Molecular Genetics & Genomic Medicine
·
2023
·Vol. 11
·期 5
·e2150
·
IF 2
Fang Wang,Haiqin Cheng,Qin Zhang,Jin Guo
Background Rare mutations in multiple genes have been associated with human neural tube defects (NTDs), but their causative roles in NTDs disease are poorly understood. Insufficiency of the ribosomal biogenesis gene treacle ribosome biogenesis factor 1( Tcof1 ) results in cranial NTDs and craniofacial malformations in mice. Here, we aimed to identify genetic association of TCOF1 with human NTDs. Methods High-throughput sequencing targeted on TCOF1 was performed on samples from 355 human cases affected by NTDs and 225 controls from a Han Chinese population. Results Four novel missense variants were found in the NTD cohort. Cell-based assays indicated that the p.(A491G) variant carried by an individual, who shows anencephaly and single-nostril abnormality, attenuates production of total proteins, suggesting a loss-of-function mutation in ribosomal biogenesis. Importantly, this variant promotes nucleolar disruption and stabilizes p53 protein, highlighting an unbalancing effect on cell apoptosis. Conclusions This study explored the functional impact of a missense variant in TCOF1 , implicating a set of novel causative biological factors involved in the pathogenicity of human NTDs, particularly whom combined with craniofacial abnormality.
研究领域:
遗传学
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分子生物学
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神经发育障碍
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Qinyuan Shen,Weitao Hu,Fasheng Liu,Si Dong,Xinya Peng,Yihang Zhong,Chao Chen,Yuhua Zuo,Chenkai Ge,Weirong Li,Wenwen Zha,Zhijun Ye,Zigang Cao,Lan Liao
Dipropyl phthalate (DPRP), a plasticizer commonly utilized in the plastics industry, has been identified in food and the environment and has the potential to present a hazard to human health and the environment. In this study, the first comprehensive evaluation of DPRP-induced craniofacial chondrogenic defects was conducted using a zebrafish model. Zebrafish embryos were exposed to 1, 2, and 4 mg/L DPRP from 6 to 96 h post-fertilization. At 80 hpf, it was observed that exposure to DPRP resulted in craniofacial developmental malformations, which were mainly characterized by the shortening of the mandibular pharyngeal arches and the inability of the accompanying artery to elongate forward. The resulting phenotype was similar to that of micrognathia syndrome. Transcriptome sequencing and molecular docking analyses revealed that DPRP down-regulated chondrocyte-related genes and induced activation of the FoxO signaling pathway, which in turn interfered with cell proliferation and apoptosis. In this process, DPRP induced elevated levels of oxidative stress in the craniofacial pharyngeal arch while promoting inflammatory responses. This ultimately led to craniofacial chondrogenic malformations in zebrafish. The present study demonstrates that DPRP induces developmental toxicity of zebrafish craniofacial cartilage, which may have adverse effects on other aquatic organisms and humans.
研究领域:
环境毒理学
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发育生物学
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DOI
PubMed
高影响因子
PLANT DISEASE
·
2023
·
IF 4.5
Miss Chunlan Zhang,Miss Odeshnee Naicker,Miss Bo Zhang,Mr. Zhengwen Jin,Miss Shujing Li,Mr. Liu Miao,Mr. Samantha C. Karunarathna
Agaricus bisporus (Lange) Imbach is the most widely cultivated mushroom in the world. Agaricus bisporus wet bubble disease is one of the most severe diseases of white button mushrooms and is caused by the fungal pathogen Hypomyces perniciosus. The pathogen causes a drastic reduction in mushroom yield due to malformation and deterioration of the basidiomes. However, the mechanism of the button mushroom's malformation development after infection with H. perniciosus remains obscure. Therefore, to reveal the mechanism of A. bisporus malformation by H. perniciosus, the interaction between the pathogen and host was investigated in this study using histopathology, physiological and transcriptomic analyses. Results show that irrespective of the growth stages of A. bisporus basidiomes infected with H. perniciosus, the host's basidiome with malformed basidiomes and enlarged mycelia and basidia indicated that the earlier the infection with H. perniciosus, the more the malformation of the basidiomes. Analyzing physiological and transcriptomic results in tandem, we concluded that H. perniciosus causes malformation development of A. bisporus mainly by affecting the level of phytohormones (N6-isopentenyladenyladenosine, cis-Zeatin and N6-(daelta2-lsopentenyl)-adenine) metabolism of the host's fruiting bodies, rather than by use of toxins. Our findings revealed the mechanism of the button mushroom's malformation development after infection with H. perniciosus, providing a reference for developing realistic approaches to control mushroom diseases. Our results further clarified the interaction between A. bisporus and H. perniciosus and identified the candidate genes for the A. bisporus wet bubble disease resistance breeding. Additionally, our work provides a valuable theoretical basis and technical support for studying the interaction between other pathogenic fungi and their fungal hosts.
研究领域:
真菌学
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植物病理学
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分子生物学
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DOI
PubMed
高影响因子
International Journal of Oral Science
·
2019
·Vol. 11
·期 1
·1-12
·
IF 2.75
Jiang Yuanjing,Zhang Shixian,Mao Chuanqing,Lai Yongzhen,Wu Di,Zhao Hu,Liao Caiyu,Chen Weihui
The Hedgehog (Hh) signalling pathway is essential for cellular proliferation and differentiation during embryonic development. Gain and loss of function of Hh signalling are known to result in an array of craniofacial malformations. To determine the critical period for Hh pathway antagonist-induced frontal bone hypoplasia, we examined patterns of dysmorphology caused by Hh signalling inhibition. Pregnant mice received a single oral administration of Hh signalling inhibitor GDC-0449 at 100 mg•kg − 1 or 150 mg•kg − 1 body weight at preselected time points between embryonic days (E)8.5 and 12.5. The optimal teratogenic concentration of GDC-0449 was determined to be 150 mg•kg − 1 . Exposure between E9.5 and E10.5 induced frontal bone dysplasia, micrognathia and limb defects, with administration at E10.5 producing the most pronounced effects. This model showed decreased ossification of the frontal bone with downregulation of Hh signalling. The osteoid thickness of the frontal bone was significantly reduced. The amount of neural crest-derived frontal bone primordium was reduced after GDC-0449 exposure owing to a decreased rate of cell proliferation and increased cell death.
研究领域:
发育生物学
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分子生物学
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颅面发育
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DOI
PubMed
高影响因子
Toxics
·
2023
·Vol. 11
·期 5
·469
·
IF 4.6
Qiang Zhang,Wenjie Ma,Jingmin Zhu
The increasing concern for the ecological risks of microplastics (MPs) as carriers of hydrophobic organic contaminants is evident. Di-butyl phthalate (DBP) is extensively utilized as an additive in plastic products, and both DBP and MPs are widespread in the environment. However, the combined toxicity of these substances remains uncertain. In this study, zebrafish embryos were employed to assess the toxic effects of polyethylene terephthalate (PET, MPs) and DBP, with a focus on the DBP toxicities influenced by PET. The embryonic chorion was partially covered by PET particles, and PET led to a delayed hatching of zebrafish embryos without inducing death or teratogenesis. On the other hand, exposure to DBP considerably inhibited the hatching of embryos, leading to severe lethal and teratogenic effects. The most common phenotypes induced by DBP exposure were delayed yolk sac absorption and pericardial edema. The mortality increased in co-treatment with 100 particles/mL PET and 2 mg/L DBP at 24 hpf and 48 hpf. The malformation phenotype, bent notochord, and delayed yolk sac absorption became more severe in 1 mg/L DBP exposition with the co-exposure of 100 particles/mL PET at 72 hpf. PET might act as a carrier that enhances the bioavailability of ambient DBP.Keywords:polyethylene terephthalate;di-butyl phthalate;zebrafish embryos;malformation phenotype;transport carrier
研究领域:
环境科学
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毒理学
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2024
·
IF 4.4
Ling-Zi Xia,Li-Lan Liu,Jun-Zhe Yue,Zhen-Yu Lu,Ru-Ya Deng,Xi He,Can-Can Li,Burong Hu,Hai-Tao Gao
Objective Phthalates (PEs) could cause reproductive harm to males. A mixture of three widely used PEs (MPEs) was used to investigate the ameliorative effects of zinc (Zn) and vitamin E (VE) against male reproductive toxicity. Methods Fifty male SD rats were randomly divided into five groups ( n = 10). Rats in MPEs group were orally treated with 160 mg/kg/d MPEs, while rats in MPEs combined Zn and/or VE groups were treated with 160 mg/kg/d MPEs plus 25 mg/kg/d Zn and/or 25 mg/kg/d VE. After intervention for 70 days, it's was measured of male reproductive organs' weight, histopathological observation of sperms and testes, serum hormones, PIWI proteins and steroidogenic proteins. Results Compared with control, anogenital distance, testes weight, epididymides weight, and sex hormones were significantly decreased, while the sperm malformation rate was markedly increased in MPEs group ( p < .05); the testicular tissues were injured in MPEs group with disordered and decreased spermatids, and arrested spermatogenesis. PIWIL1, PIWIL2, StAR, CYP11A1 and CYP19A1 were down-regulated in MPEs group ( p < .05). However, the alterations of these parameters were restored in MPEs combined Zn and/or VE groups ( p < .05). Conclusion Zn and/or VE improved steroid hormone metabolism, and inhibited MPEs' male reproductive toxicity.
研究领域:
毒理学
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生殖生物学
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营养科学
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2018
·
IF 4.358
Hangjun Zhang,Wenli Liu,Bin Chen,Jianbo He,Feifei Chen,Xiaodong Shan,Qiongxia Du,Ning Li,Xiuying Jia,Juan Tang
Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) are persistent toxic environmental pollutants that cause severe reproductive toxicity in animals. The goal of this study was to compare the reproductive toxic effects of TBBPA and TCBPA on male Rana nigromaculata and to expound on the mechanisms leading to these effects. Healthy adult frogs were exposed to 0, 0.001, 0.01, 0.1, and 1 mg/L of TBBPA and TCBPA for 14 days. Sperm numbers were counted by erythrometry. Sperm mobility and deformities were observed under a light microscope (400 × ). We used commercial ELISA kits to determine the serum content of testosterone (T), estradiol (E2), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Expression of androgen receptor (AR) mRNA was detected using real-time qPCR. Sperm numbers and sperm mobility were significantly decreased and sperm deformity was significantly increased in a concentration dependent manner following exposure to TBBPA and TCBPA. Sperm deformity was significantly greater in the 1 mg/L TCBPA (0.549) treatment group than in the 1 mg/L TBBPA (0.397) treatment group. Serum T content was significantly greater in the 0.01, 0.1 and 1 mg/L TBBPA and TCBPA experimental groups compared with controls, while E2 content was significantly greater in only the 1 mg/L TBBPA and TCBPA experimental groups. Expression levels of LH and FSH significantly decreased in the 1 mg/L TBBPA and TCBPA treatment groups. AR mRNA expression decreased markedly in all the treated groups. Our results indicated that TBBPA and TCBPA induced reproductive toxicity in a dose-dependent manner, with TCBPA having greater toxicity than TBBPA. Furthermore, changes in T, E2, LH, and FSH levels induced by TBBPA and TCBPA exposure, which led to endocrine disorders, also caused disturbance of spermatogenesis through abnormal gene expressions of AR in the testes .
研究领域:
环境毒理学
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内分泌学
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生殖生物学
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DOI
PubMed
高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 14
·e70765
·
IF 4.2
Xianbin Zeng,Zhongxiao Cong,Meng Xu,Yujie Ju,Yong Huang,Mingkai Zuo,Bo Cheng,Guiyou Tian,Xiaoping Xiao,Danmei Zhao,Wei Yuan,Huiqiang Lu,Yiyue Zhang,Yan Zhao
The widespread use of veterinary antibiotics in animal husbandry, such as tilmicosin (TIL), poses potential threats to environment pollution and human health. In this study, we conducted acute TIL exposure experiment using zebrafish model to explore the toxicological effects. In the concentration range of 20–80 mg/L, TIL did not affect zebrafish body length development but induced idiopathic scoliosis (IS)-like symptoms accompanied by impaired mobility. IS predominantly occurs in adolescents, while the etiology remains unclear. Further studies showed that the combination of quercetin and luteolin effectively alleviated TIL-induced spinal curvature and motor suppression. To explore the underlying mechanism, we performed network pharmacology analysis and enriched the PI3K-Akt pathway. We validated that the expression of key target genes in the PI3K-Akt pathway were significantly activated after TIL exposure, while quercetin and luteolin treatment effectively inhibited the PI3K-Akt pathway activation. Further experiments revealed that TIL exposure decreased brain neural cell apoptosis, thereby causing an increase in neurocytes, interfering with motor ability, and promoting IS-like vertebral malformations, which were especially noticeable during movement. This study expands our understanding that TIL exposure may be a predisposing factor for IS occurrence and progression, while the combination of quercetin and luteolin combination could protect against IS-like symptom by regulating PI3K-Akt pathway. Graphical The experiments revealed that exposure to tilmicosin (TIL) induces the development of scoliosis-like deformities, which could be effectively alleviated by the quercetin and luteolin combination. Further mechanistic studies found that TIL exposure activates the PI3K-Akt pathway, resulting in reduced apoptosis of brain neurons and increased neural cells, which could be inhibited by quercetin and luteolin. As disturbed brain development is a predisposing factor for scoliosis, the TIL-induced abnormalities in brain neurodevelopment exacerbate the progression of scoliosis-like deformities and dyskinesia.
研究领域:
环境毒理学
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发育生物学
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药理学
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神经生物学
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水生毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Hongmei Zou,Mingxuan Zhang,Jin Chen,Stanley Aniagu,Yan Jiang,Tao Chen
Benzo[ a ]pyrene (BaP) is a representative polycyclic aromatic hydrocarbon widely present in the environment. We previously reported that the aryl hydrocarbon receptor (AHR) mediates BaP-induced apoptosis and cardiac malformations in zebrafish embryos, but the underlying molecular mechanisms were unclear. Since BaP is a mutagenetic compound, we hypothesize that BaP induces apoptosis and heart defects via AHR-mediated DNA damage. In this study, zebrafish embryos were exposed to BaP at a concentration of 0.1 μM from 2 to 72 h post fertilization, either with or without inhibitors/agonists. AHR activity and levels of reactive oxygen species (ROS) were examined under a fluorescence microscope. mRNA expression levels were quantified by qPCR. DNA damage and apoptosis were detected by immunofluorescence. Our findings revealed that BaP exposure significantly increased BPDE-DNA adducts, mitochondrial damage, apoptosis and heart defects in zebrafish embryos. These effects were counteracted by inhibiting AHR/cyp1a1 using pharmaceutical inhibitors or genetic knockdown. Furthermore, we observed that spironolactone, an antagonist of nucleotide excision repair (NER), significantly enhanced BaP-induced BPDE-DNA adducts, mitochondrial damage, apoptosis and heart malformation rates. Conversely, SRT1720, a SIRT1 agonist, reduced the adverse effects of BaP. Supplementation with spironolactone also enhanced γ-H2AX signals in the heart of zebrafish embryos exposed to BaP. Additional experiments demonstrated that BaP suppressed the expression of SIRT1. We further established that AHR, when activated by BaP, directly inhibited SIRT1 transcription, leading to downregulation of XPC and XPA, which are essential NER genes involved in the recognition and verification steps of the NER process. Taken together, our results indicate that AHR mediates BaP-induced DNA damage in the heart of zebrafish embryos by inducing BPDE-DNA adduct formation via the AHR/Cyp1a1 signalling pathway, as well as suppressing NER via AHR-mediated inhibition of SIRT1.
研究领域:
毒理学
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发育生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2024
·
IF 7.6
Yingying Liu,Xudong Jin,Yanan Ye,Zeqiong Xu,Zhongkun Du,Huachang Hong,Haiying Yu,Hongjun Lin,Xianfeng Huang,Hongjie Sun
3-bromine carbazole (3-BCZ) represents a group of emerging aromatic disinfection byproducts (DBP) detected in drinking water; however, limited information is available regarding its potential cardiotoxicity. To assess its impacts, zebrafish embryos were exposed to 0, 0.06, 0.14, 0.29, 0.58, 1.44 or 2.88 mg/L of 3-BCZ for 120 h post fertilization (hpf). Our results revealed that ≥1.44 mg/L 3-BCZ exposure induced a higher incidence of heart malformation and an elevated pericardial area in zebrafish larvae; it also decreased the number of cardiac muscle cells and thins the walls of the ventricle and atrium while increasing cardiac output and impeding cardiac looping. Furthermore, 3-BCZ exposure also exhibited significant effects on the transcriptional levels of genes related to both cardiac development ( nkx2.5 , vmhc , gata4 , tbx5 , tbx2b , bmp4 , bmp10 , and bmp2b ) and cardiac function ( cacna1ab , cacna1da , atp2a1l , atp1b2b , atp1a3b , and tnnc1a ). Notably, N-acetyl-L-cysteine, a reactive oxygen species scavenger, may alleviate the failure of cardiac looping induced by 3-BCZ but not the associated cardiac dysfunction or malformation; conversely, the aryl hydrocarbon receptor agonist CH131229 can completely eliminate the cardiotoxicity caused by 3-BCZ. This study provides new evidence for potential risks associated with ingesting 3-BCZ as well as revealing underlying mechanisms responsible for its cardiotoxic effects on zebrafish embryos.
研究领域:
环境科学
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毒理学
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发育生物学
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水生毒理学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2018
·
IF 6.434
Mengmeng Huang,Jingjing Jiao,Jun Wang,Zhidan Xia,Yu Zhang
Acrylamide (AA) is a high production volume chemical in industrial applications and widely found in baked or fried carbohydrate-rich foods. In this study, we unravelled that AA induced developmental toxicity associated with oxidative stress status and disordered lipid distribution in heart region of developing zebrafish. Treatment with AA caused a deficient cardiovascular system with significant heart malformation and dysfunction. We also found that AA could reduce the number of cardiomyocytes through the reduced capacity of cardiomyocyte proliferation rather than cell apoptosis. The cardiac looping and ballooning appeared abnormal though cardiac chamber-specific identity in the differentiated myocardium was maintained well after AA treatment through MF20/S46 immunofluorescence assay. Furthermore, treatment with AA disturbed the differentiation of atrioventricular canal, which was demonstrated by the disordered expressions of the atrioventricular boundary markers bmp4 , tbx2b and notch1b and further confirmed by the ectopic expressions of the cardiac valve precursor markers has2 , klf2a and nfatc1 through whole-mount in situ hybridization. Thus, our studies provide the evidence of cardiac developmental toxicity of AA in the cardiovascular system, and also raised health concern about the harm of trans-placental exposure to high level of AA for foetuses and the risk of high exposure to AA for the pregnant women.
研究领域:
毒理学
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发育生物学
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心血管科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cardiovascular Toxicology
·
2021
·Vol. 21
·期 11
·901-913
·
IF 3.239
Du Zheng-Cai,Xia Zhong-Shang,Zhang Ming-Zhe,Wei Yan-Ting,Malhotra Nemi,Saputra Ferry,Audira Gilbert,Roldan Marri Jmelou M.,Hsiao Chung-Der,Hao Er-Wei,Hou Xiao-Tao,Deng Jia-Gang
Camphor is a terpene ketone with aromatic and volatile properties in nature derived from the bark of Cinnamomum camphora or synthesized from turpentine. Camphor exhibits various biological properties such as anti-microbial, anti-viral, anti-coccidial, and anti-cancer. It is also used as a form of topical medication for skin irritation, joint pain, and as a relief for itching from insect bites. However, even though the high dose of camphor has been documented to be toxic/lethal in humans in different studies, camphor’s developmental toxicity has not yet been explored, and its extensive mechanism of action is still unclear. In the present study, we aimed to assess the toxic effects of camphor in zebrafish embryos in the initial developmental stages. The obtained results demonstrated that a sub-lethal dose of camphor caused a decrease in hatching rate, body length, and substantial elevation in malformation rate on zebrafish embryos. On further observation, in the following time frame, curved body and pericardial edema of zebrafish were also observed. Furthermore, exposure to a sub-lethal dose of camphor was also able to trigger cardiotoxicity in zebrafish larvae. Later, on subsequent biochemical analysis, it was found that the antioxidant capacity inhibition and oxidative stress elevation that occurred after camphor exposure might be associated with the inhibition of total superoxide dismutase (SOD) activity and an increase in reactive oxygen species (ROS) and malondialdehyde (MDA) concentration. In addition, compared to the control group, several apoptotic cells in treated zebrafish were also found to be elevated. Finally, after further investigation on marker gene expressions, we conclude that the developmental toxicity of camphor exposure might be associated with apoptosis elevation and oxidative stress. Taken together, the current study provides a better understanding of the developmental toxicity of camphor on zebrafish, a promising alternative animal model to assess the developmental toxicity of chemical compounds.
研究领域:
毒理学
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发育生物学
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水生毒理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）