Lifelong Triclosan Exposure and Fatty Liver Disease
终生接触三氯生与脂肪肝
基本信息
- 批准号:10192723
- 负责人:
- 金额:$ 19.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-16 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAgeAnimal ExperimentsAnimal ModelAnti-Bacterial AgentsAntifungal AgentsAntioxidantsBenignBeta CellBirthBloodBlood GlucoseCellsChemicalsChildCirrhosisComplexDevelopmentDiabetes MellitusDiscipline of NursingDiseaseDisease ProgressionDisinfectantsDissociationDrug Metabolic DetoxicationDyslipidemiasEndoplasmic ReticulumEnvironmentEnvironmental PollutantsEnvironmental PollutionEpidemicEventExhibitsExposure toFatty LiverFatty acid glycerol estersFemaleFibrosisFood PackagingGeneral PopulationGenesGenetic TranscriptionHealthHealthcare IndustryHepaticHepatocarcinogenesisHepatocyteHepatotoxicityHigh Fat DietHomeostasisHouseholdHumanHuman MilkIndustrializationInfiltrationInflammationInflammatoryInsulin ResistanceKnockout MiceLactationLightLinkLipidsLiverLiver FibrosisLiver diseasesLocal Anti-Infective AgentsMalignant NeoplasmsMalignant neoplasm of liverMaternal ExposureMetabolicMetabolic syndromeMilkModelingMolecularMusNewborn InfantNuclear ImportObesityOutcomeOxidative StressOxidative Stress InductionPERK kinasePF4 GeneParticipantPartner in relationshipPathogenesisPathologicPathway interactionsPatternPhenolsPhosphorylationPolyribosomesPregnant WomenPrevalencePrimary carcinoma of the liver cellsProcessRNAReactive Oxygen SpeciesRegulationRogaineRoleSerumSeveritiesSignal TransductionSteatohepatitisStreptozocinStressToxic Environmental SubstancesToxic effectToxicant exposureTranscriptTranscriptional RegulationTranslatingTranslation InitiationTranslational RegulationTranslationsTriclosanTriglyceridesUrineantimicrobial drugbasebiochemical toolsbiological adaptation to stresscarcinogenesisconditional knockoutconsumer productearly onsetendoplasmic reticulum stressexperimental studyglucose metabolismisletlipid metabolismliver cell proliferationliver developmentmalemature animalnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnutritionpackaging materialpediatric non-alcoholic fatty liver diseasepersonal care productspolysome profilingprogramsprotein foldingresponsetoxicanttranscription factortranscriptome sequencingtype I diabeticyoung adult
项目摘要
ABSTRACT: Lifelong Triclosan Exposure and Fatty Liver Disease.
The rising prevalence of toxicant-associated steatohepatitis (TASH) and Nonalcoholic steatohepatitis
(NASH) – pathological conditions advanced from steatosis and characterized by inflammatory cell infiltration with
the potential progression to fibrosis, cirrhosis, and cancer-associated with an epidemic of advanced liver disease
mirrors increases in environmental toxicant exposure and obesity. Triclosan (TCS), first invented in the early
1970s to be employed as an antiseptic and disinfectant in the healthcare industry, has been widely used in the
U.S. and globally for more than 40 years. TCS now comes into direct contact with humans in household settings
through many consumer products ranging from personal care products to food packaging materials.
Consequently, its rising environmental release causes serious contamination in the environment, and it is now
known as an emerging contaminant that has been associated with numerous health concerns. While we have
previously demonstrated that TCS enhances oxidative stress, compensatory hepatocyte proliferation, and liver
fibrosis and promotes liver tumorigenesis in mice, how these events contribute to liver pathogenesis and the
regulatory mechanisms by which TCS exerts its toxicity, especially in the early stage of liver disease, are still
largely unexplored. Because TCS has been detected in pregnant women, in breast milk, and young and old
adults, there is a rising concern that TCS can exist as a lifelong toxicant in humans, potentially inducing the early
onset of toxicity in young children. We demonstrate in preliminary findings that when TCS is made available in
normal chow to female and male mating mice, TCS accumulates in milk and can be transferred through lactation
to nursing newborns. By 14 to 21 days after birth, there are early signs of accelerated lipid accumulation in
hepatocytes, indicating that TCS is inducing TASH. Using a type I diabetic adult animal model in which mice
receive streptozotocin (STZ), an agent damaging islet β cells, followed by a high-fat diet (STZ-HFD model), we
further demonstrated that TCS promotes expediting the development of steatohepatitis. Preliminary results show
that TCS activates ATF4 and Nrf2, both being endoplasmic reticulum (ER) stress-inducible transcription factors
that are jointly regulated by ER kinase PERK. Based upon our preliminary results confirming 1) TCS exposure
to newborns and 2), TCS activation of ER stress in our adult STZ-HFD model, we are proposing to leverage
these findings into a single model that will result in lifelong (newborns – adult) TCS exposure. In young adult
mice, we will examine a) the ability of TCS to activate PERK signaling that is capable of inhibiting global
translation and preferentially promoting translation of a subset of transcripts, including ATF4, by polysomal
profiling and RNA-seq analysis of total RNA and polysomal RNA, and b) the precise role of ATF4 and Nrf2 in
controlling lipid metabolism, regulating their downstream target genes that provide antioxidant defense capacity,
and impacting the TCS induced TASH disease state by using liver-specific Atf4 and Nrf2 conditional knockout
mice.
摘要:终生接触三氯生与脂肪肝。
毒物相关性脂肪性肝炎 (TASH) 和非酒精性脂肪性肝炎的患病率不断上升
(NASH) – 由脂肪变性发展而来的病理状况,其特征是炎症细胞浸润
与晚期肝病流行相关的潜在进展为纤维化、肝硬化和癌症
反映了环境毒物暴露和肥胖的增加。三氯生(TCS),早年首次发明
20世纪70年代被用作医疗保健行业的防腐剂和消毒剂,已广泛应用于
在美国和全球已有 40 多年的历史。 TCS 现在可以在家庭环境中与人类直接接触
涵盖从个人护理产品到食品包装材料等多种消费品。
因此,其不断增加的环境排放量对环境造成严重污染,目前已
被称为一种新兴污染物,与许多健康问题有关。虽然我们有
先前证明TCS可增强氧化应激、代偿性肝细胞增殖和肝脏功能
纤维化并促进小鼠肝脏肿瘤发生,这些事件如何促进肝脏发病机制以及
TCS发挥毒性作用的调节机制,特别是在肝病早期阶段,仍不清楚
很大程度上尚未探索。因为 TCS 已在孕妇、母乳以及年轻人和老年人中检测到
对于成年人来说,人们越来越担心 TCS 可能作为人类的终生毒物存在,可能会导致早期
幼儿出现毒性反应。我们在初步调查结果中证明,当 TCS 可用时
雌性和雄性交配小鼠的正常饮食中,TCS 会积聚在乳汁中,并可通过哺乳期转移
给哺乳新生儿。出生后14至21天,体内脂质加速积累的早期迹象
肝细胞,表明 TCS 正在诱导 TASH。使用 I 型糖尿病成年动物模型,其中小鼠
接受链脲佐菌素 (STZ)(一种破坏胰岛 β 细胞的药物),然后接受高脂肪饮食(STZ-HFD 模型),我们
进一步证明TCS促进脂肪性肝炎的加速发展。初步结果显示
TCS 激活 ATF4 和 Nrf2,两者都是内质网 (ER) 应激诱导转录因子
均受 ER 激酶 PERK 共同调控。根据我们确认的初步结果 1) TCS 暴露
2) 在我们的成人 STZ-HFD 模型中,TCS 激活 ER 应激,我们建议利用
将这些发现整合到一个单一模型中,该模型将导致终生(新生儿 - 成人)接触 TCS。在年轻成人中
小鼠,我们将检查 a) TCS 激活 PERK 信号传导的能力,该信号传导能够抑制全局
翻译并优先促进转录子子集的翻译,包括 ATF4,通过多聚体
总 RNA 和多核糖体 RNA 的分析和 RNA-seq 分析,以及 b) ATF4 和 Nrf2 在
控制脂质代谢,调节提供抗氧化防御能力的下游靶基因,
并通过使用肝脏特异性 Atf4 和 Nrf2 条件敲除来影响 TCS 诱导的 TASH 疾病状态
老鼠。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Robert H Tukey其他文献
Robert H Tukey的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Robert H Tukey', 18)}}的其他基金
Severe neonatal hyperbilirubinemia (SNH) and the expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) play key roles in the development of necrotizing enterocolitis (NEC)
严重新生儿高胆红素血症 (SNH) 和 UDP-葡萄糖醛酸基转移酶 1A1 (UGT1A1) 的表达在坏死性小肠结肠炎 (NEC) 的发生中起关键作用
- 批准号:
10713549 - 财政年份:2023
- 资助金额:
$ 19.74万 - 项目类别:
APOB48 downregulation is the causing factor in mediating iAs-induced lipid accumulation in enterocytes
APOB48 下调是介导 iAs 诱导的肠细胞脂质积累的原因
- 批准号:
10538854 - 财政年份:2022
- 资助金额:
$ 19.74万 - 项目类别:
Novel regulatory events that control expression of the UGT1A1 gene
控制 UGT1A1 基因表达的新调控事件
- 批准号:
10061607 - 财政年份:2018
- 资助金额:
$ 19.74万 - 项目类别:
Neonatal hyperbilirubinemia in a humanized UGT1 animal model
人源化 UGT1 动物模型中的新生儿高胆红素血症
- 批准号:
8442827 - 财政年份:2012
- 资助金额:
$ 19.74万 - 项目类别:
Neonatal hyperbilirubinemia in a humanized UGT1 animal model
人源化 UGT1 动物模型中的新生儿高胆红素血症
- 批准号:
8786086 - 财政年份:2012
- 资助金额:
$ 19.74万 - 项目类别:
Neonatal hyperbilirubinemia in a humanized UGT1 animal model
人源化 UGT1 动物模型中的新生儿高胆红素血症
- 批准号:
8238088 - 财政年份:2012
- 资助金额:
$ 19.74万 - 项目类别:
Co-repressors SMRT and NCoR1 regulate UGT1A1 gene expression
共阻遏物 SMRT 和 NCoR1 调节 UGT1A1 基因表达
- 批准号:
8898831 - 财政年份:2009
- 资助金额:
$ 19.74万 - 项目类别:
Co-repressors SMRT and NCoR1 regulate UGT1A1 gene expression
共阻遏物 SMRT 和 NCoR1 调节 UGT1A1 基因表达
- 批准号:
8761224 - 财政年份:2009
- 资助金额:
$ 19.74万 - 项目类别:
Xenobiotic sensors PXR and CAR and regulation of the UGT1 locus
异生素传感器 PXR 和 CAR 以及 UGT1 基因座的调节
- 批准号:
8117524 - 财政年份:2009
- 资助金额:
$ 19.74万 - 项目类别:
Xenobiotic sensors PXR and CAR and regulation of the UGT1 locus
异生素传感器 PXR 和 CAR 以及 UGT1 基因座的调节
- 批准号:
7911598 - 财政年份:2009
- 资助金额:
$ 19.74万 - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
- 批准号:
2341426 - 财政年份:2024
- 资助金额:
$ 19.74万 - 项目类别:
Continuing Grant
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
- 批准号:
2341424 - 财政年份:2024
- 资助金额:
$ 19.74万 - 项目类别:
Continuing Grant
PROTEMO: Emotional Dynamics Of Protective Policies In An Age Of Insecurity
PROTEMO:不安全时代保护政策的情绪动态
- 批准号:
10108433 - 财政年份:2024
- 资助金额:
$ 19.74万 - 项目类别:
EU-Funded
The role of dietary and blood proteins in the prevention and development of major age-related diseases
膳食和血液蛋白在预防和发展主要与年龄相关的疾病中的作用
- 批准号:
MR/X032809/1 - 财政年份:2024
- 资助金额:
$ 19.74万 - 项目类别:
Fellowship
Atomic Anxiety in the New Nuclear Age: How Can Arms Control and Disarmament Reduce the Risk of Nuclear War?
新核时代的原子焦虑:军控与裁军如何降低核战争风险?
- 批准号:
MR/X034690/1 - 财政年份:2024
- 资助金额:
$ 19.74万 - 项目类别:
Fellowship
Walkability and health-related quality of life in Age-Friendly Cities (AFCs) across Japan and the Asia-Pacific
日本和亚太地区老年友好城市 (AFC) 的步行适宜性和与健康相关的生活质量
- 批准号:
24K13490 - 财政年份:2024
- 资助金额:
$ 19.74万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Discovering the (R)Evolution of EurAsian Steppe Metallurgy: Social and environmental impact of the Bronze Age steppes metal-driven economy
发现欧亚草原冶金的(R)演变:青铜时代草原金属驱动型经济的社会和环境影响
- 批准号:
EP/Z00022X/1 - 财政年份:2024
- 资助金额:
$ 19.74万 - 项目类别:
Research Grant
ICF: Neutrophils and cellular senescence: A vicious circle promoting age-related disease.
ICF:中性粒细胞和细胞衰老:促进与年龄相关疾病的恶性循环。
- 批准号:
MR/Y003365/1 - 财政年份:2024
- 资助金额:
$ 19.74万 - 项目类别:
Research Grant
Doctoral Dissertation Research: Effects of age of acquisition in emerging sign languages
博士论文研究:新兴手语习得年龄的影响
- 批准号:
2335955 - 财政年份:2024
- 资助金额:
$ 19.74万 - 项目类别:
Standard Grant
Shaping Competition in the Digital Age (SCiDA) - Principles, tools and institutions of digital regulation in the UK, Germany and the EU
塑造数字时代的竞争 (SCiDA) - 英国、德国和欧盟的数字监管原则、工具和机构
- 批准号:
AH/Y007549/1 - 财政年份:2024
- 资助金额:
$ 19.74万 - 项目类别:
Research Grant














{{item.name}}会员




