Toxicology最新文献

Hexafluoropropylene oxide dimer acid (HFPO-DA), which belongs to the class of perfluoroalkyl ether carboxylic acid (PFECA), is a new alternative to perfluorooctanoic acid (PFOA). However, whether HFPO-DA is a safer alternative to PFOA in neonates remains unclear. In this study, we evaluated neonatal hepatic toxicity on postnatal days 9-10 by orally exposing pregnant CD-1 mice to 0.3 or 3.0 mg/kg/day (low or high doses) of HFPO-DA or PFOA from gestation days 15-17. The results showed that exposure of pregnant mice to HFPO-DA and PFOA induced similar phenotypic effects, including significant decreases in neonatal body weight (BW) and significant increases in liver weight relative to BW in the high-dose. Notably, HFPO-DA exposure significantly decreased in neonatal BW in the low-dose group, whereas PFOA did not. Comprehensive gene expression analysis revealed significant alterations in 408 and 1402 differentially expressed genes (DEGs) in the liver of neonates from the low- and high-dose HFPO-DA groups, respectively, while PFOA significantly altered 0 and 292 DEGs in the corresponding groups. Gene set enrichment analysis indicated that the DEGs induced by HFPO-DA and PFOA were enriched in pathway related to "PPAR signaling", "fatty acid metabolism", and "biological oxidations". In addition, transactivation assays revealed that mouse (m)PPARα and mPPARγ activity of HFPO-DA exceeds that of PFOA and molecular docking simulations analysis predicted that the binding conformation differ between PFOA and HFPO-DA. Overall, our findings demonstrate that HFPO-DA consistently affected neonatal phenotypes, liver gene expression and the molecular initiating events involving PPARα/γ, at lower concentrations than PFOA.

Although it has been confirmed that acid-sensing ion channel 1 (ASIC1) plays a critical role in acidosis-induced neuronal injury and death, its underlying mechanisms remain largely unclear. In the present study, we investigated the involvement of ASIC1 in acidosis-induced neuronal death and its underlying mechanisms in HT22 neurons. The neurons were cultured in acidic medium to mimic extracellular acidosis. Cell viability and death, autophagy, ASIC1 expression, and the phosphorylation of Akt and mTOR were evaluated. Our results demonstrated that acidosis markedly increased the cell death rate, which was profoundly reversed by 3-MA (an autophagy inhibitor) but exacerbated by rapamycin (an autophagy activator). Moreover, our results indicated that acidosis induced excessive autophagy by increasing the expression and translocation of ASIC1, and decreasing the phosphorylation of the Akt and mTOR proteins. Intriguingly, inhibiting the activation of ASIC1 with its blocker PcTx-1 not only significantly decreased acidosis-induced neurotoxicity but also markedly compromised acidosis-induced autophagy and Akt/mTOR signaling inactivation, as evidenced by a decrease in the neuronal death rate, LC3Ⅱ/LC3Ⅰ ratio, and autophagosome number as well as p62 degradation and an increase in the phosphorylation of Akt and mTOR. Collectively, these results indicate that acidosis exerts its cytotoxic effects on HT22 neurons by inducing autophagic cell death through the ASIC1-related Akt/mTOR signaling pathway.

Radon (²²²Rn) is a naturally occurring radioactive gas, ionizing radiation emitted by the radon induces oxidative stress and the up-regulation of inflammatory proteins, which may cause lung damage or cancer. However, the underlying pathogenesis remains to be determined. Effector T helper cells are key in mediating the host's protection and immune homeostasis. In this study we revealed that, accompanied by the activation of effector T helper cells, there is a significant increase in C-C motif chemokine ligand 5 (Ccl5) in the lung of mice after cumulative inhalation of radon at 3, 9, 21, 45, 90, and 180 working level months (WLM). In vitro experiments showed that Ccl5 attracts DC migration and promotes the activation of effector T helper cells in the Ccl5-DC and T cells co-culture model. Of particular interest, Ccl5 neutralization in vivo inhibited the migration of DC cells and the subsequent activation of effector T helper cells, which finally protected mice from radon-induced lung damage and inflammatory response. Ultimately, transcriptome sequencing and western blot analysis showed that Ccl5 activates the CCR5/PI3K/AKT/Nr4a1 pathway to increase the secretion of IL-12 and IFN-γ by DC cells, which then promotes the activation of effector T helper cells. Overall, these results indicate that Ccl5 significantly contributes to the progression of radon-induced lung damage by modulating DC to activate effector T helper cells.

In the present study, co-parental exposure to polystyrene nanoplastics (PS-NPs) elicits profound teratological impacts, including skeletal and visceral malformations, post-natal effects on neonatal growth and neurobehavioral development in F1 progeny. A comprehensive investigation was conducted on Swiss albino mice fetuses, neonates (PND 1-21) and adult mice offsprings (PND 60) following parental exposure during spermatogenesis and oogenesis period, as well as continued maternal exposure during gestation and weaning. The parental mice were administered PS-NPs via oral gavage at low dose (0.2mg/kg/day) and high dose (1mg/kg/day). Both male and female parental mice were exposed to PS-NPs for 60 days and 14 days, respectively before mating. After the mating, the pregnant female mice continued to receive PS-NPs treatment during the gestation, till the subsequent weaning period. Our findings revealed that PS-NPs led to significant reductions in growth, and heightened skeletal and visceral anomalies in developing fetuses. Exposure further impaired reflexes in neonatal mice such as grasping, surface righting and negative geotaxis. Moreover, the adult progeny also exhibited learning impairments. Neurodevelopmental assessment unveiled alterations in neurotransmitter levels, antioxidant enzyme activities, and structural changes in key limbic areas such as the cortex, hippocampus, and hypothalamus of adult mice offspring. These alterations included increased vacuolization, vascular dilation, and reduced pyramidal neurons in the hippocampus. Thus, this transgenerational study underscores the detrimental effects of PS-NPs on both prenatal and postnatal development, emphasizing teratological and enduring neurological consequences in the limbic regions of F1 progeny mice brains.

Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor, is suspected of disturbing brain development through largely unknown cellular and molecular mechanisms. In the central nervous system, oligodendrocytes are responsible for forming myelin sheaths, which enhance the propagation of action potentials along axons. Disruption of axon myelination can have lifelong consequences, making oligodendrocyte differentiation and myelination critical stages of brain development. In the present study, mice were exposed to BPA during gestation and lactation through drinking water at concentrations of 25 and 250μg.L^-1. These doses, corresponding to estimated exposures of 4μg.kg^-1.d^-1 and 40μg.kg^-1.d^-1, respectively, led to disturbances in lipid remodeling associated with myelination in the offspring. Importantly, changes in myelin lipid composition were selectively observed in female mice and were transient, being visible only at post-natal day P15 but not at later stages (P30 and P60). In females exposed to BPA, myelin exhibited a lower proportion of phosphatidylcholines and higher proportions of other glycerophospholipid subclasses, thus resembling more mature myelin. Conversely, male myelin was not affected, likely due to its already more mature lipid composition. Additionally, transcriptomic analysis of female oligodendrocytes at P15 did not reveal any transcriptional changes in genes related to lipid metabolism, further suggesting post-transcriptional effects of BPA via chaperone-mediated protein folding and RNA splicing. In males, the altered genes were mainly associated with synaptic transmission. Finally, alterations in chromatin accessibility were also largely sex dependent and did not correlate with transcription, with the exception of the Cwc22. At this locus, BPA exposure increased chromatin accessibility in half of mice of both sexes, leading to an "unchanged/open" bimodal profile correlated with "unchanged/upregulated" gene expression. Together, these results open new insights into the sex-dependent mechanisms of BPA's effects on brain development.

Apoptosis of alveolar macrophages (AMs) induced by silica is one of the crucial driving factors of silicosis inflammation and fibrosis. However, the mechanism of silica-induced AMs apoptosis remains unclear. In this study, transcriptome sequencing identified 11 differentially expressed (DE)-mRNAs enriched in the regulation of apoptotic signaling pathways in AMs treated with 250 μg/mL silica for 24 h, of which tripartite motif-containing 32 (Trim32) was the most significant and down-regulated. The decreased Trim32 promoted AMs apoptosis, while Trim32 overexpression inhibited the apoptosis of AMs induced by silica at 250 μg/mL for 24 h. MiR-6236-p5 was then identified by MiRNA sequencing as the most significant DE-miRNA potentially regulating Trim32 expression, and the interaction between miR-6236-p5 and Trim32 3'-UTR was confirmed by dual luciferase reporter gene assay. Treated with 100 nM miR-6236-p5 inhibitor increased the expression of Trim32 and inhibited the apoptosis of AMs induced by silica at 250 μg/mL for 24 h, while miR-6236-p5 mimic promoted the apoptosis of silica-induced AMs. In conclusion, this study identified Trim32 regulated by miR-6236-p5 played an important role in silica-induced AMs apoptosis based on RNA sequencing, which provided a novel clue for exploring the mechanism of silica-induced AMs apoptosis.

Bisphenol A (BPA) is an organic synthetic chemical used worldwide. Billions of pounds of BPA are produced annually through industrial processes to be used in commercial products, making human exposure to BPA ubiquitous. Concerns have been raised due to the potential adverse health effects of BPA, specifically in vulnerable populations, such as pregnant persons and children. BPA is an endocrine-disrupting chemical, and through this function has been linked to reproductive toxicity. We review BPA's historical and current use, health and safety concerns and regulations, sources of exposure, and evidence for male and female reproductive toxicity. Evidence from epidemiological and animal studies idenfity that low- and high-exposure levels of BPA (prenatal, postnatal and adulthood exposure) can adversely affect male and female fertility and reproductive organs. While the cause of BPA-induced reproductive toxicity is not fully understood, we discuss BPA's estrogenic and androgenic activity, and its ability to disrupt the hypothalamic-pituitary-gonadal axis as a potential associated mechanism. There are significant differences in tolerable daily intakes of BPA set by global agencies, making interpretation of previous and emerging research findings challenging and inconsistent. Although BPA is deemed toxic by some government agencies, most do not currently consider it a health risk due to low populational exposure levels. However, we highlight evidence that even at acute, low exposure, BPA can adversely affect reproductive function. We recommend continuing research into the adverse effects of BPA on human health and revisiting the regulatory measures of BPA to limit exposure and promote public awareness of its potential to cause reproductive toxicity.

Polycyclic aromatic hydrocarbons (PAHs) have been regarded as important environmental carcinogens that can cause lung cancer. However, the underlying epigenetic mechanism during PAHs-induced lung carcinogenesis has remained largely unknown. Previously, we screened some novel epigenetic regulatory genes during 3-methylcholanthrene (3-MCA)-induced lung carcinogenesis, including the potassium inwardly rectifying channel subfamily J member 15 (KCNJ15) gene. This study aimed to investigate the expression regulation, function, and mechanism of KCNJ15 through database analysis, malignant transformed cell model, and xenograft tumor models. We found that KCNJ15 was remarkably under-expressed during lung carcinogenesis and progression. Elevated levels of DNA methylation were associated with a gradual decrease of KCNJ15 expression in 3-MCA-induced malignantly transformed HBE cells. High expression of KCNJ15 was strongly correlated with good survival prognosis in lung cancer patients. KCNJ15 overexpression significantly inhibited the growth, invasion, and migration of lung cancer cells both in vitro and in vivo. Conversely, knockdown of KCNJ15 resulted in an opposite phenotype. Moreover, KCNJ15 inhibited the Hippo pathway by activating YAP phosphorylation and inhibiting YAP expression. Mechanistically, there was a significant protein-protein interaction between KCNJ15 and the G protein subunit beta 1 (GNB1). GNB1 overexpression partially restored the inhibition of Hippo pathway regulated by KCNJ15. In summary, our data demonstrated that KCNJ15, as a novel epigenetic silencing tumor suppressor, regulates cell growth, invasion, and migration by binding to GNB1 protein mediating the Hippo-YAP signaling pathway during chemical-induced lung carcinogenesis and progression. It provides novel insights into epigenetic regulation mechanism during carcinogenesis induced by environmental pollutants.

Mycotoxin occurrence in food worldwide is estimated to increase due to climate change. Moreover, studies on how these food contaminants interfere with medications and especially anticancer therapies are rare. With the rise of anticancer immunotherapies, particularly mycotoxins with immunomodulatory activity, such as alternariol (AOH) or deoxynivalenol (DON), are of great concern. Both mycotoxins interfere with the pro-inflammatory nuclear factor kappa B (NF-κB) pathway in myeloid cells. This pathway not only plays an important role in the anticancer immune response but also inflammatory side effects induced by chemotherapeutic drugs. Consequently, the aim of this study was to investigate possible beneficial or detrimental immunomodulatory interactions between these mycotoxins and anticancer drugs. To assess the combined influence of mycotoxins and anticancer therapies on immune cell stimulation, THP-1 NF-κB reporter cells were utilized as monocytes as well as differentiated and polarized macrophages. Parameters for activation (NF-κB activity and protein expression), differentiation (CD14 and CD71 surface marker expression) and polarization (interleukin 10 (IL10), interleukin 8 (CXCL8), tumor necrosis factor α (TNF), prostaglandin-endoperoxide synthase 2 expression and CXCL8 secretion) were assessed upon combinatory treatment. Both mycotoxins affected the immunostimulatory effects of the pre-selected anticancer drugs oxaliplatin and triapine, although in opposing directions. While AOH generally suppressed a drug-induced activation and increased anti-inflammatory IL10 levels, DON potentiated activation and pro-inflammatory markers, such as CXCL8 and TNF in immune cells. In conclusion, AOH and DON have the potential to alter the immunological effects of anticancer therapies, which should be considered during therapy as well as in their future risk assessment.