Adult and Transgenerational Toxicity Due to Developmental TCDD Exposure
发育期接触 TCDD 导致的成人和跨代毒性
基本信息
- 批准号:8443233
- 负责人:
- 金额:$ 13.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:ARNT geneAdultAdverse effectsAdvisory CommitteesAffectAgonistAreaAryl Hydrocarbon ReceptorAutomobile DrivingAwardBiological ModelsChemicalsChildhoodChromatinChromatin StructureClinicalCollagenCore FacilityDNA MethylationDataDefectDeformityDevelopmentDevelopment PlansDioxinsDiseaseDown-RegulationEnvironmentEpigenetic ProcessExposure toFemaleFeminizationFertilizationFetal DevelopmentFishesFundingFutureGene ExpressionGenerationsGenesGerm CellsGoalsGonadal structureGrantHealthHistologyHomologous GeneHumanIn Situ HybridizationIncidenceJawLinkMagnetic Resonance ImagingManuscriptsMeasuresMentorsMethodsMolecularMorphologyOvaryParentsPathologyPopulationPregnancyPublic HealthPublishingReporterResearchResearch PersonnelRiskScientistSex CharacteristicsSex RatioShapesSiteSkeletal DevelopmentSkeletonSourceSpinalStagingStaining methodStainsStretchingTechniquesTestingTestisTetrachlorodibenzodioxinTissuesToxic Environmental SubstancesToxic effectToxicant exposureTrainingTraining ProgramsTranscriptTransgenic OrganismsTranslational ResearchUnited States National Institutes of HealthUniversitiesVertebral columnWisconsinWorkWritingY ChromosomeZebrafishbasebody systembonecareercareer developmentdevelopmental toxicologyexperiencehistone modificationimprovedmalemalformationmeetingsoffspringpublic health relevancereproductiveresearch and developmentresponsescoliosissexskeletalskeletal abnormalityspine bone structuresry Genestranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): An important goal in improving human health is to understand how exposure to environmental toxicants during gestation and childhood leads to disease later in adulthood. It is also vital to determine whether a single early toxicant exposure can affect the health of subsequent generations. Understanding and identifying these risks will positively impact human health. My research focus is to use zebrafish to understand two toxic responses seen in adults exposed during development to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD, dioxin), at the parts per trillion (ppt) level. Our published work and my preliminary results indicate that a single exposure during development can cause skeletal malformation and reproductive toxicity in the adults, and various forms of toxicity in the subsequent F1 and F2 generations. F0 adult toxicity includes an apparent male feminization in which fish with female secondary sex characteristics have testes. A goal is to determine whether TCDD alters gonadal fate, changing ovaries to testes, or feminizes the body of males. Another major sign of toxicity in
adults exposed during early development is malformations in the axial skeleton resembling human scoliosis. I will identify the source of these changes in skeletal development examining bone and collagen by staining and measuring alterations in gene expression. Down-regulation of the sox9b gene is the cause of TCDD-induced jaw malformation in zebrafish. The human sox9 gene is a master regulator of both skeletal formation and sex specification: sox9 is thought to be the target of the male Y-chromosome sry gene. I have also observed sox9b expression at the site of vertebral development in zebrafish. Therefore, I will examine the expression of both zebrafish homologs of human sox9: sox9a and sox9b in developing bone and gonad of TCDD-treated zebrafish. I find reproducible toxicity in F1 and F2 offspring of F0 fish that were exposed
only briefly during development. I will better characterize this transgenerational toxicity, measuring changes in global gene expression in affected tissues from each generation and will use both gene- specific and global techniques to examine alterations in DNA methylation and chromatin structure induced by TCDD exposure and transmitted into F1 and F2 fish. In year 3 of this project, I plan to use the results from this work as preliminary data to apply for an R21 or R03 grant. Transgenerational work, even in zebrafish, takes several years to mature, so the proposed work would allow a future grant to focus on mechanisms driving my results. As a K01 recipient, I will follow a career development plan with very specific research and development milestones for each award year. I will meet regularly with my mentors and advisory committee to strengthen my ability to link translational and mechanistic research. I will obtain experiential training in areas needed for a successful career in translational research, including project planning, manuscript and grant writing, and identification and mastery of cellular and molecular techniques needed to move my research forward. I have a clinical background with a research emphasis. I will gain experience in mechanistic, hypothesis testing driven research. This plan will stretch my research expertise and enhance my training in developmental toxicology research. The University of Wisconsin has numerous NIH-sponsored training programs, core facilities and funded researchers making it an ideal training environment for me to develop as an independent scientist.
描述(由申请人提供):改善人类健康的一个重要目标是了解妊娠期和儿童期暴露于环境毒物如何导致成年后的疾病。同样重要的是,要确定一次早期有毒物质接触是否会影响后代的健康。了解和识别这些风险将对人类健康产生积极影响。我的研究重点是使用斑马鱼了解在发育过程中暴露于2,3,7,8四氯二苯并对二恶英(TCDD,二恶英)的成年人中观察到的两种毒性反应,在万亿分之一(ppt)水平。我们发表的工作和我的初步结果表明,在发育过程中的单次暴露可导致骨骼畸形和生殖毒性的成年人,并在随后的F1和F2代的各种形式的毒性。F0成体毒性包括明显的雄性雌性化,其中具有雌性第二性征的鱼具有睾丸。目标是确定TCDD是否改变性腺命运,将卵巢变为睾丸,或使男性身体女性化。毒性的另一个主要迹象是,
成年人在早期发育过程中暴露的是类似于人类脊柱侧凸的中轴骨骼畸形。我将通过染色和测量基因表达的变化来检查骨骼和胶原蛋白,从而确定骨骼发育中这些变化的来源。Sox9b基因的下调是TCDD诱导斑马鱼颌骨畸形的原因。人类sox9基因是骨骼形成和性别特化的主要调节因子:sox9被认为是男性Y染色体sry基因的靶基因。我还观察到sox9b在斑马鱼脊椎发育部位的表达。因此,我将研究人类sox9的斑马鱼同源物:sox9a和sox9b在发育中的骨和性腺的TCDD处理的斑马鱼的表达。我发现暴露于F0鱼的F1和F2后代具有可重复的毒性,
只是在发展过程中短暂地。我将更好地描述这种跨代毒性,测量每一代受影响组织中整体基因表达的变化,并将使用基因特异性和整体技术来检查TCDD暴露诱导的DNA甲基化和染色质结构的改变,并传递到F1和F2鱼。在这个项目的第三年,我计划使用这项工作的结果作为初步数据,申请R21或R03资助。跨代的研究,即使是在斑马鱼身上,也需要几年的时间才能成熟,因此,拟议的工作将允许未来的拨款专注于推动我的结果的机制。作为K01获奖者,我将遵循职业发展计划,每个获奖年度都有非常具体的研发里程碑。我将定期与我的导师和咨询委员会会面,以加强我将转化和机械研究联系起来的能力。我将获得成功的职业生涯所需的领域在转化研究,包括项目规划,手稿和赠款写作,并确定和掌握所需的细胞和分子技术,以推动我的研究。我有一个临床背景与研究重点。我将获得经验,在机械,假设检验驱动的研究。这项计划将扩展我的研究专长,并加强我在发育毒理学研究方面的培训。威斯康星州的大学有许多NIH赞助的培训项目,核心设施和资助的研究人员,使它成为一个理想的培训环境,我发展为一个独立的科学家。
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 }}
Tracie R Baker其他文献
Tracie R Baker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('Tracie R Baker', 18)}}的其他基金
Transcriptomic and epigenetic mechanisms of lead (Pb)-induced neurobehavioral disease in aged populations and subsequent generations
铅(Pb)诱导的老年人群及后代神经行为疾病的转录组和表观遗传机制
- 批准号:
10577926 - 财政年份:2023
- 资助金额:
$ 13.15万 - 项目类别:
Developmental VOC Exposure in Zebrafish: Toxic Mechanisms and Biomarkers
斑马鱼发育过程中 VOC 暴露:毒性机制和生物标志物
- 批准号:
10700804 - 财政年份:2022
- 资助金额:
$ 13.15万 - 项目类别:
Developmental VOC Exposure in Zebrafish: Toxic Mechanisms and Biomarkers
斑马鱼发育过程中 VOC 暴露:毒性机制和生物标志物
- 批准号:
10352964 - 财政年份:2022
- 资助金额:
$ 13.15万 - 项目类别:
Genetic and epigenetic mechanisms of infertility caused by endocrine disrupting chemicals
内分泌干扰物引起不孕症的遗传和表观遗传机制
- 批准号:
10516110 - 财政年份:2021
- 资助金额:
$ 13.15万 - 项目类别:
Genetic and epigenetic mechanisms of infertility caused by endocrine disrupting chemicals
内分泌干扰物引起不孕症的遗传和表观遗传机制
- 批准号:
10487840 - 财政年份:2021
- 资助金额:
$ 13.15万 - 项目类别:
Genetic and epigenetic mechanisms of infertility caused by endocrine disrupting chemicals
内分泌干扰物引起不孕症的遗传和表观遗传机制
- 批准号:
9911309 - 财政年份:2019
- 资助金额:
$ 13.15万 - 项目类别:
Adult and Transgenerational Toxicity Due to Developmental TCDD Exposure
发育期接触 TCDD 导致的成人和跨代毒性
- 批准号:
8685364 - 财政年份:2013
- 资助金额:
$ 13.15万 - 项目类别:
Adult and Transgenerational Toxicity Due to Developmental TCDD Exposure
发育期接触 TCDD 导致的成人和跨代毒性
- 批准号:
8827435 - 财政年份:2013
- 资助金额:
$ 13.15万 - 项目类别:
Adult and Transgenerational Toxicity Due to Developmental TCDD Exposure
发育期接触 TCDD 导致的成人和跨代毒性
- 批准号:
9252687 - 财政年份:2013
- 资助金额:
$ 13.15万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 13.15万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 13.15万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 13.15万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 13.15万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 13.15万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 13.15万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 13.15万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 13.15万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 13.15万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 13.15万 - 项目类别:
Grant-in-Aid for Scientific Research (C)