Toxicology Research最新文献

Radiation esophagitis (RE) and Radiation-induced lung injury (RILI) are the main side effects of radiotherapy for esophageal squamous cell cancer (ESCC), which seriously affect the quality of life and therapeutic effect of patients. Then, how to reduce the incidence of RE and RILI is an important topic. We try to establish RE and RILI's prediction scheme based on the gene expression patterns in tumor tissues from patients with ESCC. A total of 37 patients who pathological preliminary diagnosed as ESCC and received radical radiotherapy from 2016 January 1 to 2019 December 31 were enrolled in this study. Use 3-plex qPCR to detect gene expression in ESCC. Our results showed that gene expressions in the Mitogen-activated protein (MAP) kinase signaling (HRAS, MAP2K1, MAPK1, CRAF and KRAS) were positively related to Severe RE (SRE), while Fibroblast growth factor (FGF) signaling showed a negative correlation. We established a c-Index calculation model to predict SRE. Receiver operating characteristic curve were applied to determine the prognostic value of the risk model. Besides, patients with SRE seem to be more easily to develop higher-level of RILI. Taken together, we constructed a novel radiotherapy response-related gene signature, which may be developed into a powerful tool for forecasting the risk of SRE in ESCC radiotherapy patients.

With the widespread application of electromagnetic technology, electromagnetic fields (EMFs) emitted from various electric and electronic devices have significantly altered the electromagnetic environment. This has raised concerns about the potential health impacts of EMFs. Previous studies have indicated that EMFs may influence male infertility, with oxidative stress proposed as a key factor; however, the underlying mechanisms remain unclear. In this study, we aimed to determine whether EMFs enhance the impact of oxidative stress on male infertility. We investigated the effects of 50 Hz magnetic fields (MFs) on the sensitivity of mouse spermatogenic cell lines (GC-1 spg and GC-2 spd) to low-dose hydrogen peroxide (H₂O₂, 5 and 10 μM). Our findings revealed that pre-exposure to 2.0 mT 50 Hz MFs for 24 h increased the sensitivity of GC-2 spd cells to low-dose H₂O₂ in terms of γH2AX foci formation, a marker for DNA damage repair. However, no significant changes were observed in DNA fragmentation, cell viability, or cell cycle progression in either GC-1 spg or GC-2 spd cells. In conclusion, our results suggest that 50 Hz MFs do not significantly enhance the sensitivity of mouse spermatogenic cell lines to low-dose H₂O₂.

Spinal cord injury (SCI)-induced ischemic delayed paralysis is one of the most serious side effects of aneurysms surgeries. Recent studies prove that the activation of autophagy, including macroautophagy and micro-autophagy pathways, occur during SCI-induced brain neuron damage. However, the role of chaperone mediated autophagy (CMA) during SCI remains to be unveiled. In the present work, rat model of delayed paralysis after aneurysms operation and adenovrius induced LAMP2A knockdown in microglia cells were applied in the present work to investigate the involvement of LAMP2A-mediated CMA in the aneurysm operation related SCI and delayed paralysis. The results showed that LAMP2A was upregulated in the SCI procedure, and contributed to neuron death and pro-inflammation perturbation via inducing iNOS⁺ polarization in microgila. We additionally observed that knockdown of LAMP2A resulted in the shift of microglia from iNOS⁺ to ARG1⁺ phenotype, as well as alleviated neuron damage during SCI. Furthermore, the analysis of BBB score, the result of immunohistological staining, and protein detection confirmed the activation of LAMP2A-mediated CMA activation and its interaction with NF-κB signaling, which leads to neuron death and motor function loss. These results prove that LAMP2A-mediated CMA contributes to the upregulation of pro-inflammatory cytokines and results in cell death in neurons during ischemic delayed paralysis via activating NF-κB signaling. Inhibition of LAMP2A promotes neurons survival during ischemic delayed paralysis.

This study aims to elucidate the molecular mechanism mechanism by which FTO affects fibroblast proliferation and collagen deposition in keloids. Human keloid fibroblasts (KFs) and normal fibroblasts were cultured in vitro. FTO expression was silenced in KFs, and cell viability and proliferation were evaluated via CCK-8 and clone formation assays. FTO, KLF4, and MC1R expressions were quantified via qRT-PCR, while the protein levels of FTO, KLF4, MC1R, Collagen I, and Collagen III were determined by Western blot. The m⁶A RNA methylation status of total RNA was evaluated using the EpiQuik m6A RNA Methylation Quantification Kit. Post-actinomycin D treatment, the stability of KLF4 mRNA and its m⁶A modification level were measured. ChIP and dual-luciferase reporter assays confirmed the binding between KLF4 and MC1R promoter. KFs presented with significantly enhanced proliferation and collagen deposition, correlating with elevated FTO expression. Silence of FTO repressed the proliferation and collagen deposition of KFs, and elevated the m6A levels of total RNA and KLF4 mRNA in KFs, resulting in enhanced KLF4 mRNA stability and expression. KLF4 bound to the MC1R promoter and promoted MC1R expression. In conclusion, FTO represses KLF4 expression by removing m6A modification and further diminishes MC1R expression, thereby facilitating KF proliferation and collagen deposition.

The current study examined the potential therapeutic advantages of catechin, either alone or in combination with docetaxel (DTX), against PC-3 prostate cancer cells. Following the MTT assay's determination of the IC₅₀ concentrations, the cell lines were subjected to 48 h of treatment in the following protocol: untreated PC-3 control cells, docetaxel treatment, catechin (Cat) treatment, and DTX + Cat therapy at a ratio of 1:1. Treatments with DTX and Cat significantly decreased the number of viable cells in PC-3 cells in a dose-dependent manner. Additionally, the combo treatments caused the highest cytotoxicity compared with the other treatments. Also, when DTX and Cat were combined, they caused a significant synergistic effect (CI < 1) (combination index < 1). Furthermore, it was demonstrated that all treatments increased the expression of BAX, Caspase-3, and P21 mRNA in PC-3 cells while decreasing that of BCL-2 mRNA. The highest proportion of overexpression was observed in the combo therapy. A greater proportion of early and late apoptotic cells were caused by the combined treatment than by > DTX > Cat, according to flow cytometry. DNA damage in PC-3 cells was detected using the comet assay, and values of DNA tail, tail length, and tail moment increased considerably with increasing treatment dose. According to this study, Cat is effective against PC-3 cells when used in conjunction with DTX; by causing apoptosis, it enhances DTX's chemotherapeutic capability in cancerous cells.

With the development of science and technology and the acceleration of industrialization, environmental pollution is becoming more and more serious, and the global fertility rate is decreasing every year, which makes people pay more attention to reproductive health. Nitrosamines are a kind of easy to contact food pollutants, widely exist in pickled food (10.2-14.8 mg/kg) and contaminated water sources (10-150 ng/L), etc. They have been confirmed to be carcinogenic, but the reproductive and developmental toxic effects of nitrosamines have not been systematically reported. Based on relevant researches, the classification, distribution and metabolism kinetics of nitrosamines were summarized in this review. In addition, nitrosamines can inhibit testosterone synthesis (Leydig cells) and spermatogenesis (spermatogenic cells) in F0 male, and reduce ovary functions in F0 female, finally induce parental reproductive toxic effects. Meanwhile, the effects of parental (including maternal pregnancy, paternal) nitrosamine exposure on offspring development (such as cancer susceptibility) and related research deficiencies were summarized. To sum up, this paper systematically reviewed the reproductive and developmental toxic effects caused by exposure to nitrosamines, enabling people to fully understand the negative effects of nitrosamines on the body, so as to effectively avoid and reduce intake in daily life, and at the same time provide a theoretical and literature basis for guiding the healthy life and maintaining fertility.

Fine particulate matter (PM_2.5) exposure is significantly linked to lung epithelial cell senescence, and autophagy dysfunction being a key contributor to the aging process. Although the anti-aging properties of ellagic acid (EA) are well-documented, its specific protective effect on PM_2.5-induced lung epithelial cell senescence still needs to be studied in depth. To investigate the impacts of PM_2.5 on autophagy and senescence in lung epithelial cells, 16HBE and A549 cells were exposed to PM_2.5 suspension. Additionally, to explore the potential intervention effect of EA, cells were pretreated with EA before exposure to PM_2.5 suspension. Cell morphology, proliferation, senescence-related markers, senescence-associated secretory phenotype (SASP), and autophagy-related markers were then assessed. Our results showed that the proliferation of 16HBE and A549 cells were inhibited and autophagy dysfunction and senescence were induced under PM_2.5 exposure. However, pretreatment with EA can significantly improve the obstruction of autophagy flux caused by PM_2.5, thereby effectively alleviating cell senescence. This study reveals the mechanism by which PM_2.5 induces senescence in lung epithelial cells and confirms the protective role of ellagic acid in this process.

This opinion article questions the underlying causes of malformations observed in early developmental stages of zebrafish exposed to a range of chemicals. The research focuses on determining whether these developmental abnormalities arise due to the inherent sensitivity of zebrafish to chemical exposure or if they are related to the ubiquitous expression of certain genes within the zebrafish genome. By analysing different studies on zebrafish embryos to various chemical agents and analysing the resulting malformations, the study aims to differentiate between the effects of chemical sensitivity and the role of gene expression in developmental disruptions. Findings from this investigation will contribute to a deeper understanding of the mechanisms driving developmental toxicity in zebrafish, with implications for broader environmental and genetic research.

Benzo(a)pyrene (B(a)P), a polycyclic aromatic hydrocarbon (PAH), is a known endocrine disruptor linked to various environmentally induced diseases. While recent studies have explored its role in short- and long-term disease development, there is limited research on B(a)P's cytotoxic effects across different cell types. This study aims to evaluate the cytotoxicity of B(a)P exposure in several human cell lines under controlled conditions. We employed flow cytometry (FACS) for quantitative cytotoxicity analysis at the single-cell level. Our findings revealed that B(a)P exhibited minimal cytotoxicity in lung and liver cells, but potent toxicity in breast cells. Notably, B(a)P-induced cytotoxicity in breast cells was associated with increased cleaved caspase-3 expression, leading to cell death. This process was further linked to cell cycle arrest, as indicated by altered cyclin B1 expression in a B(a)P-dependent manner, resulting in reduced cell viability. In summary, these results suggest that breast cells are particularly sensitive to B(a)P-induced cytotoxicity, which is driven by apoptosis and cell cycle disruption.

The hippocampus executes the integration of memory and spatial learning information. This study evaluated the effect of rice bran extract (RBE) on heavy metal mixture (MM) induced hippocampal toxicity and its underlying mechanism in albino rats. Thirty five rats were exposed to MM alone at Pb 20 mg/kg, Al 35 mg/kg, and Mn 0.564 mg/kg body weight or co-exposed with RBE at 125, 250 and 500 mg/kg body weight, 125 RBE mg/kg b.wt only, and 500 RBE mg/kg b.wt only 5 days a wk for 13 wk (90 days). Subsequently, oxidative stress, inflammation (cyclooxygenase-2) and caspase-3, amyloid precursor proteins (Aβ40 and Aβ42), HMOX-1, occludin and BDNF and transcription factor Nrf-2 in the hippocampus were investigated. MM treatment resulted in significantly higher escape latency time than both the control and MM plus RBE group. MM exposure induced increased oxidative stress, inflammation resulting in enhanced hippocampal apoptosis. MM significantly increased bioaccumulation of Pb, Al, and Pb; increased caspase-3, Nrf-2, Aβ40 and Aβ42 and significantly decreased occludin, BDNF, HMOX-1 when compared with the control. All these effects were reversed by RBE. Collectively, RBE ameliorated MM - induced oxidative stress, neuro-inflammation and hippocampal apoptosis via attenuation of oxidative damages of cellular constituents, neuronal inflammation and subsequent down regulation of amyloid precursor proteins Aβ40, Aβ42 and up regulation of occludin, BDNF, HMOX-1 protein expression via Nrf-2 dependent pathways to abrogate hippocampal toxicity associated with spatial learning and memory deficits.