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：
KEVIN G OSTEEN
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
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

来源：
https://reporter.nih.gov/project-details/10054144
关键词：
3-Dimensional Acute Address Adult Affect Afghanistan Animal Model Anti-Inflammatory Agents Area Awareness Bacterial Infections Biological Biological Markers Biological Models Birth Body Burden Cells Coculture Techniques Data Decidual Cell Decidual Cell Reactions Development Diet Dioxins Endocrine Endocrine Disruptors Endocrine disruption Environment Environmental Exposure Evaluation Exhibits Exposure to Face Failure Fathers Female Fertility Fetal Membranes Fire - disasters Future Generations Health Herbicides Human Hypersensitivity Immune In Vitro Incineration Infection Inflammation Inflammatory Inhalation Inhalation Exposure Intervention Iraq Life Long-Term Effects Maintenance Maternal-Fetal Exchange Mediating Membrane Military Personnel Modeling Modification Mus Nutritional Oils Oral Parents Partner in relationship Paternal Exposure Pattern Perinatal mortality demographics Pharmacologic Substance Phenotype Placenta Play Pregnancy Pregnancy Maintenance Pregnancy Outcome Premature Birth Progesterone Recording of previous events Reproductive Health Research Research Project Grants Research Proposals Risk Risk Factors Role Services Signal Transduction Stromal Cells System Testis Tetrachlorodibenzodioxin Therapeutic Therapeutic Agents Toxic Environmental Substances Toxicant exposure Toxin Translating Translations Treatment Efficacy Veterans Vietnam Virus Diseases Woman adverse pregnancy outcome agent orange cell type combat combustion product cytotrophoblast design environmental stressor exposure route female fertility in vivo instrument male male fertility man mouse model negative affect novel offspring organ on a chip perinatal morbidity pre-clinical research prenatal exposure public health relevance reproductive response secondary infection sex stressor three dimensional structure toxicant trophoblast wasting

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通常是服兵役的结果。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，对内分泌剂的预想暴露不仅可以降低男性和女性的生育能力，而且会对妊娠结局产生不利影响。与历史兵役模式相同，我们在鼠模型中证明，父亲的毒物暴露历史可能是早产（PTB）的重要危险因素（PTB）。尽管许多内分泌干扰的毒物会对怀孕的生育能力和维持产生负面影响，但TCDD（2,3,7,8-四氯迪本培苯甲酸 - 苯甲酸 - 通常，通常是二恶英）是越南时代的Herbicide剂橙色的主要污染物。作为组合的产物，TCDD继续引起关注，因为这种有毒物质已在伊拉克和阿富汗记录在受石油火灾和废物感染影响的地区。本应用程序中提出的研究将检查父亲对TCDD的暴露的作用，重点是占地表型的能力破坏孕酮在母亲界面上的作用。我们的初步研究表明，TCDD在怀孕期间破坏孕酮的抗炎作用的能力使这种毒物既是内分泌和免疫破坏者，从而大大增加了这种毒物的负面影响。更具体地说，我们的鼠模型中过去的TCDD暴露显着增加了与常见感染相关的炎症可能导致PTB。由于在期限分娩中经常发现孕产妇感染，因此我们的建议将集中于父亲的毒物暴露历史 “缺失”以了解为什么产妇感染并不总是会出现不良妊娠结局的风险。此外，我们将研究可通过活跃的军事人员使用的饮食/治疗修饰的潜力将保护其未来的生殖健康。同样重要的是，我们将评估典型的西方饮食将进一步加剧毒物暴露之前的负面影响的潜力。为了解决这些问题，我们将同时利用我们已建立的赞助PTB的鼠标模型和允许口服和吸入式途径的新模型。体内研究结果的体内翻译将使用与小鼠和人类基质/dec骨细胞和细胞增多质细胞细胞的传统共培养系统进行。最后，我们将在芯片（MFICHIP）系统上建立一种新型的母亲膜膜，该膜重现早期人类怀孕的三维结构。 MFICHIP将我们的鼠数据转化为早期妊娠模型。我们提出以下建议：特定目的1：确定暴露于TCDD的雄性小鼠睾丸中与炎症相关的生物标志物，这与安慰剂 - 特定功能的改变相关，以使早产发生在其对照交配伴侣中。具体目的2：检查男性对TCDD的环境相关的身体伯恩的影响，有或没有继发成年人暴露于妊娠结局。特定目的3：使用芯片（MFICHIP）系统上独特的人类胎儿界面将我们的体内鼠研究转化为人类状况。战斗区域内发生的环境有毒物质暴露是一个古老的问题。但是，认识到这种暴露可能会对我们的退伍军人的短期和长期健康产生负面影响，这是相对较新的。由于降低战时的暴露是不现实的，因此该研究项目的重点是确定可能使我们能够保护退伍军人免受某些环境有毒物质带来的生殖风险的策略。