Journal of Applied Toxicology最新文献

The extensive industrial use of lead (Pb) and chromium (Cr) has led to their persistent release into aquatic ecosystems, posing severe ecological and toxicological challenges. While the individual toxicities of these metals are well-documented, their combined effects, particularly on toxicity mechanisms and cellular stress responses, remain inadequately understood. This study investigated the hepatotoxic effects of Pb and Cr, both individually and in combination, in zebrafish (Danio rerio), focusing on oxidative stress and the Nrf2-Keap1-ARE signaling pathway. Zebrafish were exposed to environmentally relevant concentrations of Pb (2.5, 5, and 10 ppb), Cr (0.5, 1, and 2 ppm), and their combination for 15, 30, and 60 days. Combined exposure elicited heightened oxidative stress, marked by elevated reactive oxygen species, lipid peroxidation, catalase activity, and a significant reduction in glutathione levels. Histopathological analysis revealed severe alterations, including vacuolation, sinusoidal dilation, and necrosis, with the most pronounced effects observed in the combined exposure groups. Gene expression analysis demonstrated the upregulation of oxidative stress-related genes (nrf2, ho1, nqo1, gpx1, catalase, gst, cu/znsod, mnsod, and cyp1a) and heat shock protein (hsp70) and the downregulation of keap1, and ucp2, particularly in co-treated groups. Immunofluorescence observation confirmed enhanced nuclear translocation of Nrf2, while atomic absorption spectrophotometry studies revealed significant bioaccumulation of Pb and Cr in the liver, especially during combined exposures. These findings underscore that Pb and Cr co-exposure intensifies oxidative stress and hepatotoxicity via the Nrf2-Keap1-ARE pathway, emphasizing the environmental and health risks associated with heavy metal contamination in aquatic ecosystems.

Retinal toxicity is of great concern during drug development due to the irreversibility. Circulating microRNA (miRNA) is reported to be useful for detecting retinal toxicity in rats, although there has been no assessment of the diagnostic performance with statistical analysis. Therefore, we comparatively analyzed the diagnostic performance of circulating miRNAs enriched in the retina such as rno-miR-124-3p, -183-5p, -96-5p, -182, -9a-5p, -125b-5p, -204-5p and -211-5p. The toxicants used in this study resulted in three types of retinal injury in photoreceptor (PR) cells, neuroretinal (NR) cells and retinal pigment epithelium (RPE) cells in rats. The performance of these biomarkers of retinal toxicity were assessed by receiver operator characteristic (ROC) analysis, then cut-off values indicating the histopathological retinal lesions and performance indexes such as area under the ROC curve (ROC-AUC), sensitivity and specificity were calculated. The ROC-AUC for PR cell toxicity in relation to rno-miR-183-5p and -182 were 0.970 and 0.873, respectively, and for NR cell toxicity in relation to rno-miR-124-3p it was 0.896. Our results suggest that plasma rno-miR-124-3p and -183-5p/-182 would be suitable for detecting NR cell toxicity and PR cell toxicity, respectively. In conclusion, these plasma miRNAs may be an effective screening tool to detect drug-induced retinal toxicity in preclinical toxicology studies.

Detailed studies on the embryotoxic and teratogenic effects of synthetic cannabinoids known to be abused are very limited. The present study aimed to evalutate the possible embryotoxic, teratogenic, behavioral, and molecular effects of 4F-MDMB-BUTICA, a new generation synthetic cannabinoid, using zebrafish embryos. The zebrafish embryos were exposed to the cannabinoid at 0.15, 0.30, 0.60, 1.20, 2.40, and 4.80 mg/L from 3 to 24 hpf (acute) and 3 to 120 hpf (subacute). No developmental abnormalities and mortality were observed in embryos after acute exposure. Subacute 4F-MDMB-BUTICA exposure induced mortality of the embryos with the 120 hpf LC₅₀ and EC₅₀ of 1.932 and 0.960 mg/L, respectively. 4F-MDMB-BUTICA also caused embryonic deformities, including spine formation, pericardial edema, impaired blood flow, yolk sac edema, and delayed development. Additionally, subacute cannabinoid exposure induced hypoactivity in response to the stimulus in 120-hpf larvae. qPCR analyses were performed on a subset of 19 genes associated with specific adverse outcomes. The cannabinoid exposure altered the transcriptional expression levels of apoptosis (casp3a, casp8, ifng1, and tp53) DNA repair (rad51), dopamine (dat, drd1, and drd3), serotonin (5ht1aa, 5ht1a, 5ht1b, and 5ht2c), γ-aminobutyric acid (gabra1, gat1, abat, and gad1b), and behavior (gnrh3, gnrhr3, and kiss2)-related genes. In conclusion, the subacute exposure to 4F-MDMB-BUTICA induces mortality, developmental toxicity, hypoactivity of larval behavior, and changes in some essential genes in zebrafish. These findings suggest that 4F-MDMB-BUTICA may have similar embryotoxic effects in humans.

Despite the high frequency of pregnancies complicated by abnormal glucose metabolism associated with obesity, methylmercury (MeHg) metabolism in pregnant women with abnormal glucose metabolism is unclear. We aimed to elucidate the MeHg tissue distribution in obese female mice with abnormal glucose metabolism and their fetuses. Female C57BL/6J mice were fed a high-fat diet (HFD) or a standard diet (Ctrl) for 12 weeks and mated. HFD mice showed mild glucose metabolism abnormalities as assessed by an oral glucose tolerance test. Maternal tissues (brain, liver, and kidney) and blood (plasma and blood cells) and fetal tissues (brain, liver, kidney, and placenta) were collected from these mice 24 h after oral administration of MeHg (a single dose of 1 or 5 mg Hg/kg) on Day 16 of mating. The total mercury level was determined in each sample, and its distribution to each tissue was estimated using K_p values (total mercury in each tissue/total mercury in maternal plasma). The K_p values for the maternal brain and liver were lower in HFD mice than in Ctrl mice, but no significant difference between groups was observed in the kidney or blood cells. The K_p values for all fetal tissues were lower in HFD mice than in Ctrl mice. Pregnant mice showed higher K_p values for the brain and lower K_p values for the kidney than those in nonpregnant mice, regardless of diet. These results will provide useful information to assess the risk of MeHg in obese mothers with glucose metabolism abnormalities and their fetuses.

As a group I carcinogen, environmental exposures to formaldehyde (FA) have been associated with various types of malignancies. However, exact mechanisms of FA-triggered carcinogenesis are still not clear. Lactylation is recently identified as a post-translational modification driven by overproduced lactic acid (LA) that regulates protein activities in different cellular processes. Our previous studies clearly demonstrated that environmentally relevant levels of FA could elevate LA in tumor cells. Poly (ADP-ribose) polymerase 1 (PARP1) is a major player in DNA repair and tumor cell survival, which has been shown to be activated by lactylation. In order to examine if PARP1 lactylation is promoted by FA environmental exposure, subcutaneous tumor models were established using BALB/c nude mice, which were exposed to 2.0 mg/m³ FA for 14 days. FA significantly elevated LA concentrations (p = 0.011) in the tumor tissues, which was confirmed in A549 cells treated with 100 μM FA in vitro. Both activity and lactylation of PARP1 were found to be induced by FA, which also enhanced DNA repair and tumor-promotive functions in vitro. Inhibition of LA production through lactate dehydrogenase A (LDHA) knockout reduced FA-potentiated PARP1 lactylation and activity. Collectively, these results revealed for the first time that FA promoted tumor cell growth through enhanced PARP1 lactylation, which could be the underlying mechanism of FA-related carcinogenesis.

Polystyrene microplastics (PS-MPs) are an emerging environmental pollutant posing significant risks to aquatic organisms. This study investigates the hepatic biotransformation responses and histopathological changes in the liver tissues of Anabas testudineus exposed to environmentally relevant concentrations of PS-MPs (13.6 and 23.6 mg L^-1) over durations of 1, 7, 15, 30, and 60 days, followed by a 60-day depuration phase. The study assessed the activities of key phase I and phase II detoxification enzymes in cytosolic and microsomal fractions, including ethoxyresorufin-O-deethylase (EROD), pentoxyresorufin O-dealkylase (PROD), flavin-containing monooxygenase (FMO), NADPH-cytochrome P450 reductase (CPR), sulfotransferase (SULT), UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST), alongside mRNA expression analysis of Cyp1a1 and Ugt. Results indicated significant induction of phase I enzymes, particularly EROD, and a subsequent alterations in phase II enzyme activities, reflecting an adaptive detoxification response. Histopathological examination revealed persistent lesions, necrosis, vacuolization, and melanomacrophage aggregation, even after the depuration period, indicating liver tissue damage. The findings highlight the adverse effects of A. testudineus to MP exposure and suggest potential risks to other aquatic organisms, emphasizing the importance of mitigating plastic pollution in aquatic environments.

As a light rare earth element, Sm and Sm₂O₃ are widely used in various fields such as electronics, chemistry, and medicine. Their distribution in the environment, accumulation in biological organisms and exposure through medicinal pathways have attracted increasing public attention. It is crucial to clarify the impact of Sm₂O₃ on human health. In this study, we applied Sm₂O₃ to 24 h post-fertilization (hpf) zebrafish embryos and investigated the toxic effects and mechanisms of Sm₂O₃. The results showed that Sm₂O₃ induced developmental abnormalities in zebrafish embryos, such as prominent pericardial swelling, slight curvature of the spine, and decreased body length. The incidence of abnormalities in zebrafish significantly increased. The scanning electron microscopy and transmission electron microscopy results showed that Sm₂O₃ accumulated in the zebrafish induced the shortening or disappearance of microcrest in zebrafish skin cells. The Lyz-fish system results demonstrated that macrophages migrated to the skin, suggesting that Sm₂O₃ caused damage. Laser confocal microscopy revealed that the heart ventricles of zebrafish embryos exhibited compensatory swelling, ventricular atrophy, and abnormal heart rates. Acridine orange (AO) staining showed obvious green fluorescence. Embryos proteins at 96 hpf were extracted after Sm₂O₃ treatment, revealing that the anti-apoptosis bcl-2 protein decreased with an increase in the Sm₂O₃ concentration. The caspase-3 apoptosis executioner protein also showed concentration-dependent expression, indicating that Sm₂O₃ promotes apoptosis in cardiac tissue cells. DCFH-DA staining showed significant reactive oxygen species (ROS) accumulation in the hearts and brains in zebrafish. In summary, Sm₂O₃ caused ROS accumulation and activated apoptotic pathways in zebrafish embryos, thereby inducing developmental abnormalities and exhibiting biological toxicity. This study demonstrated that 3-day exposure of 24 hpf zebrafish embryos to Sm₂O₃ resulted in pericardial edema, body length reduction, macrophage migration, and shortened micro-ridges of skin cells. Notably, cardiac anomalies included ventricular swelling, atrophy, and arrhythmia, which correlated with elevated ROS levels and apoptotic signals. Mechanistically, Sm₂O₃ promoted apoptosis through downregulation of Bcl-2 and upregulation of caspase-3 expression. These findings collectively reveal that Sm₂O₃ induces developmental toxicity via ROS accumulation and activation of caspase-dependent apoptotic pathways, highlighting its potential biological hazards in early vertebrate development.

Nitrogen and sulfur mustards, often acting as vesicants, have significant consequences for public health. Skin is a common site for exposure to these vesicants that can result in considerable morbidity and mortality. Given that the treatment options are limited, new insights into the mechanisms for the toxicity of these vesicants that can be translated into preventative/therapeutic strategies are desperately needed. Importantly, like most antineoplastic agents, including chemotherapy, the cytotoxic activity of vesicants such as nitrogen mustard (i.e., mustargen/mechlorethamine) and sulfur mustard is primarily mediated via their ability to act as alkylating agents. The current review highlights the underlying mechanisms, effects as well as approaches to mitigate sulfur and nitrogen mustard-induced effects, and their potential to be explored as therapeutic agents. Insights into the mediating roles and impacts of mustard agents could lead to future research and interventions that raise public health awareness to circumvent their adverse events and exploit desirable effects against proliferative diseases such as cancer.

Hexavalent chromium (Cr (VI)) poses a major health risk due to its high solubility and cell permeability, often exceeding permitted drinking water limits globally. Research has highlighted a strong correlation between Cr (VI) exposure through drinking water and increased cancer rates, particularly in near chrome industries. Our previous research demonstrated that chronic low-dose Cr (VI) exposure (2, 5 and 10 ppm) via drinking water stimulated hepatotoxicity in Swiss albino mice. In this study, we investigated the effects of the same doses over 4 and 8 months on the brain and kidney tissues of Swiss albino mice. It was found that oxidative stress markers, including catalase activity, malondialdehyde (MDA) and reduced glutathione (GSH) levels, were significantly elevated in both the tissues post-treatment. Prolonged exposure to Cr (VI) led to DNA fragmentation and a reduced organo-somatic index in the affected tissues. Additionally, histoarchitectural alterations were observed in the brain and kidney. Apoptotic gene expression was significantly upregulated after 8 months of exposure, confirmed by immunohistochemical studies indicating apoptosis. DNA repair genes (Rad51, Mutyh, Ogg1, and Mlh1) and genes coding enzymes regulating epigenetics (Sirt1, Dnmt1, Kdm1a, and Ezh2) showed significantly varied expression patterns compared to control. Methylation-specific PCR revealed DNA hypermethylation as a factor in the transcriptional reduction of specific DNA repair genes in these tissues. This study denotes that long-term low-dose Cr (VI) exposure not only surges oxidative stress and changes histoarchitecture and gene expression but also results in epigenetic modifications via DNA hypermethylation, impacting organs like the brain and kidney.

In the environment, nanoplastics (NPs) have been shown to adversely impact reproductive health, yet research on their effects during early pregnancy is scarce. This study investigated the impact of NPs on endometrial decidualization in early pregnant mice and fertility. Female mice were administered polystyrene nanoplastics (PS-NPs) orally for 90 days before pregnancy. Our findings indicated that PS-NPs exposure decreased the live birth rate and neonatal crown-rump length. Decreased embryo implantation sites and uterine wet weight were observed post PS-NPs exposure. Histological examination revealed structural defects in the uteri of early pregnant mice and a significant reduction in follicular count across all stages in the PS-NPs-treated groups. Serum levels of estradiol (E₂) and progesterone (P) were elevated, while follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were diminished post-exposure. Additionally, PS-NPs exposure upregulated the expression of the endometrial decidualization marker HOXA10 in uterine decidua. In conclusion, our results suggest that exposure to PS-NPs may disrupt endometrial decidualization during early pregnancy. This disruption is likely due to the perturbation of hormonal balance within the hypothalamic-pituitary-ovary including FSH, LH, E₂, and P levels. These hormonal alterations may arrest follicular development, consequently leading to detrimental pregnancy outcomes and compromised neonatal birth conditions. Our study provided a new perspective on understanding the possible effects of microplastics on female fertility.