Paternal Toxicant Exposure Impacts Testicular-Placental Crosstalk

父亲接触有毒物质会影响睾丸-胎盘串扰

基本信息

  • 批准号:
    10054144
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-01-01 至 2020-12-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Environmental exposures to a wide array of natural toxins and man-made toxicants are often a consequence of military service; thus it is important to consider the long-term effects of such exposures on our Veterans and their offspring. In particular, our studies have shown that preconception exposures to endocrine disrupting agents can not only reduce both male and female fertility but also adversely affect pregnancy outcomes regardless of which parent had the toxicant exposure. Of equal relevance to historical military service patterns, we demonstrated in a murine model that the toxicant exposure history of the father can be a significant risk factor fo preterm birth (PTB) in his unexposed female partner. While a number of endocrine disrupting toxicants can negatively impact fertility and maintenance of pregnancy, TCDD (2,3,7,8-tetrachlorodibenzo-pdioxin or, commonly, dioxin) was a major contaminant of the Vietnam-era herbicide Agent Orange. As product of combustion, TCDD continues to be of concern since this toxicant has been documented in Iraq and Afghanistan in areas affected by oil fires and waste incineration. The studies proposed within this application will examine the role of paternal exposures to TCDD, focusing on the capacity of the placental phenotype to disrupt the action of progesterone at the maternal-fetal interface. Our preliminary studies indicate that the ability of TCDD to disrupt the anti-inflammatory action of progesterone during pregnancy allows this toxicant to act as both an endocrine and immune disruptor, significantly increasing the negative impact of this toxicant. More specifically, a past TCDD exposure in our murine model significantly increased the likelihood that inflammation associated with common infections would result in PTB. Since maternal infections are frequently identified in term deliveries, our proposal will focus on the toxicant exposure history of the father as a significant "missing piece" to understanding why maternal infection does not always pose a risk for adverse pregnancy outcomes. Furthermore, we will examine the potential that dietary/therapeutic modifications, which can be utilized by active military personnel, will protect their future reproductive health. Equally, important, we will assess the potential that a typical Western-style diet will further exacerbate the negative effects of a prior toxicant exposure. In order to address these issues, we will utilize both our established mouse model of spontaneous PTB and new models allowing oral and inhalation exposure routes. In vivo translation of the in vivo findings will be done using traditional co-culture systems with mouse and human stromal/decidual cells and cytotrophoblast cells. Lastly, we will establish a novel Maternal-Fetal Membrane on a chip (MFIchip) system that recreates the 3-dimensional structure of early human pregnancy. The MFIchip will translate our murine data to a model of early human pregnancy. We propose the following: Specific Aim 1: To identify inflammation-related biomarkers within the testis of TCDD-exposed male mice which correlate to alterations in placental-decidual function such that preterm birth occurs in their control mating partners. Specific Aim 2: To examine the impact of males with an environmentally relevant body burden of TCDD, with and without a secondary adult exposure, on pregnancy outcomes. Specific Aim 3: To translate our in vivo murine studies to the human condition using a unique human maternal fetal interface on a chip (MFIchip) system. Environmental toxicant exposure occurring within combat zones is an ancient problem; however, the recognition that such exposures may have negative consequences on both the short and long-term health of our Veterans is relatively new. Since reducing exposures in wartime is not realistic, this research project is focused on identifying strategies that it may enable us to protect our Veterans from the future reproductive risks posed by certain environmental toxicants.
 描述(由申请人提供): 环境暴露于各种天然毒素和人造毒物往往是军事服务的结果;因此,重要的是要考虑这种暴露对我们的退伍军人及其后代的长期影响。特别是,我们的研究表明,孕前暴露于内分泌干扰物不仅会降低男性和女性的生育能力,而且会对妊娠结果产生不利影响,无论父母中的哪一方接触过有毒物质。与历史兵役模式同样相关的是,我们在小鼠模型中证明,父亲的毒物暴露史可能是其未暴露的女性伴侣早产(PTB)的重要风险因素。虽然一些内分泌干扰毒物会对生育能力和怀孕的维持产生负面影响,但TCDD(2,3,7,8-四氯二苯并二恶英,或通常的二恶英)是越南时代除草剂橙子的主要污染物。作为燃烧的产物,四氯二苯并对二恶英仍然令人关切,因为在伊拉克和阿富汗受石油火灾和废物焚烧影响的地区,已有这种有毒物质的记录。本申请中提出的研究将检查父亲暴露于TCDD的作用,重点是胎盘表型的能力, 破坏孕激素在母胎界面的作用。我们的初步研究表明,TCDD在怀孕期间破坏孕酮抗炎作用的能力允许这种有毒物质作为内分泌和免疫干扰物,显着增加这种有毒物质的负面影响。 更具体地说,在我们的小鼠模型中,过去的TCDD暴露显著增加了与常见感染相关的炎症导致PTB的可能性。由于母亲感染经常在足月分娩中被发现,我们的建议将重点放在父亲的毒物暴露史上, “缺失的部分”,以了解为什么产妇感染并不总是对不良妊娠结局构成风险。此外,我们还将研究现役军人可以利用的饮食/治疗调整保护其未来生殖健康的潜力。同样重要的是,我们将评估典型的西式饮食是否会进一步加剧先前有毒物质暴露的负面影响。为了解决 鉴于这些问题,我们将利用我们建立的自发性PTB小鼠模型和允许口服和吸入暴露途径的新模型。将使用传统的小鼠和人基质/蜕膜细胞和细胞滋养层细胞共培养系统进行体内结果的体内转化。最后,我们将建立一种新的芯片上的母胎膜(MFICip)系统,重现人类早期妊娠的三维结构。MFI芯片将把我们的小鼠数据转化为人类早期妊娠的模型。我们建议如下:具体目标1:确定TCDD暴露雄性小鼠睾丸内炎症相关生物标志物,这些生物标志物与胎盘-蜕膜功能的改变相关,从而导致其对照交配伴侣发生早产。具体目标二:研究男性与环境相关的TCDD的身体负担,有和没有二次成人暴露,对妊娠结局的影响。具体目标3:使用独特的人类母胎界面芯片(MFI芯片)系统将我们的体内小鼠研究转化为人类条件。在战区内发生的环境毒物暴露是一个古老的问题;然而,认识到这种暴露可能对我们退伍军人的短期和长期健康产生负面影响是相对较新的。由于减少战时暴露是不现实的,本研究项目的重点是确定战略,它可能使我们能够保护我们的退伍军人免受某些环境毒物造成的未来生殖风险。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Compartmentalized Culture of Perivascular Stroma and Endothelial Cells in a Microfluidic Model of the Human Endometrium.
  • DOI:
    10.1007/s10439-017-1797-5
  • 发表时间:
    2017-07
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Gnecco JS;Pensabene V;Li DJ;Ding T;Hui EE;Bruner-Tran KL;Osteen KG
  • 通讯作者:
    Osteen KG
Environmental Endocrine Disruptors and Endometriosis.
Paternal Environmental Toxicant Exposure and Risk of Adverse Pregnancy Outcomes.
父亲环境有毒物质的暴露和不良怀孕结果的风险。
  • DOI:
    10.1007/s13669-019-00265-w
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0.5
  • 作者:
    Bruner-Tran KL;Mokshagundam S;Barlow A;Ding T;Osteen KG
  • 通讯作者:
    Osteen KG
Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models.
  • DOI:
    10.1016/j.reprotox.2016.07.007
  • 发表时间:
    2017-03
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bruner-Tran KL;Gnecco J;Ding T;Glore DR;Pensabene V;Osteen KG
  • 通讯作者:
    Osteen KG
Rodent Models of Experimental Endometriosis: Identifying Mechanisms of Disease and Therapeutic Targets.
  • DOI:
    10.2174/1573404813666170921162041
  • 发表时间:
    2018-06
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bruner-Tran KL;Mokshagundam S;Herington JL;Ding T;Osteen KG
  • 通讯作者:
    Osteen KG
{{ 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 }}

KEVIN G OSTEEN其他文献

KEVIN G OSTEEN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('KEVIN G OSTEEN', 18)}}的其他基金

Epithelial-Dominant Cell-Cell Communication and Endometriosis
上皮优势细胞间通讯和子宫内膜异位症
  • 批准号:
    8256514
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Epithelial-Dominant Cell-Cell Communication and Endometriosis
上皮优势细胞间通讯和子宫内膜异位症
  • 批准号:
    7318132
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
Loss of Complement-Protective CD55 Expression in Endometriosis
子宫内膜异位症中补体保护性 CD55 表达缺失
  • 批准号:
    7250451
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
Loss of Complement-Protective CD55 Expression in Endometriosis
子宫内膜异位症中补体保护性 CD55 表达缺失
  • 批准号:
    8054242
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
Loss of Complement-Protective CD55 Expression in Endometriosis
子宫内膜异位症中补体保护性 CD55 表达缺失
  • 批准号:
    7416834
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
Loss of Complement-Protective CD55 Expression in Endometriosis
子宫内膜异位症中补体保护性 CD55 表达缺失
  • 批准号:
    7799132
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
Loss of Complement-Protective CD55 Expression in Endometriosis
子宫内膜异位症中补体保护性 CD55 表达缺失
  • 批准号:
    7600311
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
Mouse Modeling Core
鼠标建模核心
  • 批准号:
    7318143
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
Dioxin Exposure and the Invasive Pathogenesis of Endometriosis
二恶英暴露与子宫内膜异位症的侵袭性发病机制
  • 批准号:
    7900906
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
Dioxin Exposure and the Invasive Pathogenesis of Endometriosis
二恶英暴露与子宫内膜异位症的侵袭性发病机制
  • 批准号:
    7279168
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:

相似海外基金

Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
  • 批准号:
    2244994
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了