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A multi-omics approach reveals molecular mechanisms by which phthalates induce cardiac defects in zebrafish (Danio rerio)
2020
Mu, Xiyan | Chen, Xiaofeng | Liu, Jia | Yuan, Lilai | Wang, Donghui | Qian, Le | Qian, Yu | Shen, Gongming | Huang, Ying | Li, Xuxing | Li, Yingren | Lin, Xiangming
The potential risks of phthalates affecting human and animal health as well as the environment are emerging as serious concerns worldwide. However, the mechanism by which phthalates induce developmental effects is under debate. Herein, we found that embryonic exposure of zebrafish to di-(2-ethylhexyl) phthalate (DEHP) and di-butyl phthalate (DBP) increased the rate of heart defects including abnormal heart rate and pericardial edema. Changes in the transcriptional profile demonstrated that genes involved in the development of the heart, such as tbx5b, nppa, ctnt, my17, cmlc1, were significantly altered by DEHP and DBP at 50 μg/L, which agreed with the abnormal cardiac outcomes. Methylated DNA immunoprecipitation sequencing (MeDIP-Seq) further showed that significant hypomethylation of nppa and ctnt was identified after DEHP and DBP exposure, which was consistent with the up-regulation of these genes. Notably, hypermethylation on the promoter region (<1 kb) of tbx5b was found after DEHP and DBP exposure, which might be responsible for its decrease in transcription. In conclusion, phthalates have the potential to induce cardiac birth defects, which might be associated with the transcriptional regulation of the involved developmental factors such as tbx5b. These findings would contribute to understand the molecular pathways that mediated the cardiac defects caused by phthalates.
Mostrar más [+] Menos [-]Exposure to diclofop-methyl induces cardiac developmental toxicity in zebrafish embryos
2020
Cao, Zigang | Huang, Yong | Xiao, Juhua | Cao, Hao | Peng, Yuyang | Chen, Zhiyong | Liu, Fasheng | Wang, Honglei | Liao, Xinjun | Lu, Huiqiang
Diclofop-methyl (DM) is one of the most widely used herbicides in agriculture production and has been frequently detected in both freshwater and environments, even agricultural products. However, the potential toxic effects of DM on organisms and the underlying mechanisms are still poorly understood. In this study, we utilized zebrafish to evaluate the toxicity of DM during the cardiovascular developmental process. Exposure of zebrafish embryos to 0.75, 1.0 and 1.25 mg/L DM induced cardiac defects, such as pericardial edema, slow heart rate and long SV-BA distance but the vascular development in zebrafish larvae was not influenced by DM treatment. The expression of cardiac-related genes were disordered and DM exposure initiated disordering cardiogenesis from the period of precardiac mesoderm formation. Moreover, the apoptosis and proliferation of cardiomyocytes were not influenced but the levels of oxidative stress were upregulated by DM exposure. Fullerenes and astaxanthin was able to rescue cardiac defects caused by DM via downregulating oxidative stress. Wnt signaling was downregulated after DM treatment and activation of Wnt signaling could rescue cardiac defects. Therefore, our results suggest that DM has the potential to induce cardiac developmental toxicity through upregulation of Wnt-Mediated (reactive oxygen species) ROS generation in zebrafish larvae.
Mostrar más [+] Menos [-]Microcystin-LR exposure decreased the fetal weight of mice by disturbance of placental development and ROS-mediated endoplasmic reticulum stress in the placenta
2020
Zhao, Sujuan | Zhong, Shengzheng | Wang, Fang | Wang, Honghui | Xu, Dexiang | Li, Guangyu
The placenta is essential for sustaining the growth of the fetus. The aim of this study was to investigate the role of the placenta in MCLR-induced significant reduction in fetal weight, especially the changes in placental structure and function. Pregnant mice were intraperitoneally injected with MCLR (5 or 20 μg/kg) from gestational day (GD) 13 to GD17. The results showed MCLR reduced fetal weight and placenta weight. The histological specimens of the placentas were taken for light and electron microscopy studies. The internal space of blood vessels decreased obviously in the placental labyrinth layer of mice treated with MCLR. After the ultrastructural examination, the edema and intracytoplasmic vacuolization, dilation of the endoplasmic reticulum and corrugation of the nucleus were observed. In addition, maternal MCLR exposure caused a reduction of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) expression in placentae, a critical regulator of fetal development. Several genes of placental growth factors, such as Vegfα and Pgf and several genes of nutrient transport pumps, such as Glut1 and Pcft were depressed in placentas of MCLR-treated mice, however nutrient transporters Fatp1 and Snat4 were promoted. Moreover, significant increases in malondialdehyde (MDA) revealed the occurrence of oxidative stress caused by MCLR, which was also verified by remarkable decrease in the glutathione levels, total antioxidant capacity (T-AOC) as well as the activity of antioxidant enzymes. Real-time PCR and western blot analysis revealed that GRP78, CHOP, XBP-1, peIF2α and pIRE1 were remarkable increased in placentas of MCLR-treated mice, indicating that endoplasmic reticulum (ER) stress pathway was activated by MCLR. Furthermore, oxidative stress and ER stress consequently triggered apoptosis which contributed to the impairment of placental development. Collectively, these results suggest maternal MCLR exposure results in reduced fetal body weight, which might be associated with ROS-mediated endoplasmic reticulum stress and impairment in placental structure and function.
Mostrar más [+] Menos [-]Bisphenol-A induced antioxidants imbalance and cytokines alteration leading to immune suppression during larval development of Labeo rohita
2020
Faheem, Mehwish | Adeel, Muhammad | Khaliq, Saba | Lone, Khalid P. | El-Din-H-Sayed, Alaa
Recently, the oxidative stress and immunotoxicity biomarkers have been extensively used in embryotoxicity using fish embryos as promising models especially after exposure to chemical-like environmental estrogens. Bisphenol-A (BPA) is an estrogenic endocrine disruptor and is ubiquitous in the aquatic environment. Larvae of Labeo rohita were exposed to low concentrations of BPA (10, 100, 1000 μg/l) for 21 days. Innate immune system, antioxidants parameters, and developmental alterations were used as biomarkers. Exposure to BPA caused developmental abnormalities including un-inflated swim bladder, delayed yolk sac absorption, spinal curvature, and edema of pericardium. Lipid peroxidation increased and activity of catalase (p < 0.05), superoxide dismutase (p < 0.05), and glutathione peroxidase (p < 0.01) decreased after exposure to BPA. Level of reduced glutathione also decreased (p < 0.05) in BPA-exposed group. Lower expression of tumor necrosis factor-α (p < 0.05) and interferon-γ (p < 0.001) was observed in BPA-exposed groups while expression of interleukin-10 increased (p < 0.05) in larvae exposed to 10 μg/l BPA. Moreover, exposure of BPA caused a concentration-dependent increase in expression of heat shock protein 70 (p < 0.05). The present study showed that the exposure to BPA in early life stages of Labeo rohita caused oxidative stress and suppress NF-κB signaling pathway leading to immunosuppression. The results presented here demonstrate the cross talk between heat shock protein 70 and cytokines expression.
Mostrar más [+] Menos [-]Pro-inflammatory or anti-inflammatory effects of pulsed magnetic field treatments in rats with experimental acute inflammation
2020
Mert, Tufan | Yaman, Selma
In this study, we evaluated the possible effects of sequenced pulsed magnetic fields (PMF) of 1-mT treatments with designed different frequencies (PMF-1—1, 3, 5, 7 Hz or PMF-2—7, 9, 12, 14 Hz) on the inflammatory signs such as abnormal pain behaviors, hyperalgesia and allodynia, edema, and fever in carrageenan (CG)-induced hind paw inflammation model in rats. Paw tissues were also histologically examined. PMF exposure was applied 3 times in 24 h. CG injection gradually decreased the thermal latencies and mechanical threshold and caused significant increases in temperature and mass of paw. PMF treatments significantly reduced the temperature and mass in the paw of rats with inflammation. PMF-1 treatments caused significant increases in the latencies and thresholds. However, administration of PMF-2 treatment was significantly decreased the latency and threshold. Furthermore, the histological pieces of evidence also suggested the anti-inflammatory effects of PMF-1 treatments or inflammatory actions of PMF-2 treatments. Findings presented in this paper suggest that 1-mT PMF treatments may have anti-edematous and antipyretics activities in inflamed rats. However, the effects of PMF treatments on abnormal pain hypersensitivities may be different. PMF treatments may make inflammatory pain relief or worse in inflamed rats depending on the PMF frequencies in sequence.
Mostrar más [+] Menos [-]What is the possible therapeutic effect of Ginkgo biloba on gastric ulcer induced by ammonia in albino rats?
2020
El-Medany, Azza | Guemei, Aida Ahmed Said | Abdel Twab, Raeesa | Al-Matrafi, Tahani | El-Medany, Jamila
Gastric ulcer is a worldwide disease. Helicobacter pylori is one of the most common chronic bacterial infections that induce chronic inflammation in the gastric mucosa, mediated by an array of pro-and inflammatory cytokines. The aim of this study was to investigate the possible therapeutic effects of Ginkgo biloba extract on gastric ulcer induced by ammonium hydroxide in rats and the potential underlying mechanisms. The study was done on 32 adult male Wistar albino rats, divided equally into 4 groups: normal control, gastric ulcer–induced group using 1 ml of 1% NH₄OH orally, ulcer control group; rats received 1% carboxymethyl cellulose daily for 14 days after induction of ulcer and treated rats received orally 200 mg/kg Ginkgo biloba once daily for 14 days after induction of ulcer. The study revealed administration of ammonia showed multiple gastric lesions; edema, hyperemia, hemorrhage, and ulcers with a significant increase in ulcer score, myeloperoxidase (MPO), and interleukin-1β (IL-1β) and a significant decrease in reduced glutathione (GSH), mucus amount, and gastric pH. After the administration of Ginkgo biloba, there was an improvement in gastric lesions, with a significant reduction of ulcer score, MPO, and IL-1β and a significant increase in GSH, mucus content, and gastric pH. Moreover, collagen types I and IV were gradually increased in the treated group.
Mostrar más [+] Menos [-]Multiorgan histopathological changes in the juvenile seabream Sparus aurata as a biomarker for zinc oxide particles toxicity
2020
Beegam, Asfina | Lopes, Maria | Fernandes, Tiago | Jose, Jiya | Barreto, Angela | Oliveira, Miguel | Soares, Amadeu M. V. M. | Trindade, Tito | Thomas, Sabu | Pereira, Maria L.
Zinc oxide nanoparticles are widely used in some domains (cosmetics, pharmaceuticals optical devices, and agricultural field) due to their physical, optical, and antimicrobial properties. However, the release of ZnO-NPs into the environment may affect organisms like fish with potential consequences for human health. Histological approaches of the acute effects of these materials on fish are scarce; thus, the present study aimed to investigate the potential toxic effects of acute exposure to ZnO particles in marine environments, by assessing histological changes in the gills, liver, spleen, and muscle of gilthead seabream (Sparus aurata) juveniles. Thus, fish were exposed for 96 h, via water, to 1 mg L⁻¹ of ionic zinc and zinc oxide particles (1.1, 1.2, and 1.4 μm of size). Histological examination revealed gills as the most affected organ, followed by liver, muscle, and spleen. In the gills, histopathological changes included hyperplasia of epithelial cells, fusion of the secondary lamellae, and lifting of the lamellar epithelium with edema. In the liver, lipid vacuolation of several degrees, necrosis of hepatic and pancreatic tissues, blood congestion in sinusoids and hepatoportal vessels, presence of cellular infiltrate, and melano-macrophages diffusion was found. Muscle showed degeneration, atrophy, thickening and necrosis of muscle fibers with edema between them, and presence of melano-macrophages in the muscle layer. Spleen was the less damaged organ, displaying congested blood, white pulp increase/rupture, and bigger and darker melano-macrophage aggregates in the splenic stroma. These results underline that the size of particles plays a determinant role in their potential pernicious effects. A short-term exposure caused major histopathological changes in relevant organs of S. aurata juveniles, possibly affecting their function.
Mostrar más [+] Menos [-]2,4-Dichlorophenoxyacetic acid herbicide effects on zebrafish larvae: development, neurotransmission and behavior as sensitive endpoints
2020
Gaaied, Sonia | Oliveira, Miguel | Domingues, Inês | Banni, Mohamed
Assessment of pesticides toxicity using zebrafish early life stages is relevant for aquatic systems safety. This study aimed to evaluate the short-term effects of 2,4-dichlorophenoxyacetic acid (2,4-D) on zebrafish (Danio rerio) embryos from 3 h post fertilization to 96 hpf. A set of 2,4-D concentrations ranging from 0.32 to 80 mg/L were tested and median lethal concentration (LC₅₀) at 96-h was calculated as 2.86 mg/L. A sub-teratogenic concentrations range from 0.02 to 0.8 mg/L was then used to assess effects at ontogenic, biochemical, and behavioral levels. The main developmental defects were tail deformities and pericardial edema at concentrations equal or above 0.32 mg/L. Cholinesterase activity (at 96 hpf) and larvae swimming behavior (at 120 hpf) were affected even at the lowest tested dose (0.02 mg/L). The behavior analysis was a sensitive endpoint, with a decrease in the swimming distance of exposed larvae during light period. The effect of 2,4-D in ChE was translated by an inhibition of the enzyme activity in all treated groups. These findings demonstrate that 2,4-D can alter the cholinergic system by affecting ChE activity which may be involved in the locomotion reduction of exposed larvae and emphasize the potential of neurotransmission and behavioral endpoints as early warning signs of herbicides contamination in aquatic ecosystems.
Mostrar más [+] Menos [-]Toxic effects of a mancozeb-containing commercial formulation at environmental relevant concentrations on zebrafish embryonic development
2020
Vieira, Raquel | Venâncio, Carlos A. S. | Félix, Luís M.
The toxicological knowledge of mancozeb (MZ)-containing commercial formulations on non-target species is scarce and limited. Therefore, the objective of this work was to represent a realistic application scenario by evaluating the toxicity of environmental relevant and higher concentrations of a commercial formulation of MZ using zebrafish embryos. Following determination of the 96-h LC₅₀ value, the embryos at the blastula stage (~ 2 h post-fertilisation, hpf) were exposed to 0.5, 5, and 50 μg L⁻¹ of the active ingredient (~ 40× lower than the 96-h LC₅₀). During the exposure period (96 h), lethal, sublethal, and teratogenic parameters, as well as behaviour analysis, at 120 hpf, were assayed. Biochemical parameters such as oxidative stress–linked enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR)), reactive oxygen species (ROS) levels, and glutathione levels (GSH and GSSG), as well as the activity of degradation (glutathione S-transferase (GST) and carboxylesterase (CarE)), neurotransmission (acetylcholinesterase (AChE)), and anaerobic respiration (lactate dehydrogenase (LDH))–related enzymes, were analysed at the end of the exposure period. Exposed embryos showed a marked decrease in the hatching rate and many malformations (cardiac and yolk sac oedema and spinal torsions), with a higher prevalence at the highest concentration. A dose-dependent decreased locomotor activity and a response to an aversive stimulus, as well as a light-dark transition decline, were observed at environmental relevant concentrations. Furthermore, the activities of SOD and GR increased while the activity of GST, AChE, and MDA contents decreased. Taken together, the involvement of mancozeb metabolites and the generation of ROS are suggested as responsible for the developmental phenotypes. While further studies are needed to fully support the hypothesis presented, the potential cumulative effects of mancozeb-containing formulations and its metabolites could represent an environmental risk which should not be disregarded.
Mostrar más [+] Menos [-]Protective effect of aged garlic extracts against hepatotoxicity induced by ethephon in Wistar albino rat
2020
Al-Brakati, Ashraf
The current study was designed to demonstrate the hepatoprotective effect of aged garlic extract (AGE) against ethephon-induced liver toxicity in rats. Sixty male Wistar albino rats were divided into four groups as follows: the control group; AGE group was administered with 250 mg/kg; the ethephon group was orally given 200 mg/kg; and AGE + ethephon group was treated with ethephon for 4 weeks and then given AGE for another 4 weeks using the same dosage. The ethephon administration impaired the balance between oxidants and antioxidants as evidenced by the increased level of malondialdehyde (MDA) and the decreased concentration of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Biochemical findings showed a significant decrease in the red blood corpuscles (RBCs) count, hemoglobin (Hb) content, and hematocrit (HCT) level, with a significant increase in the white blood cells count. In addition, ethephon produced a significant decrease in levels of aspartate transaminase (AST) and alanine transaminase (ALT) with a decrease in albumin level. Furthermore, histological investigation showed dilation of the hepatic central vein and dilation of blood sinusoids which were congested with inflammatory cellular infiltrate. Moreover, examination of the liver using transmission electron microscopy showed a disturbance in the nuclear membranes and degenerating mitochondria with a rise in the cytoplasmic vacuoles by cellular edema. Interestingly, AGE administration was found to attenuate the histological deformations and biochemical alteration produced by ethephon. These findings suggest that AGE supplementation could be used to reverse the hepatic injury following ethephon exposure through its antioxidant capacity.
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