Journal of Applied Toxicology最新文献

Zotepine is a second-generation antipsychotic that demonstrates significant efficacy in antagonizing D₂ and 5-HT_2A receptors. Although clinical investigations have shown that administering zotepine is associated with an increased prevalence of hyperglycemia and a heightened risk of cardiovascular disease, the side effects of zotepine on voltage-gated K⁺ (Kv) channels have not been established. Zotepine suppressed the vascular Kv channels in rabbit coronary arterial smooth muscle cells in a concentration-dependent manner, with an IC₅₀ of 5.3 ± 0.4 μM and a Hill coefficient of 1.6 ± 0.2. The decay rate of inactivation was significantly accelerated by zotepine. Applying zotepine (10 μM) shifted the steady-state inactivation curve in a negative direction. Applying train pulses at 1 and 2 Hz resulted in a progressive increase in blockage of the Kv currents by zotepine. Furthermore, zotepine prolonged the recovery time from inactivation. Although pretreatment with the Kv2.1 subtype inhibitor stromatoxin-1 and the Kv7 subtype inhibitor linopirdine did not change the degree of zotepine-induced inhibition of Kv currents, pretreatment with the Kv1.5 channel inhibitor DPO-1 decreased the inhibitory effects of zotepine on Kv currents. Zotepine also induced membrane depolarization. These results indicate that zotepine inhibits Kv currents (mainly Kv1.5 subtype) in dose-, time-, and use (state)-dependent manners by changing the steady-state inactivation curve.

Manganese (Mn) is an essential and important metal; however, overexposures lead to adverse neurological outcomes. Nonoccupational Mn overexposure occurs primarily through consumption of Mn-contaminated drinking water (DW). Sex differences in terms of nervous and immune systems' responsiveness to excessive Mn in the DW are understudied. Thus, this study investigated behavioral and sex differences in response to Mn DW treatment (0.4 g Mn/L for up to 8 weeks) and a lipopolysaccharide (LPS) challenge of adult C57BL/6 mice with GFP-tagged monocytes/microglia. After 6 weeks, in motor function tests, Mn exposure resulted in decreased activity and gait deficits. In two different mood tests (open field test [OFT]/elevated zero maze), Mn-exposed mice exhibited decreased fear/anxiety-like behavior. Two weeks after behavioral assessment, when mice were challenged with LPS, circulating inflammatory cytokines, and acute phase proteins increased in both sexes. After 8 weeks of Mn exposure, liver and brain Mn levels were increased, but Mn alone did not affect circulating cytokines in either sex. Notably, Mn-exposed/LPS-challenged males had potentiated plasma cytokine output, whereas the reverse was seen in females. Males, but not females, continued to exhibit increased fearlessness (i.e., increased OFT center time), even when challenged with LPS. Overall, our results show that Mn DW exposure increases brain Mn levels and it leads to behavioral alterations in both sexes. However, males might be more susceptible to the effect of Mn on mood, and this effect is recalcitrant to an inflammagen challenge. Mn augmented post-LPS cytokine production only in males, further indicating that important Mn effects are sex-biased.

Carbon monoxide (CO) poisoning is among the main causes of poisoning-related mortality and morbidity, primarily affecting the central nervous system and leading to delayed neurological sequelae. Idebenone exerts antioxidant and neuroprotective effects. In this study, we aimed to evaluate the specific neuroprotective effects of idebenone against CO poisoning. Forty female Wistar Albino rats were used in this study. Except the controls, the other rats inhaled 5000 ppm CO until a change in consciousness was observed. Rats with carboxyhemoglobin concentrations over 20% in blood samples collected from the tail vein were considered successful acute CO poisoning models. The rats were divided into five groups: healthy control (HC; group 1), CO + saline (CO-S; group 2), CO + 100 mg/kg idebenone (CO-I₁₀₀; group 3), CO + 200 mg/kg idebenone (CO-I₂₀₀; group 4), and CO + 300 mg/kg idebenone (CO-I₃₀₀; group 5). Pre-determined doses of idebenon were orally administered to the rats at 24-h intervals for 5 days. The rats were anesthetized and sacrificed 24 h after the last drug dose. Histopathological and biochemical parameters were examined in the blood and hippocampus samples of the rats. Histopathological grading of neurons in the hippocampus revealed that the CO-S group exhibited the highest number of grade 1, 2, and 3 degenerative cells (all p = 0.001). Apoptotic index was the highest in the CO-S group and significantly low in the idebenone-treated groups (p = 0.001). Neuron-specific enolase and malondialdehyde levels and oxidative stress index were significantly lower in both the hippocampus and serum samples of the idebenone-treated groups than in those of the CO-S group (all p values = 0.001). Overall, idebenone inhibited degeneration due to CO-induced brain damage and exerted neuroprotective effects against oxidative stress in rats.

The transgenic maize DBN9936 × DBN9501, which confers resistance to insects and tolerance to herbicides, was developed via conventional cross breeding of transgenic maize DBN9936 and DBN9501. In our present study, a 90-day feeding toxicity study was conducted on Sprague Dawley rats to evaluate the safety of the maize. A total of 140 rats were randomly assigned to seven groups (n = 10/sex/group): one control group, three genetically modified (GM) groups with 17.5%, 35%, and 70% (wt/wt) GM maize, respectively, and three non-GM groups with corresponding incorporation rate of parental maize DBN318. The rats of control group were fed with AIN93G diet. The parameters including body weights, food consumption, hematology, serum biochemistry, organ weights, and histopathology were examined during the course of the study. Compared with the non-GM group or AIN93G control group, minor statistical differences were observed for some parameters in some groups, yet none of them was considered a GM-related adverse effect. In conclusion, the results demonstrated that no adverse effect was observed on rats following 90 days feeding with diet containing up to 70% GM maize. The results indicated that stacked maize DBN9936 × DBN9501 was as safe as its parental DBN318 maize.

Ischemic heart disease remains a global health problem with high morbidity and mortality. Butorphanol, as a novel opioid, has been discovered with its cardioprotective properties. The purpose of this study was to explore that butorphanol can alleviate hypoxia/reoxygenation (H/R)-induced myocardial injury by activating the Wnt/β-catenin signal pathway. In this study, Cell Counting Kit-8 (CCK-8), lactate dehydrogenase (LDH) kit, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and Western blotting experiments were performed to observe butorphanol cardioprotective function and expression of Wnt signaling pathway proteins. For the main result, anti-apoptotic effect and higher expression of Wnt signaling pathway proteins were observed with the increasing concentrations of butorphanol. Compared with the H/R group, higher cellular viability, lower LDH release, and smaller apoptotic cell population were found in the butorphanol group. In addition, expression levels of apoptosis-related protein Bax and Cleaved Caspase-3 decreased, and increased expression of Bcl-2 were observed. Conversely, the protective effects of butorphanol were attenuated in the XAV939 group. In summary, butorphanol attenuates hypoxia/reoxygenation-induced myocardial injury by activating the Wnt/β-catenin signal pathway. Our work provides a theoretical basis for butorphanol's myocardial protective function.

In recent years, nonanimal approaches for skin sensitization have been developed in response to political, regulatory, and ethical demands. The reconstructed human epidermis (RhE)-based testing strategy (RTS)v1-defined approach (DA) is used to categorize skin sensitization potency. However, the RTSv1 DA alone cannot be used to predict potency based on EC3 values [the estimated concentration that produces a stimulation index of 3 in the local lymph node assay (LLNA)], and underpredictions have been reported. Read-across (RAx) can complement DA data and improve prediction confidence. Although case studies combining new approach methodology/DA data with RAx have been reported, they focus on a single target chemical and lack a comprehensive and robust strategy with well-examined reliability. This study developed a strategy incorporating the RTSv1 DA into RAx (RTSv1-based RAx) to predict skin sensitization potency, applying it to 43 chemicals. The predictive performance of RTSv1-based RAx was evaluated by comparing its predicted potency category and EC3 outcomes with those of RTSv1 DA and the LLNA. RTSv1-based RAx accurately predicted the Globally Harmonized System of Classification (GHS) subcategorization for 38 chemicals and determined the predicted EC3 values for 17 sensitizers within a fourfold range of LLNA-derived EC3 values. This study demonstrates that RTSv1-based RAx offers robust predictivity for both GHS subcategorization and predicted EC3 values, making it useful for quantitative risk assessment.

The chronic intake of excessive fluoride (F^-) (>  1.5 mg/L) affects several tissues, organs, and systems. This represents a worldwide issue due to the presence of the compound in nature, with drinking water being the main source of exposure. The underlying mechanisms by which F^- is toxic are not completely understood, but proinflammatory cytokine activity is implicated in these events. The aim of this study was to perform a systematic review of the health implications of proinflammatory cytokine activity at different levels of F^- exposure. The search for original studies in which the activity of proinflammatory cytokines was assessed under exposure to F^- was performed using the PubMed, Scopus, Springer, EBSCO, and Google Scholar databases by applying the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The study protocol was registered with PROSPERO (CRD42024546726). Sixteen studies were analyzed in the present review. Tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 beta (β), IL-6, IL-2, IL-12, IL-17, IL-18, C-reactive protein, and transforming growth factor-β (TGF-β) were the proinflammatory cytokines identified in the included reports. Alterations in cytokine activity were observed in response to varying levels of F^- exposure, implicating an increased risk of toxicity and damage to the evaluated structures by highlighting the role of inflammation in the progression of these processes. Hence, the activity of proinflammatory cytokines at different levels of F^- exposure has important implications for health, where inflammation plays a relevant role in the underlying mechanisms related to the resulting toxicity.

Accumulating evidences have proved Arenobufagin (ArBu) exhibited cytotoxic effects to multiple types of cancer. However, in glwioblastoma (GBM), which is easy to develop resistance to classic chemotherapy reagent, the therapeutic effects of ArBu have not been explored. In the current study, we found that GBM cells were sensitive to ArBu treatment and ArBu induced cell death both in a dose-dependent and a time-dependent manner. ArBu was observed to promote ROS accumulating and elevate Fe²⁺/MDA/GSH level, which lead to ferroptosis. Mechanistically, ArBu significantly downregulated AEBP1 expression and decreased the mRNA stability of AEBP1 without affecting its transcription. Then, AEBP1 mRNA was predicted to bind with miR-149-5p in GBM cells, which directly target its 3'UTR. At last, we found ArBu could upregulate miR-149-5p to suppress AEBP1 expression, and the rescue experiments confirmed miR-149-5p/AEBP1 axis regulated ferroptosis, which underlay the therapeutic effects of ArBu in GBM cells. This study revealed that ArBu induced ferroptosis in a dose-dependent manner via modulating miR-149-5p/AEBP1 axis. It provides evidences for clinical application of ArBu for GBM.

Parabens are widely used because of their antimicrobial properties in drugs, cosmetics, and food; however, it has been reported that methylparaben may adversely influence female reproduction. Methylparaben decreases oocyte in vitro maturation at a maturation inhibition concentration 50 of 780.31 μM but also decreases oocyte viability at a lethal concentration 50 of 2028.38 μM. Additionally, parabens are endocrine disruptors, affecting steroidogenesis as well as cumulus cell expansion. Therefore, the aim of this study was to elucidate some of the mechanisms by which methylparaben alters cumulus cell expansion and decreases oocyte maturation through the evaluation of gene expression related to cumulus cell expansion, hyaluronic acid, and progesterone synthesis. For this, oocytes were exposed to different methylparaben concentrations of 0 (control), 650, 780, and 1000 μM for 20 and 44 h of in vitro maturation. The cumulus cell expansion rates, maturation rates, gene expression rates, and hyaluronic acid and progesterone concentrations were revaluated after 20 and 44 h of culture. At sublethal concentrations, methylparaben decreased in vitro maturation as well as cumulus cell expansion at 44 h. Additionally, methylparaben decreased the expression of Has2 and Cd44 at 20 and 44 h of maturation. The expression levels of Stard1, Cyp11a1, and Hsd3b1 were also altered by methylparaben exposure at 20 and 44 h of maturation, suggesting its role as an endocrine disruptor. Hyaluronic acid and progesterone concentrations in the culture medium decreased at 20 and 44 h. These findings could partially explain some of the mechanisms by which methylparaben alters female fertility.