The natural estrogens,including estrone(E_(1)),17β-estradiol(E_(2)),and estriol(E_(3)),are frequently detected in aquatic environment at relatively high levels.The most commonly used biomarkers for estrogens are main...The natural estrogens,including estrone(E_(1)),17β-estradiol(E_(2)),and estriol(E_(3)),are frequently detected in aquatic environment at relatively high levels.The most commonly used biomarkers for estrogens are mainly expressed in the liver of fish.Analyses of the global gene profiling in fish liver cells under estrogens treatment will provide precise toxicogenomic information of the natural estrogens which is still not well known.In this study,we developed methods for isolation and culture of primary hepatocytes from liver tissue of male Chinese medaka(Oryzias sinensis),and analyzed the global gene expression profiling in the primary hepatocytes treated with E_(1)(1,10,and 100 nmol/L),E_(2)(0.01,0.1,1,10,and 100 nmol/L),and E_(3)(1,10,and 100 nmol/L)using RNA-seq.It was found that 175,248,and 218 genes were differentially expressed in the E_(1),E_(2),and E_(3) groups,respectively.These differentially expressed genes(DEGs)were mainly enriched in Gene Ontology(GO)terms of“response to estradiol”,“response to estrogen”,and“lipid transport”.Of the DEGs,vitellogenin genes,including vtg1,vtg2,and vtg3,were the mostly up-regulated and followed by zona pellucida genes which include zp2.3,zp2l1 and zp3a.2.In addition,genes of slc41a1,zp2.1,esr1,pkd1l1,fam^(2)0ca,best3,etc.were also obviously up-regulated by the estrogens in concentration-dependent patterns.RT-qPCR was used to validate the results of RNA-seq and found that vtg2 should be the best biomarker gene for estrogen study,which could well response to natural estrogens and weak estrogenic chemical,propyl 4-hydroxybenzoate.展开更多
Alga toxins have recently emerged as an environmental risk factor,especially to neurodegenerative diseases,such as Alzheimer's disease,Parkinson's disease and amyotrophic lateral sclerosis.However,the associat...Alga toxins have recently emerged as an environmental risk factor,especially to neurodegenerative diseases,such as Alzheimer's disease,Parkinson's disease and amyotrophic lateral sclerosis.However,the association between the alga toxinsβ-N-methylamino-L-alanine(BMAA),brevetoxin B,cyanoginosin LR,okadaic acid and neurodegenerative diseases remains inadequately investigated.Therefore,the aim of this study was to elucidate the potential associations.Four sets of differentially expressed genes related with BMAA,brevetoxin B,cyanoginosin LR and okadaic acid in Homo sapiens and genes linked to neurodegenerative disease development were respectively collected from the Comparative Toxicogenomic Database.Metascape analysis and cluster community analysis of four alga toxins highlighted protein-protein interaction enrichment and hub genes,while biological processes analysis showed that the dominant pathways involved in harmful effects triggered by four alga toxins were the apoptotic signaling pathway,regulation of amyloid protein formation,inflammatory response and endoplasmic reticulum stress.Genes related to the interactions between four alga toxins and neurodegenerative diseases were selected and analyzed,revealing that the relevant pathways and genes were those involved in apoptotic mitochondrial changes and neuroinflammatory response pathways.The adverse outcome pathway frameworks were constructed according to the analysis results for toxins and associated neurodegenerative diseases.These discoveries provide a new perspective for us to gain a deeper understanding of the neurotoxic effects of four alga toxins.展开更多
Head and neck cancer(HNC) is the sixth most common human malignancy worldwide. The main forms of treat ment for HNC are surgery, radiotherapy(RT) and che motherapy(CT). However, the choice of therapy de pends on the t...Head and neck cancer(HNC) is the sixth most common human malignancy worldwide. The main forms of treat ment for HNC are surgery, radiotherapy(RT) and che motherapy(CT). However, the choice of therapy de pends on the tumor staging and approaches, which are aimed at organ preservation. Because of systemic RT and CT genotoxicity, one of the important side effects is a secondary cancer that can result from the activity of radiation and antineoplastic drugs on healthy cells Ionizing radiation can affect the DNA, causing single and double-strand breaks, DNA-protein crosslinks and oxidative damage. The severity of radiotoxicity can be directly associated with the radiation dosimetry and the dose-volume differences. Regarding CT, cisplatin is stil the standard protocol for the treatment of squamous cell carcinoma, the most common cancer located in theoral cavity. However, simultaneous treatment with cisplatin, bleomycin and 5-fluorouracil or treatment with paclitaxel and cisplatin are also used. These drugs can interact with the DNA, causing DNA crosslinks, double and single-strand breaks and changes in gene expression. Currently, the late effects of therapy have become a recurring problem, mainly due to the increased survival of HNC patients. Herein, we present an update of the systemic activity of RT and CT for HNC, with a focus on their toxicogenetic and toxicogenomic effects.展开更多
Aristolochic acid(AA)is a group of structurally related nitrophenanthrene carboxylic acids found in many plants that are widely used by many cultures as traditional herbal medicines.AA is a causative agent for Chinese...Aristolochic acid(AA)is a group of structurally related nitrophenanthrene carboxylic acids found in many plants that are widely used by many cultures as traditional herbal medicines.AA is a causative agent for Chinese herbs nephropathy,a term replaced later by AA nephropathy.Evidence indicates that AA is nephrotoxic,genotoxic,and carcinogenic in humans;and it also induces tumors in the forestomach,kidney,renal pelvis,urinary bladder,and lung of rats and mice.Therefore,plants containing AA have been classified as carcinogenic to humans(Group 1)bytheInternational AgencyforResearchonCancer.In our laboratories,we have conducted a series of genotoxicity and toxicogenomic studies in the rats exposed to AA of 0.1–10 mg/kg for 12 weeks.Our results demonstrated that AA treatments induced DNA adducts and mutations in the kidney,liver,and spleen of rats,as well as significant alteration of gene expression in both its target and nontarget tissues.AA treatments altered mutagenesis-or carcinogenesis-related microRNA expression in rat kidney and resulted in significant changes in protein expression profiling.We also applied benchmark dose(BMD)modeling to the 3-month AA-induced genotoxicity data.The obtained BMDL10(the lower 95%confidence interval of the BMD10 that is a 10%increase over the background level)for AA-induced mutations in the kidney of rats was about 7μg/kg body weight per day.This review constitutes an overview of our investigations on AA-induced genotoxicity and toxicogenomic changes including gene expression,microRNA expression,and proteomics;and presents updated information focused on AA-induced genotoxicity in rodents.展开更多
High-throughput next generation sequencing(NGS)is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known r...High-throughput next generation sequencing(NGS)is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known reference genome or by de novo assembly without reference genome.This technology has led researchers to conduct an explosion of sequencing related projects in multidisciplinary fields of science.However,due to the limitations of sequencing-based chemistry,length of sequencing reads and the complexity of genes,it is difficult to determine the sequences of some portions of the human genome,leaving gaps in genomic data that frustrate further analysis.Particularly,some complex genes are difficult to be accurately sequenced or mapped because they contain high GC-content and/or low complexity regions,and complicated pseudogenes,such as the genes encoding xenobiotic metabolizing enzymes and transporters(XMETs).The genetic variants in XMET genes are critical to predicate interindividual variability in drug efficacy,drug safety and susceptibility to environmental toxicity.We summarized and discussed challenges,wet-lab methods,and bioinformatics algorithms in sequencing"complex"XMET genes,which may provide insightful information in the application of NGS technology for implementation in toxicogenomics and pharmacogenomics.展开更多
基金supported by the Fisheries Innovation Team of Beijing Agriculture Innovation Consortium(No.BAIC07–2023–02)the National Natural Science Foundation of China(Nos.22176004 and 21777003).
文摘The natural estrogens,including estrone(E_(1)),17β-estradiol(E_(2)),and estriol(E_(3)),are frequently detected in aquatic environment at relatively high levels.The most commonly used biomarkers for estrogens are mainly expressed in the liver of fish.Analyses of the global gene profiling in fish liver cells under estrogens treatment will provide precise toxicogenomic information of the natural estrogens which is still not well known.In this study,we developed methods for isolation and culture of primary hepatocytes from liver tissue of male Chinese medaka(Oryzias sinensis),and analyzed the global gene expression profiling in the primary hepatocytes treated with E_(1)(1,10,and 100 nmol/L),E_(2)(0.01,0.1,1,10,and 100 nmol/L),and E_(3)(1,10,and 100 nmol/L)using RNA-seq.It was found that 175,248,and 218 genes were differentially expressed in the E_(1),E_(2),and E_(3) groups,respectively.These differentially expressed genes(DEGs)were mainly enriched in Gene Ontology(GO)terms of“response to estradiol”,“response to estrogen”,and“lipid transport”.Of the DEGs,vitellogenin genes,including vtg1,vtg2,and vtg3,were the mostly up-regulated and followed by zona pellucida genes which include zp2.3,zp2l1 and zp3a.2.In addition,genes of slc41a1,zp2.1,esr1,pkd1l1,fam^(2)0ca,best3,etc.were also obviously up-regulated by the estrogens in concentration-dependent patterns.RT-qPCR was used to validate the results of RNA-seq and found that vtg2 should be the best biomarker gene for estrogen study,which could well response to natural estrogens and weak estrogenic chemical,propyl 4-hydroxybenzoate.
基金supported by the Natural Science Foundation of Shandong province(Nos.ZR2019MH048 and ZR2022QC149)the Double First-class Disciplines Construction Fund Project from Harbin Institute of Technology at Weihai(No.2023SYLHY18)Weihai Science and Technology Development Program。
文摘Alga toxins have recently emerged as an environmental risk factor,especially to neurodegenerative diseases,such as Alzheimer's disease,Parkinson's disease and amyotrophic lateral sclerosis.However,the association between the alga toxinsβ-N-methylamino-L-alanine(BMAA),brevetoxin B,cyanoginosin LR,okadaic acid and neurodegenerative diseases remains inadequately investigated.Therefore,the aim of this study was to elucidate the potential associations.Four sets of differentially expressed genes related with BMAA,brevetoxin B,cyanoginosin LR and okadaic acid in Homo sapiens and genes linked to neurodegenerative disease development were respectively collected from the Comparative Toxicogenomic Database.Metascape analysis and cluster community analysis of four alga toxins highlighted protein-protein interaction enrichment and hub genes,while biological processes analysis showed that the dominant pathways involved in harmful effects triggered by four alga toxins were the apoptotic signaling pathway,regulation of amyloid protein formation,inflammatory response and endoplasmic reticulum stress.Genes related to the interactions between four alga toxins and neurodegenerative diseases were selected and analyzed,revealing that the relevant pathways and genes were those involved in apoptotic mitochondrial changes and neuroinflammatory response pathways.The adverse outcome pathway frameworks were constructed according to the analysis results for toxins and associated neurodegenerative diseases.These discoveries provide a new perspective for us to gain a deeper understanding of the neurotoxic effects of four alga toxins.
文摘Head and neck cancer(HNC) is the sixth most common human malignancy worldwide. The main forms of treat ment for HNC are surgery, radiotherapy(RT) and che motherapy(CT). However, the choice of therapy de pends on the tumor staging and approaches, which are aimed at organ preservation. Because of systemic RT and CT genotoxicity, one of the important side effects is a secondary cancer that can result from the activity of radiation and antineoplastic drugs on healthy cells Ionizing radiation can affect the DNA, causing single and double-strand breaks, DNA-protein crosslinks and oxidative damage. The severity of radiotoxicity can be directly associated with the radiation dosimetry and the dose-volume differences. Regarding CT, cisplatin is stil the standard protocol for the treatment of squamous cell carcinoma, the most common cancer located in theoral cavity. However, simultaneous treatment with cisplatin, bleomycin and 5-fluorouracil or treatment with paclitaxel and cisplatin are also used. These drugs can interact with the DNA, causing DNA crosslinks, double and single-strand breaks and changes in gene expression. Currently, the late effects of therapy have become a recurring problem, mainly due to the increased survival of HNC patients. Herein, we present an update of the systemic activity of RT and CT for HNC, with a focus on their toxicogenetic and toxicogenomic effects.
文摘Aristolochic acid(AA)is a group of structurally related nitrophenanthrene carboxylic acids found in many plants that are widely used by many cultures as traditional herbal medicines.AA is a causative agent for Chinese herbs nephropathy,a term replaced later by AA nephropathy.Evidence indicates that AA is nephrotoxic,genotoxic,and carcinogenic in humans;and it also induces tumors in the forestomach,kidney,renal pelvis,urinary bladder,and lung of rats and mice.Therefore,plants containing AA have been classified as carcinogenic to humans(Group 1)bytheInternational AgencyforResearchonCancer.In our laboratories,we have conducted a series of genotoxicity and toxicogenomic studies in the rats exposed to AA of 0.1–10 mg/kg for 12 weeks.Our results demonstrated that AA treatments induced DNA adducts and mutations in the kidney,liver,and spleen of rats,as well as significant alteration of gene expression in both its target and nontarget tissues.AA treatments altered mutagenesis-or carcinogenesis-related microRNA expression in rat kidney and resulted in significant changes in protein expression profiling.We also applied benchmark dose(BMD)modeling to the 3-month AA-induced genotoxicity data.The obtained BMDL10(the lower 95%confidence interval of the BMD10 that is a 10%increase over the background level)for AA-induced mutations in the kidney of rats was about 7μg/kg body weight per day.This review constitutes an overview of our investigations on AA-induced genotoxicity and toxicogenomic changes including gene expression,microRNA expression,and proteomics;and presents updated information focused on AA-induced genotoxicity in rodents.
基金supported by the FDA Project(E0765001)the National Key Research and Development Program of China(2016YFC0902100 to Geng Chen)
文摘High-throughput next generation sequencing(NGS)is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known reference genome or by de novo assembly without reference genome.This technology has led researchers to conduct an explosion of sequencing related projects in multidisciplinary fields of science.However,due to the limitations of sequencing-based chemistry,length of sequencing reads and the complexity of genes,it is difficult to determine the sequences of some portions of the human genome,leaving gaps in genomic data that frustrate further analysis.Particularly,some complex genes are difficult to be accurately sequenced or mapped because they contain high GC-content and/or low complexity regions,and complicated pseudogenes,such as the genes encoding xenobiotic metabolizing enzymes and transporters(XMETs).The genetic variants in XMET genes are critical to predicate interindividual variability in drug efficacy,drug safety and susceptibility to environmental toxicity.We summarized and discussed challenges,wet-lab methods,and bioinformatics algorithms in sequencing"complex"XMET genes,which may provide insightful information in the application of NGS technology for implementation in toxicogenomics and pharmacogenomics.
