-MPs induced significant effects on the activities of Alanine Aminotransferase (ALT), Catalase (CAT) and Superoxide Dismutase (SOD) in the liver (p < 0.001). Additionally, the levels of total carbohydrates, total proteins, Reduced Glutathione (GSH) and Thiobarbituric acid reactive substances (TBARS) were also significantly altered (p < 0.001; p < 0.01 for proteins). Upon completion of the depuration phase, parameters largely reverted to baseline although several remained statistically distinct from the control values, except for GSH and TBARS. Genotoxicity assessed by the comet assay was not observed with the concentrations used in the study.

Benzodiazepines (BZDs) are widely used but are often associated with significant side effects such as amnesia, dependence, and withdrawal syndrome, prompting the search for safer alternatives. The current study aimed to assess the possible toxic effects of a novel 1,5-BZD derivative, which we named MAL. In silico analysis showed that MAL binds to the GABA-A receptor with a binding energy of -8.9 kcal/mol, and to its α1, β2, and γ2 subunits with binding energies of -7.6, -7.5, and -7.6 kcal/mol, respectively, indicating strong receptor affinity. To explore the safety of MAL, toxicological testing was conducted in laboratory animals in accordance with internationally accepted guidelines. Acute toxicity was evaluated by a single oral administration of 2 g/kg body weight to male mice, monitored over 14 days. Since BZDs are typically prescribed for up to two weeks in clinical practice, a 28-day repeated-dose toxicity study was also conducted. Mice received MAL (5, 25, 50, and 100 mg/kg) daily for 28 days to evaluate potential toxic effects. No adverse effects were observed on body weight gain, relative organ weights, or food and water consumption. Histological examination of major organs revealed no abnormalities, and biochemical analyses confirmed the absence of hepatotoxicity or nephrotoxicity. Additionally, we present ProTox, a comprehensive, open-source webserver designed for in silico toxicity prediction. In this study, ProTox predicted an oral LD50 of MAL at 3 g/kg. Based on the Globally Harmonized System (GHS) of classification, this places MAL in Category V. These findings support the potential safety of MAL for pharmaceutical formulations.

The babassu (Attalea speciosa Mart. ex Spreng, syn. Orbignya phalerata Mart), native to Brazil, is valued for its medicinal properties. Babassu mesocarp flour has attracted interest for its high flavonoid content. Given the antioxidant effects of flavonoids-and the potential for pro-oxidant or hepatotoxic effects at high doses, and their interactions with other phytochemicals, this study assessed the toxicity and antioxidant activity of a well- characterized hydroethanolic babassu mesocarp extract following in vitro human gastrointestinal digestion to mimic physiological conditions. Additionally, this study offered a physicochemical characterization of the extract's lipid derivatives. Beyond flavonoids, the crude extract exhibited a complex lipid profile, mainly phytosterols. The digested extract (DBME) showed reduced particle size, and it was not cytotoxic to human liver (HepG2) cells. Strong antioxidant effects were observed in HepG2 under oxidative stress conditions, even at low doses. DBME lowered reactive oxygen species (ROS), restored mitochondrial function, and downregulated ROS-induced antioxidant gene expression, highlighting its protective role against oxidative damage and mitochondrial dysfunction. Our findings reinforce the therapeutic potential of babassu mesocarp extracts as antioxidant agents and support their future consideration as an ingredient in functional foods or dietary supplements, based on the potential synergistic action between flavonoids and phytosterols identified within the same food matrix.

Semen Trichosanthis (ST), derived from Trichosanthes kirilowii seeds, has been traditionally used in ancient China to clear heat, resolve phlegm, moisten lungs, and relieve cough. Despite its therapeutic potential, systematic safety data remain limited. This study conducted comprehensive toxicological evaluations through genetic toxicity tests (Ames test, mammalian erythrocyte micronucleus test, mouse spermatocyte chromosome aberration assay), acute (14-day), subchronic (90-day), and teratogenicity assessments. Genetic toxicity tests demonstrated no mutagenicity at doses ≤ 10 g·kg^-1 BW. Acute oral administration in institute of cancer research (ICR) mice revealed no mortality or toxicity (LD₅₀ > 20 g·kg^-1 BW). Subchronic exposure in Sprague Dawley (SD) rats (5 g·kg^-1 BW) showed no adverse effects, establishing a NOAEL ≥ 5 g·kg^-1 BW. Teratogenicity studies in pregnant rats (5 g·kg^-1 BW) confirmed normal maternal, embryonic, and fetal development without skeletal/visceral abnormalities. Collectively, ST exhibited no detectable genotoxic, acute, subchronic, or teratogenic risks under tested conditions. These findings validate the safety profile of ST for clinical and nutraceutical applications, providing critical data to support its development as a novel food resource. This systematic assessment addresses existing safety knowledge gaps and offers a scientific basis for regulatory decision-making.

The existing study was conducted to evaluate the toxic potential of Acid Red 119 (AR 119) in fish Channa punctata by assessing DNA damage, biochemical alterations and histopathological changes in liver tissue after acute exposure. Fish were subjected to two sub-lethal concentrations of AR 119, (15.90 mg/L and 31.81 mg/L), alongside a control group (water only) for 96h. Samples of liver were harvested at 24, 48, 72 and 96h after acute exposure. Compared to the control group, fish exposed to AR 119 exhibited a significant, time-dependent increase in DNA damage. Additionally, oxidative stress measured by malondialdehyde (MDA) level was markedly higher in both exposed groups. Superoxide dismutase (SOD) and glutathione-S-transferase (GST) enzymatic activities were significantly reduced following acute exposure. Histopathological examination of liver tissues revealed distinct structural anomalies (sinusoid dilation, erythrocytic infiltration, congested portal vein, vacuolization) in exposed fish. Overall, the findings indicate that AR 119 induced genotoxic effects in Channa punctata, potentially mediated by oxidative stress mechanisms.

Pharmaceutical contamination of the aquatic ecosystem has become an emerging challenge because of their impact on non-target aquatic organism. The sub lethal effect of naproxen-a non-steroid anti-inflammatory drug was studied for 28 days in a semi-static bioassay system on the African fresh water catfish (Clarias gariepinus). Acute toxicity study was carried out to determine the median lethal concentration (LC₅₀) of the pharmaceutical. After the LC₅₀, of the drug was determined, the fish was exposed to 0.0 mg/L (control) and the different sub-lethal concentrations of naproxen (3.46, 2.31 and 1.73 mg/L which are 1/10th, 1/15th, and 1/20th of the LC₅₀ of naproxen, respectively). The fish blood, brain, liver and gill were assessed to study the effects of the drug on haematological, biochemical, oxidative stress and neurotoxic parameters in the fish. The fish was exposed to the drug for 21 days followed by depuration for 7 days. The study revealed significant reduction (p < 0.05) in the activities of superoxide dismutase, catalase and total protein levels in a dose dependent manner while neutrophil counts, lipid peroxidation, acetylcholinesterase, gluthathione reductase and gluthathione peroxidase significantly increased (p < 0.05) in a dose and duration dependent manner in the groups exposed to naproxen. The liver enzymes such as alanine aminotransferase, aspartate aminotransfearase and alkaline phosphatase showed a significantly increased level in all the groups exposed to naproxen. The observations from this study revealed that naproxen is toxic to Clarias gariepinus juveniles by the evidenced negative impact on the parameters studied and should, therefore, be closely monitored in the aquatic environment.

Methanol (CH₃OH) is one of the toxic alcohols that has high morbidity and mortality. It causes lipid peroxidation and oxidative stress. Antioxidants and neuroprotective agents could have therapeutic roles in case of methanol exposure. The aim of this research was to assess the therapeutic impact of royal jelly (RJ) versus Nigella sativa oil (NS) on brain areas affected by acute methanol poisoning in rats. This research was performed on 60 adult male albino rats that were randomly assigned to four groups: the negative control group (I), the positive control group (II), the methanol-intoxicated group (III), and the methanol and adjuvant treatment treated group (IV) which were categorized into two subgroups: the methanol and RJ treated group (IV a) and the methanol and NS treated group (IV b). After two weeks, the blood samples were obtained to determine the total antioxidant capacity (TAC). The frontal cortex, cerebellum, and hippocampus were excised and subjected to histopathological and transmission electron microscopic examination. Acute methanol poisoning induced oxidative stress, indicated by a significant reduction of TAC and marked degenerative changes in nerve cells and nerve fibers. Moreover, the administration of RJ and NS six hours after induction of acute methanol poisoning showed an increase in TAC compared to group III and a non-significant reduction compared to group II, with marked improvement and restoration of the normal brain architecture. Therefore, RJ and NS are effective in reducing the oxidative stress induced by acute methanol poisoning.