Toxicant disruption of receptor-mediated endocytosis in oogenesis and later life metabolic dysfunction
卵子发生和晚年代谢功能障碍中受体介导的内吞作用的毒性破坏
基本信息
- 批准号:9757769
- 负责人:
- 金额:$ 38.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAddressAdultAffectAlcohol consumptionAnimal ModelAreaBiochemicalCaenorhabditis elegansChemicalsCholesterolComplexConceptionsCounselingDataDepositionDevelopmentDietary InterventionDigestionDimethyl SulfoxideDiseaseDrosophila melanogasterElderlyEmbryoEndocytosisEnergy-Generating ResourcesEnvironmental PollutionExposure toFirst Pregnancy TrimesterFishesFood PackagingGenerationsGerm CellsGlucoseGoalsHealthHeat-Shock ResponseHomologous GeneHumanHypertriglyceridemiaImpairmentIncidenceIndividualInsulinInvestigationIslets of LangerhansKnowledgeLDL-Receptor Related Protein 2LarvaLifeLife Cycle StagesLipidsMaternal ExposureMeasuresMediatingMetabolicMetabolic Syndrome PathwayMetabolic dysfunctionMetabolic syndromeModelingNational Institute of Environmental Health SciencesNematodaNutrientNutritionalOocytesOogenesisOrganogenesisOutcomeOxidation-ReductionOxidative StressPancreasPathologicPlacentaPlacentationPlant RootsProcessProteinsPublic HealthRNA InterferenceReproductive BiologyResearchRiskRoleSmokingSolventsSourceSpeedStressStudy modelsSuggestionSurfaceTestingTimeToxicant exposureToxicologyTransgenic OrganismsZebrafishadverse outcomeblood glucose regulationcomparativecookingdetection of nutrientdeviantdrinking watereggflyhazardhealthspanintrinsic factor-cobalamin receptorisletknock-downlipid biosynthesismetabolic phenotypemother nutritionmutantnutritionoffspringoocyte maturationoocyte qualitypancreas developmentprogramsprotein complexprotein functionreceptorreceptor expressionreceptor mediated endocytosisreproductiveresponsesensortooltoxicanttranscription factor
项目摘要
Summary
Before the placenta becomes fully functional late in the first trimester, the human embryo's primary source of
nutrients is the yolk—a cache of maternally-deposited lipids and proteins. The deposition of yolk into the
oocyte is governed by receptor-mediated endocytosis, namely by a receptor complex called MERC.
Preliminary studies in zebrafish (Danio rerio) have shown that maternal exposures to perfluorinated
compounds (PFCs) disrupted MERC expression and altered oocyte nutrient quantity and composition. Further,
these preconception PFC exposures impaired pancreatic organogenesis, decreasing insulin-producing islet
area in the resulting embryos. In the nematode (Caenorhabditis elegans), preconception exposed eggs
developed elevated triglyceride levels as adults, suggestive of metabolic dysfunction. The goal of this study is
to gain a mechanistic understanding of the process by which preconception PFC exposures impair oocyte
nutrient deposition, induce nutritional stress and predispose individuals to metabolic dysfunction later in life.
We will use an evolutionary, three-model approach combining the strengths of the zebrafish, nematode, and
fruitfly (Drosophila melanogaster) models (e.g. transparent, high numbers of progeny, short generation time,
and transgenic and mutant lines) to assess the nutritional and metabolic consequences of preconception
exposures to two persistent perfluorinated compounds: the legacy toxicant perfluorooctanesulfonic acid, and its
emerging replacement chemical perfluorobutanesulfonic acid. The first aim of this study will elucidate the
mechanisms by which these maternal preconception exposures disrupt MERC function, and impair nutrient
deposition in the oocyte. The second aim will assess how these exposures affect embryonic nutrition and
development of the pancreas—a master regulator of glucose homeostasis and digestion. The third aim will
delineate the truncation of the healthspan by assessing metabolic dysfunction later in life. Overall, this project
will identify a mechanism by which maternal preconception exposures can reduce oocyte quality and impair
metabolic function throughout the life course. This project addresses NIEHS goals to 1) identify key “sensitive”
windows during which exposures may contribute to the Developmental Origins of Health and Disease
paradigm, and 2) discover hazards posed by emerging contaminants.
摘要
在胎盘在妊娠早期晚期完全发挥功能之前,人类胚胎的主要来源是
营养素是蛋黄--母体沉积的脂肪和蛋白质的储藏库。蛋黄的沉淀物
卵母细胞由受体介导的内吞作用控制,也就是由一种称为Merc的受体复合体控制。
对斑马鱼(Danio Rerio)的初步研究表明,母亲暴露在全氟化环境中
化合物(PFC)扰乱了Merc的表达,改变了卵母细胞的营养量和组成。此外,
这些先入为主的PFC暴露损害了胰腺器官的生成,减少了胰岛素的产生
所产生的胚胎的面积。在线虫(秀丽线虫)中,先入为主的卵子暴露出来
成年后甘油三酯水平升高,提示代谢功能障碍。这项研究的目标是
为了从机制上理解先入为主的PFC暴露损害卵母细胞的过程
营养沉积,引发营养压力,使人在以后的生活中容易出现代谢功能障碍。
我们将使用一种进化的三模型方法,结合斑马鱼、线虫和
果蝇模型(如透明的,后代数量多,世代时间短,
以及转基因和突变品系),以评估先入为主的营养和代谢后果
暴露于两种持久性全氟化合物:遗留毒物全氟辛烷磺酸及其
新兴的替代化学品全氟丁磺酸。这项研究的第一个目的是阐明
这些母体先入为主的暴露扰乱Merc功能并损害营养的机制
在卵母细胞中沉积。第二个目标将评估这些暴露如何影响胚胎营养和
胰腺的发育--葡萄糖动态平衡和消化的主要调节器。第三个目标将是
通过在以后的生活中评估代谢功能障碍来描绘健康寿命的截断。总体而言,这个项目
将确定母体暴露于先孕会降低卵子质量和损害卵子质量的机制
整个生命过程中的代谢功能。该项目旨在实现NIEHS的目标:1)确定关键的“敏感”
暴露可能有助于健康和疾病的发育起源的窗口
范例,以及2)发现新出现的污染物造成的危险。
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)
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Alicia R Timme-Laragy其他文献
37 - Perfluorooctanesulfonic Acid Alters Embryonic Redox Signaling and Pancreatic Organogenesis in the Zebrafish, Danio Rerio
- DOI:
10.1016/j.freeradbiomed.2015.10.074 - 发表时间:
2015-10-01 - 期刊:
- 影响因子:
- 作者:
Karilyn E Sant;Haydee Jacobs;Alicia R Timme-Laragy - 通讯作者:
Alicia R Timme-Laragy
Alicia R Timme-Laragy的其他文献
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{{ truncateString('Alicia R Timme-Laragy', 18)}}的其他基金
Developmental toxicants and congenital pancreas malformations
发育毒物和先天性胰腺畸形
- 批准号:
10317634 - 财政年份:2021
- 资助金额:
$ 38.6万 - 项目类别:
Toxicant disruption of receptor-mediated endocytosis in oogenesis and later life metabolic dysfunction
卵子发生和晚年代谢功能障碍中受体介导的内吞作用的毒性破坏
- 批准号:
10008145 - 财政年份:2017
- 资助金额:
$ 38.6万 - 项目类别:
Toxicant disruption of receptor-mediated endocytosis in oogenesis and later life metabolic dysfunction
卵子发生和晚年代谢功能障碍中受体介导的内吞作用的毒性破坏
- 批准号:
10246504 - 财政年份:2017
- 资助金额:
$ 38.6万 - 项目类别:
Activation of Nrf2 during embryonic development - mechanisms and consequences
胚胎发育过程中 Nrf2 的激活 - 机制和后果
- 批准号:
10467508 - 财政年份:2016
- 资助金额:
$ 38.6万 - 项目类别:
Activation of Nrf2 during embryonic development: mechanisms and consequences
胚胎发育过程中 Nrf2 的激活:机制和后果
- 批准号:
9113725 - 财政年份:2016
- 资助金额:
$ 38.6万 - 项目类别:
Activation of Nrf2 during embryonic development: mechanisms and consequences
胚胎发育过程中 Nrf2 的激活:机制和后果
- 批准号:
9924600 - 财政年份:2016
- 资助金额:
$ 38.6万 - 项目类别:
Activation of Nrf2 during embryonic development - mechanisms and consequences
胚胎发育过程中 Nrf2 的激活 - 机制和后果
- 批准号:
10589883 - 财政年份:2016
- 资助金额:
$ 38.6万 - 项目类别:
Differential Sensitivity to Oxidative Stress during Embryonic Development
胚胎发育过程中对氧化应激的不同敏感性
- 批准号:
7751682 - 财政年份:2009
- 资助金额:
$ 38.6万 - 项目类别:
Differential Sensitivity to Oxidative Stress during Embryonic Development
胚胎发育过程中对氧化应激的不同敏感性
- 批准号:
8097330 - 财政年份:2009
- 资助金额:
$ 38.6万 - 项目类别:
Differential Sensitivity to Oxidative Stress during Embryonic Development
胚胎发育过程中对氧化应激的不同敏感性
- 批准号:
7886877 - 财政年份:2009
- 资助金额:
$ 38.6万 - 项目类别:
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