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）：环境中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，考虑此类暴露对退伍军人及其后代的长期影响非常重要，特别是我们的研究表明。孕前接触内分泌干扰剂不仅会降低男性和女性的生育能力，而且无论父母中哪一方接触过有毒物质，都会对妊娠结局产生不利影响，我们在小鼠模型中证明了有毒物质接触史。父亲的影响可能是其未接触的女性伴侣早产 (PTB) 的一个重要危险因素，而许多内分泌干扰毒物会对生育能力和妊娠维持产生负面影响，TCDD（2,3,7,8-四氯二苯并-二恶英）。 TCDD（通常是二恶英）是越战时期除草剂橙剂的主要污染物。作为燃烧产物，TCDD 一直受到关注，因为这种有毒物质已在伊拉克和阿富汗被记录。本申请中提出的研究将研究父亲暴露于 TCDD 的作用，重点关注胎盘表型的能力。我们的初步研究表明，TCDD 在怀孕期间破坏黄体酮的抗炎作用的能力使该毒物同时充当内分泌和免疫干扰物，从而显着增加负面影响。更具体地说，我们的小鼠模型中过去的 TCDD 暴露显着增加了与常见感染相关的炎症导致 PTB 的可能性，因为母体感染经常在足月分娩中被发现，因此我们的建议将重点关注有毒物质的暴露。父亲作为一个重要的历史人物了解为什么孕产妇感染并不总是会带来不良妊娠结局的风险是“缺失的一部分”。此外，我们将研究现役军人可以利用的饮食/治疗改变是否会同样保护他们未来的生殖健康。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接触有毒物质的负面影响，以解决这一问题。对于这些问题，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，将使用小鼠和人类基质/蜕膜细胞的传统共培养系统来完成体内研究结果的体内翻译。最后，我们将建立一种新型母胎膜芯片 (MFIchip) 系统，该系统可重现人类早期妊娠的 3 维结构。我们提出以下建议：具体目标 1：确定暴露于 TCDD 的雄性小鼠睾丸内的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伙伴发生早产。 2：研究具有 TCDD 环境相关身体负担的男性，无论是否有二次成人暴露，对妊娠结局的影响。具体目标 3：使用小鼠体内研究将我们的研究转化为人类状况。独特的人类母体胎儿芯片接口（MFIchip）系统在战区发生的环境毒物暴露是一个古老的问题，然而，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的认识相对较少；由于减少战时接触是不现实的，因此该研究项目的重点是确定策略，使我们能够保护退伍军人免受某些环境毒物造成的未来生殖风险。