Di-(2-ethylhexyl) phthalate (DEHP) in the environment and food chain may impact cerebrum development and neurobehavioral in humans and wildlife. However, it is unclear that DEHP exposure caused ...cerebral toxicity. This experiment used gavage to expose female quail to 0, 250, 500, and 1000 mg/kg BW/day for 45 days to assess the potential neurotoxicity of DEHP to the cerebrum. It can be observed that there will be obvious neurological abnormalities in the experiment. Cerebrum histological lesions can be observed with HE-staining. Detecting oxidative stress indices, Nrf2 pathway, and mitochondrial dynamics factor, by analyzing the results, these results were observed that DEHP exposure can cause damage to the cerebrum by causing oxidative stress and affecting the balance of mitochondrial dynamics. Nrf2-mediated defense is not activated by exposure to 250 mg/kg DEHP. Nrf2-mediated defense is activated but is not resistant to exposure to medium and high doses of DEHP (500 mg/kg; 1000 mg/kg). DEHP triggers cerebral mitochondrial dysfunction via modulating mitochondrial dynamics.
DEHP exposure causes cerebral toxicity. DEHP causes oxidative stress in the cerebrum. DEHP regulates oxidative stress by activating the Nrf2 defense response. DEHP exposure also triggers disruption of mitochondrial dynamics leading to mitochondrial damage leading to oxidative stress. Display omitted
•DEHP induces the cerebral toxicity.•DEHP activates Nrf2-mediated antioxidant defense in the cerebrum.•DEHP induced cerebral toxicity via disrupting mitochondrial dynamics.•DEHP triggers mitochondrial dysfunction via modulating mitochondrial dynamics.
An increasing number of epidemiologic studies show that women have a special exposure profile to phthalates, and the exposures have attracted attention regarding their potential health hazards. Here, ...we developed a model for studying the ovarian action of di-(2-ethylhexyl) phthalate (DEHP) and its major metabolite monoethylhexyl phthalate (MEHP). In vivo, treatment with DEHP (250, 500, and 1000 mg kg^-1) induced decreased thickness of ovarian granulosa cell layer and mitochondrial damage in quail, caused oxidative stress, interfered with the transcription of hypothalamic-pituitary-ovarian axis (HPOA) steroid hormone-related factors (increased transcription of StAR, 3β-HSD, P450scc, and LH and decreased transcription of 17β-HSD, P450arom, FSH, and ERβ), and blocked the secretion of steroid hormones (decreased FSH, E2, and T levels and increased LH, P, and PRL levels). In vitro, granulosa cells were cultured with MEHP (50, 100, and 200 μM), activator of PPARγ (rosiglitazone, 50 μM), or antagonist of PPARγ (GW9662, 10 μM) for 24 h and gene and protein expression were analyzed by real time RT-PCR and western blot. Rosiglitazone, like MEHP, significantly decreased mRNA and protein levels of P450arom. Antagonist GW9662 partially blocked the suppression of P450arom by MEHP, suggesting that MEHP acts through PPARγ, but not exclusively. Our model shows that MEHP acts on granulosa cells in quail by stimulating PPARs, which leads to decreased gene and protein expression of P450arom. Therefore, the environmental endocrine disruptor DEHP and its major metabolite MEHP act through a receptor-mediated signaling pathway to inhibit the production of estradiol, interfere with the modulation of HPOA, suppress the synthesis of sex hormones, and cause sex hormone secretion disorders, resulting in severe toxicity in the female reproductive system. A framework for an adverse outcome pathway of DEHP/MEHP-induced ovarian toxicity was constructed, which can facilitate an improved understanding of the mechanism of female reproductive toxicity.
The environmental contaminant DEHP and its metabolite MEHP act through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, interfere with the regulation of the hypothalamus-pituitary-ovarian gonadal axis, hinder the synthesis of sex hormones, and trigger sex hormone secretion disorders, leading to serious dose-dependent toxicity of the reproductive system. A framework for an adverse outcome pathway of DEHP/MEHP-induced ovarian toxicity was constructed, which can facilitate an improved understanding of the mechanism of female reproductive toxicity. Display omitted
•Exposure to DEHP induced ovarian developmental disorders in quail.•DEHP disrupted sex hormone levels by interfering with the regulation of HPOA.•MEHP decreased aromatase level in the granulosa cell by activating the PPARs.•DEHP and its metabolite MEHP lead to toxicity on the reproductive system.•A framework for an AOP of DEHP/MEHP-induced ovarian toxicity was constructed.
Perfect matching of an assembled physical sequence to a specified designed sequence is crucial to verify design principles in genome synthesis. We designed and de novo synthesized 536,024-base pair ...chromosome synV in the "Build-A-Genome China" course. We corrected an initial isolate of synV to perfectly match the designed sequence using integrative cotransformation and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated editing in 22 steps; synV strains exhibit high fitness under a variety of culture conditions, compared with that of wild-type V strains. A ring synV derivative was constructed, which is fully functional in
under all conditions tested and exhibits lower spore viability during meiosis. Ring synV chromosome can extends Sc2.0 design principles and provides a model with which to study genomic rearrangement, ring chromosome evolution, and human ring chromosome disorders.
In this study, a dual-tuned mode of liquid crystal (LC) material was proposed and adopted on reconfigurable metamaterial antennas to expand the fixed-frequency beam-steering range. The novel ...dual-tuned mode of the LC is composed of double LC layers combined with composite right/left-handed (CRLH) transmission line theory. Through a multi-separated metal layer, the double LC layers can be loaded with controllable bias voltage independently. Therefore, the LC material exhibits four extreme states, among which the permittivity of LC can be varied linearly. On the strength of the dual-tuned mode of LC, a CRLH unit cell is elaborately designed on three-layer substrates with balanced dispersion values under arbitrary LC state. Then five CRLH unit cells are cascaded to form an electronically controlled beam-steering CRLH metamaterial antenna on a downlink Ku satellite communication band with dual-tuned characteristics. The simulated results demonstrate that the metamaterial antenna features' continuous electronic beam-steering capacity from broadside to -35° at 14.4 GHz. Furthermore, the beam-steering properties are implemented in a broad frequency band from 13.8 GHz to 17 GHz, with good impedance matching. The proposed dual-tuned mode can make the regulation of LC material more flexible and enlarge the beam-steering range simultaneously.
Among ubiquitously found environmental contaminants in the ecosystem, di(2-ethylhexyl) phthalate (DEHP) is an important environmental contaminant used as plasticizer in medical and consumer goods. ...The bioaccumulation and environmental persistence of DEHP cause serious global health effects in wildlife animals and human, especially hepatotoxicity. Herein, to explore the mechanisms of DEHP induced hepatotoxicity, quail were exposed with 0, 250, 500 and 1000 mg/kg BW/day DEHP by gavage administration daily for 45 days. Notably, the adipose tissue degeneration was observed in the liver of DEHP-exposed quail under the histopathological analysis. DEHP exposure increased the peroxidation product (MDA), GSH and GST, but decreased antioxidant function (T-AOC, SOD and GPX). DEHP induced the oxidative stress and pulsed on NRF2 signal pathway through activating downstream genes. Furthermore, DEHP induced mitochondrial ultrastructural abnormalities and mitochondrial dysfunctions. Mitochondrial unfolded protein response (mtUPR) was activated to relieve mitochondrial dysfunctions and mitigated oxidative stress. These findings showed that mitochondrial functions and redox homeostasis were affected by DEHP and resulted in irreversible hepatic injury. In Conclusion, this study suggested that DEHP-induced hepatotoxicity in quail was associated with activating the NRF2 mediated antioxidant defense and mtUPR. These results provided new evidence on molecular mechanism of DEHP induced hepatotoxicity.
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•DEHP causes hepatotoxicity through oxidative stress.•DEHP causes mitochondrial ultrastructural abnormality and dysfunctions.•DEHP triggers the Nrf2-mediated antioxidant defense.•MtUPR relieves DEHP-induced mitochondrial damage.
Atrazine (ATR) is a most used herbicide which is believed as a pivotal determinant of environmental nephrosis, but potential mechanism is still largely unclear. This study intends to reveal a novel ...mechanism of ATR-induced nephrotoxicity. Quail were treated with 0, 50, 250 and 500 mg ATR/kg/d by oral gavage for 45 days. Kidney coefficient was decreased, biochemical and morphologic indices reflecting the kidney injury were significantly increased in ATR-exposed quail. ATR exposure upregulated the expression of proapoptotic factors (Bax, Caspase 3 and FasL) and downregulated antiapoptotic factor (Bcl-2). Notably, cristae of mitochondria decreased, mitochondrial malformation and mitochondrial vacuolar degeneration were observed in ATR-exposed quail. ATR induced the disorder of mitochondrial function related factors expressions and promoted oxidative damage. Furthermore, ATR induced toxicities in the expression of Nrf2 and Nrf2-target genes. In conclusion, ATR altered the microstructure and function of quail kidney. ATR induced renal damage via causing mitochondrial dysfunction, influencing mitochondrial function related genes expression, modulating Nrf2 signaling pathway. This study suggested ATR induced the nephrotoxicity via disturbing the transcription of mitochondrial function related factors and Nrf2 signaling pathway.
Graphical abstract illustrating the proposed mechanism by ATR-induced nephrotoxicity in quail. Nrf2 signaling pathway was blocked by ATR in kidney of quail. Mitochondria in quail kidney were the target organelles of ATR induced nephrotoxicity. ATR damaged mitochondrial function and morphology. It is deduced that ATR-induced nephrotoxicity is associated with mitochondrial dysfunction and interruption of Nrf2 signaling pathway. Display omitted
•ATR decreased kidney coefficient, impaired histology and function of kidney.•ATR disturbed mitochondrial structure and function related genes expression.•ATR exposure stimulated apoptosis and oxidative stress.•ATR induced variation of Nrf2 signaling pathway and antioxidant response.
Cadmium (Cd) is widespread globally in the environment as a toxic metal. Although it is well known to induce hepatotoxicity in the cells, defense mechanisms against the detrimental effects of Cd are ...still unknown. We examined the role of autophagy (a cellular defense mechanism) on Cd-induced cytotoxicity in bird hepatocytes. Primary chicken hepatocytes were cultured with different concentrations (0, 1, 2.5, 5, and 10 μM) of cadmium chloride (CdCl2) for 12 h. We assessed the effects of CdCl2 on the cell viability, antioxidant status, reactive oxygen species (ROS) generation, autophagy response and endoplasmic reticulum (ER) stress. Further, it is also evaluated that insight into underling molecular mechanisms involved in the study. In this study, CdCl2-induce hepatotoxicity was caused by drastically increased ROS generation as well as a reduction level of antioxidant enzymes. It was also demonstrated that marked activation of ER stress markers (GRP78, IRE1, PERK, ATF4, ATF6 and XBP-1 s) was observed. Simultaneously, increased activation of autophagy in low-dose CdCl2 (1 μM) exposed group was observed, but high-dose CdCl2 (10 μM) inhibited autophagy and significantly promoted apoptosis, as indicated by the expression of the autophagy related genes for P62, Beclin-1, ATG3, ATG5, ATG9, and the detection of autophagic vacuoles. Pretreatment with autophagy agonist Rapamycin (RAP) has successfully reduced ROS production, attenuated ER stress and enhanced hepatocytes viability, while the autophagy inhibitor 3-Methyladenine (3-MA) had the opposite effect. Hence, these findings stipulate that Cd could inhibit viability of hepatocytes in a dose-dependent manner. Autophagy relieves hepatotoxicity of Cd via reducing ROS generation and regulating ER stress. We identified autophagy as a novel protective mechanism involved in Cd-mediated chicken hepatotoxicity.
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•Cadmium indued autophagy and apoptosis in chicken hepatocytes.•Redox homeostasis disruption and ER stress was involved toxicity of Cadmium.•Autophagy relieves hepatotoxicity of Cadmium by relieving oxidative stress and ER stress.
Emerging evidence suggests that epithelial‐mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is ...crucial for improving treatment of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play important roles in HCC; however, the mechanisms by which miRNAs target the EMT and their therapeutic potential remains largely unknown. To better explore the roles of miRNAs in the EMT process, we established an EMT model in HCC cells by transforming growth factor beta 1 treatment and found that several tumor‐related miRNAs were significantly decreased. Among these miRNAs, miR‐125b expression was most strongly suppressed. We also found down‐regulation of miR‐125b in most HCC cells and clinical specimens, which correlated with cellular differentiation in HCC patients. We then demonstrated that miR‐125b overexpression attenuated EMT phenotype in HCC cancer cells, whereas knockdown of miR‐125b promoted the EMT phenotype in vitro and in vivo. Moreover, we found that miR‐125b attenuated EMT‐associated traits, including chemoresistance, migration, and stemness in HCC cells, and negatively correlated with EMT and cancer stem cell (CSC) marker expressions in HCC specimens. miR‐125b overexpression could inhibit CSC generation and decrease tumor incidence in the mouse xenograft model. Mechanistically, our data revealed that miR‐125b suppressed EMT and EMT‐associated traits of HCC cells by targeting small mothers against decapentaplegic (SMAD)2 and 4. Most important, the therapeutic delivery of synthetic miR‐125b mimics decreased the target molecule of CSC and inhibited metastasis in the mice model. These findings suggest a potential therapeutic treatment of miR‐125b for liver cancer. Conclusion: miR‐125b exerts inhibitory effects on EMT and EMT‐associated traits in HCC by SMAD2 and 4. Ectopic expression of miR‐125b provides a promising strategy to treat HCC. (Hepatology 2015;62:801–815)
Selenium (Se), a highly beneficial animal feed additive, exhibits remarkable antioxidant and anti-inflammatory properties. Nano‑selenium (Nano-Se) is an advanced formulation of Se featuring a ...specialized drug delivery vehicle, with good bioavailability, higher efficacy, and lower toxicity compared to the traditional form of Se. With the advancement of industry, cadmium (Cd) contamination occurs in different countries and regions and thereby contaminating different food crops, and the degree of pollution is degree increasing year by year. The present investigation entailed the oral administration of CdCl2 and/or Nano-Se to male chickens of the Hy-Line Variety White breed, which are one day old, subsequent to a 7-day adaptive feeding period, for a duration of 90 days. The study aimed to elucidate the potential protective impact of Nano-Se on Cd exposure. The study found that Nano-Se demonstrates potential in mitigating the blood-brain barrier (BBB) dysfunction characterized by impairment of adherens junctions (AJS) and tight junctions (TJS) by inhibiting reactive oxygen species (ROS) overproduction. In addition, the data uncovered that Nano-Se demonstrates a proficient ability in alleviating BBB impairment and inflammatory reactions caused by Cd through the modulation of the Wnt7A/β-catenin pathway, highlights its potential to maintain brain homeostasis. Hence, this research anticipates that the utilization of Nano-Se effectively mitigate the detrimental impacts associated with Cd exposure on the BBB.
Nano-Se shows superior antioxidant effects with lower toxicity, and higher absorption and bioavailability. This research endeavors to explicate the mechanism through which Nano-Se mitigates Cd from entering the cerebrum and causing damage. Nano-Se reduces ROS production and ameliorates BBB dysfunction. In addition, it discovered that Nano-Se effectively mitigates damage caused by Cd-induced BBB injury and inflammatory response by regulating the Wnt7A/β-catenin pathway, which highlights its potential to maintain cerebral homeostasis. Display omitted
•Nano-Se alleviates the damage of BBB caused by Cd.•Nano-Se ameliorates Cd-induced AJs and TJs damage.•Nano-Se reduces ROS generation induced by Cd.•Nano-Se can modify Wnt7A/FZD4/β-catenin pathway.
Di (2-ethylhexyl) phthalate (DEHP) is a hazardous compound used as a plasticizer in plastic products. As a natural carotenoid, lycopene (LYC) is considered an effective protective agent against ...various types of organ damage. The present study aimed to investigate the role of mitochondria-endoplasmic reticulum (ER) coupling in LYC preventing DEHP-induced hepatotoxicity. The mice were treated with LYC (5 mg kg
) and/or DEHP (500 or 1000 mg kg
). In the present study, LYC prevented DEHP-induced histopathological changes including fibrosis and glycogen storage in the liver. Additionally, LYC alleviated DEHP-induced ultrastructural injury of mitochondria and ER. LYC had the underlying preventability against DEHP-induced mitochondrial dynamics imbalance including an increase in fission and a decrease in fusion. Furthermore, DEHP induced mitochondria-associated endoplasmic reticulum membrane (MAM) disorder-induced ER stress through the ER unfolded protein response (UPR
), but LYC alleviated these alterations. Therefore, LYC prevented DEHP-induced hepatic mitochondrial dynamics and MAM disorder, leading to ER stress. The present study provides novel evidence of mitochondria-ER coupling as a target for LYC that prevents DEHP-induced hepatotoxicity.