Investigating the Perturbation of Bone Health by Per/Polyfluoroalkyl Substances
研究全氟烷基/多氟烷基物质对骨骼健康的干扰
基本信息
- 批准号:10589459
- 负责人:
- 金额:$ 8.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdolescentAdultAdverse effectsAgeAmericanAmerican dietAttentionBiochemicalBiologicalBloodBone DensityCarboxylic AcidsCell physiologyChemical ExposureChemistryChildDataDatabasesDetectionDiagnosisDietEatingEpidemiologyEstrogen ReceptorsEthersEtiologyExposure toFemaleFoodFoundationsGenotypeHealthHistologicHomeostasisHumanImpairmentIn VitroIndustrializationInvestigationKnockout MiceLifeLightLipidsLiverLong-Term EffectsLongevityMeasuresMental HealthMetabolicModelingMonitorMusNational Health and Nutrition Examination SurveyNatural regenerationNatureNuclear ReceptorsOccupational ExposureOsteoblastsOsteoclastsOsteoporosisOutcomePPAR alphaPathway interactionsPerinatalPersonsPhenotypePlayPoly-fluoroalkyl substancesPopulationPositioning AttributeProcessPublic HealthQuality of lifeReceptor SignalingReportingResearchRiskRoleSamplingSerumSourceStructureSulfonic AcidsTestingTherapeutic EffectTissuesToxic Environmental SubstancesWild Type MouseWomanagedaging populationbonebone cellbone healthbone lossbone metabolismbone qualitycell typeconstitutive androstane receptorconsumer productcontaminated drinking waterdefined contributiondrinking waterepidemiologic dataepidemiology studyexperienceexperimental studyexposed human populationfracture riskhealthy agingimmune system functionimprovedin vivoin vivo Modellipid metabolismmalemathematical modelmenmortalitynovelosteoporosis with pathological fractureperfluorooctanoic acidphysical conditioningpregnane X receptortoxicant interactiontranscriptometranscriptomics
项目摘要
Project Summary
Per- and polyfluoroalkyl substances (PFAS) are pervasive in everyday life. Their extensive use in consumer
products, industrial processes and fire-fighting foam has led to significant contamination of drinking water and
food resulting in universal human exposure. While many studies have investigated the disruption of lipid
metabolism and immune system function by PFAS, less attention has been paid to the adverse effects of
PFAS on bone health. In light of the epidemiological associations between PFAS and lower bone density in
children and adults and the lack of studies investigating the causality and/or mechanisms by which PFAS could
interfere with bone metabolism, the objective of this study is to begin to define the effects of perfluorooctanoic
acid (PFOA) on bone quality. Our research focuses on the interaction of PFAS with nuclear receptors, a likely
mechanism through which PFAS could perturb bone cell function. We have developed a novel, human-relevant
model in which to study the adverse health effects of PFAS: mice expressing human peroxisome proliferator
activated receptor α (PPARα) fed a diet based on the What We Eat In America analysis in NHANES. Our
working hypothesis is that PFAS reduce bone quality through their interaction with nuclear receptors in multiple
bone cell types. To generate the preliminary data needed to support the proof-of-principle for an association
between PFAS exposure and bone health and to hone our working hypothesis, we propose the following
specific aim. We will define the effect of long term PFOA exposure on cortical and trabecular structure,
osteoblast and osteoclast number and function, and the bone transcriptome. We propose to take
advantage of bone and serum samples collected from experiments already conducted in humanized PPARα
mice, PPARα null mice and PPARα wildtype mice: Study 1 – young female and male mice, fed an adolescent
American diet, exposed to PFOA in drinking water for 6 weeks and Study 2 – adult female and male mice, fed
an adult American diet exposed to PFOA in drinking water for 14 weeks. Biological effects on liver and serum
lipid homeostasis are evident in these mice, which have serum PFOA concentrations similar to occupationally
exposed people. Bone structural, histological, biochemical and transcriptomic data will be analyzed.
Comparison between genotypes will begin to define the contribution of PPARα in PFAS-induced adverse
effects on bone quality. The results of this research will provide essential new data on how PFAS negatively
impact bone health and provide the needed foundation to begin to address a critical gap in PFAS research,
establishing the potential for causality in associations between PFAS and loss of bone quality in humans.
项目摘要
全氟烷基和多氟烷基物质(PFAS)在日常生活中普遍存在。广泛应用于消费者
产品、工业过程和消防泡沫的使用导致饮用水受到严重污染,
导致人类普遍接触的食物。虽然许多研究已经调查了脂质的破坏,
PFAS对机体代谢和免疫系统功能的影响,
PFAS对骨骼健康的影响。根据PFAS和低骨密度之间的流行病学联系,
儿童和成人,缺乏研究调查的因果关系和/或机制,
干扰骨代谢,本研究的目的是开始确定全氟辛酸的影响
PFOA(PFOA)对骨质的影响我们的研究重点是PFAS与核受体的相互作用,这可能是一种新的机制。
PFAS可以干扰骨细胞功能的机制。我们开发了一种新颖的,与人类相关的
研究PFAS不良健康影响的模型:表达人过氧化物酶体增殖物的小鼠
激活受体α(PPARα)的饮食基于NHANES的“我们在美国吃什么”分析。我们
工作假设是PFAS通过与多个核受体相互作用降低骨质量,
骨细胞类型生成支持关联原理证明所需的初步数据
PFAS暴露与骨骼健康之间的关系,并完善我们的工作假设,我们提出以下建议
具体目标。我们将确定长期暴露于PFOA对皮质和小梁结构的影响,
成骨细胞和破骨细胞的数量和功能,以及骨转录组。我们建议采取
从已经在人源化PPARα中进行的实验中收集的骨和血清样本的优势
小鼠、PPARα敲除小鼠和PPARα野生型小鼠:研究1 -年轻雌性和雄性小鼠,喂食青春期
美国饮食,暴露于饮用水中的PFOA 6周,研究2 -成年雌性和雄性小鼠,喂食
一个成年美国人的饮食暴露于饮用水中的PFOA 14周。对肝脏和血清的生物学效应
脂质体内平衡在这些小鼠中是明显的,其血清PFOA浓度与职业性
暴露的人。将分析骨结构、组织学、生化和转录组学数据。
基因型之间的比较将开始,以确定PPARα在PFAS诱导的不良反应中的作用。
对骨质量的影响。这项研究的结果将提供有关PFAS如何负面影响的重要新数据
影响骨骼健康,并为开始解决PFAS研究中的关键空白提供所需的基础,
建立PFAS与人类骨质量损失之间的因果关系。
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 }}
Jennifer J Schlezinger其他文献
Jennifer J Schlezinger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('Jennifer J Schlezinger', 18)}}的其他基金
Effects of High Fat Diet and Environmental Obesogen Co-Exposure on Osteoporosis
高脂肪饮食和环境致肥胖因素共同暴露对骨质疏松症的影响
- 批准号:
8258164 - 财政年份:2012
- 资助金额:
$ 8.25万 - 项目类别:
Effects of High Fat Diet and Environmental Obesogen Co-Exposure on Osteoporosis
高脂肪饮食和环境致肥胖因素共同暴露对骨质疏松症的影响
- 批准号:
8538387 - 财政年份:2012
- 资助金额:
$ 8.25万 - 项目类别:
Antagonism of the Ah Receptor in Controlling Breast Cancer Growth and Invasion
Ah 受体在控制乳腺癌生长和侵袭中的拮抗作用
- 批准号:
7738794 - 财政年份:2009
- 资助金额:
$ 8.25万 - 项目类别:
Antagonism of the Ah Receptor in Controlling Breast Cancer Growth and Invasion
Ah 受体在控制乳腺癌生长和侵袭中的拮抗作用
- 批准号:
7847519 - 财政年份:2009
- 资助金额:
$ 8.25万 - 项目类别:
Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in
研究项目 4:PPARgamma 和邻苯二甲酸盐环境介导的毒性
- 批准号:
6901355 - 财政年份:2005
- 资助金额:
$ 8.25万 - 项目类别:
ARYL HYDROCARBON RECEPTOR AND NF-KAPPAB INTERACTIONS
芳基烃受体和 NF-KAPPAB 相互作用
- 批准号:
6136278 - 财政年份:2000
- 资助金额:
$ 8.25万 - 项目类别:
Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in
研究项目 4:PPARgamma 和邻苯二甲酸盐环境介导的毒性
- 批准号:
7799051 - 财政年份:
- 资助金额:
$ 8.25万 - 项目类别:
Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in
研究项目 4:PPARgamma 和邻苯二甲酸盐环境介导的毒性
- 批准号:
7529665 - 财政年份:
- 资助金额:
$ 8.25万 - 项目类别:
Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in
研究项目 4:PPARgamma 和邻苯二甲酸盐环境介导的毒性
- 批准号:
7602950 - 财政年份:
- 资助金额:
$ 8.25万 - 项目类别:
Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in
研究项目 4:PPARgamma 和邻苯二甲酸盐环境介导的毒性
- 批准号:
7529678 - 财政年份:
- 资助金额:
$ 8.25万 - 项目类别:
相似海外基金
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:
$ 8.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The impact of changes in social determinants of health on adolescent and young adult mental health during the COVID-19 pandemic: A longitudinal study of the Asenze cohort in South Africa
COVID-19 大流行期间健康社会决定因素的变化对青少年和年轻人心理健康的影响:南非 Asenze 队列的纵向研究
- 批准号:
10755168 - 财政年份:2023
- 资助金额:
$ 8.25万 - 项目类别:
A Priority Setting Partnership to Establish a Patient, Caregiver, and Clinician-identified Research Agenda for Adolescent and Young Adult Cancer in Canada
建立优先合作伙伴关系,以建立患者、护理人员和临床医生确定的加拿大青少年和年轻人癌症研究议程
- 批准号:
480840 - 财政年份:2023
- 资助金额:
$ 8.25万 - 项目类别:
Miscellaneous Programs
Incidence and Time on Onset of Cardiovascular Risk Factors and Cardiovascular Disease in Adult Survivors of Adolescent and Young Adult Cancer and Association with Exercise
青少年和青年癌症成年幸存者心血管危险因素和心血管疾病的发病率和时间以及与运动的关系
- 批准号:
10678157 - 财政年份:2023
- 资助金额:
$ 8.25万 - 项目类别:
Fertility experiences among ethnically diverse adolescent and young adult cancer survivors: A population-based study
不同种族青少年和年轻成年癌症幸存者的生育经历:一项基于人群的研究
- 批准号:
10744412 - 财政年份:2023
- 资助金额:
$ 8.25万 - 项目类别:
Treatment development for refractory leukemia using childhood/adolescent, and young adult leukemia biobank
利用儿童/青少年和青年白血病生物库开发难治性白血病的治疗方法
- 批准号:
23K07305 - 财政年份:2023
- 资助金额:
$ 8.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular design of Two-Way Player CAR-T cells to overcome disease/antigen heterogeneity of childhood, adolescent, and young adult cancers
双向 CAR-T 细胞的分子设计,以克服儿童、青少年和年轻成人癌症的疾病/抗原异质性
- 批准号:
23H02874 - 财政年份:2023
- 资助金额:
$ 8.25万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Effects of adolescent social isolation on adult decision making and corticostriatal circuitry
青少年社会隔离对成人决策和皮质纹状体回路的影响
- 批准号:
10756652 - 财政年份:2023
- 资助金额:
$ 8.25万 - 项目类别:
Adolescent trauma produces enduring disruptions in sleep architecture that lead to increased risk for adult mental illness
青少年创伤会对睡眠结构产生持久的破坏,从而导致成人精神疾病的风险增加
- 批准号:
10730872 - 财政年份:2023
- 资助金额:
$ 8.25万 - 项目类别:
Using Tailored mHealth Strategies to Promote Weight Management among Adolescent and Young Adult Cancer Survivors
使用量身定制的移动健康策略促进青少年和年轻癌症幸存者的体重管理
- 批准号:
10650648 - 财政年份:2023
- 资助金额:
$ 8.25万 - 项目类别: