Paternal Toxicant Exposure Impacts Testicular-Placental Crosstalk

 描述(由申请人提供)： 在环境中暴露于各种天然毒素和人造毒物往往是服兵役的后果；因此，重要的是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，预先接触内分泌干扰剂不仅会降低男性和女性的生育力，而且无论父母中哪一方接触到有毒物质，都会对妊娠结局产生不利影响。与历史服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于毒物的女性伴侣早产(PTB)的重要危险因素。虽然许多干扰内分泌的毒物会对生育和妊娠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为二恶英)是越南时代除草剂橙剂的主要污染物。作为燃烧的产物，TCDD继续令人关切，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经记录了这种毒物。这项申请中提议的研究将检验父亲暴露于TCDD的作用，重点是胎盘表型的能力 扰乱孕酮在母胎界面的作用。我们的初步研究表明，TCDD在怀孕期间扰乱孕酮的抗炎作用的能力使这种毒物既可以作为内分泌又可以作为免疫干扰物，从而显著增加了这种毒物的负面影响。更具体地说，在我们的小鼠模型中，过去接触TCDD显著增加了与常见感染相关的炎症导致肺结核的可能性。由于母体感染经常在足月分娩中被发现，我们的建议将集中在父亲的毒物接触史作为一个重要的 “缺失的一块”，以理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，我们将审查现役军事人员可以利用的饮食/治疗修改是否有可能保护他们未来的生殖健康。同样重要的是，我们将评估典型的西式饮食可能会进一步加剧先前毒物暴露的负面影响。为了解决这个问题 为了解决这些问题，我们将利用我们已建立的自发性肺结核小鼠模型和允许口服和吸入暴露途径的新模型。体内发现的翻译将使用传统的共培养系统与小鼠和人类基质/蜕膜细胞和细胞滋养层细胞共同培养。最后，我们将建立一种新型的母胎膜芯片(MFIChip)系统，它重建了人类早期怀孕的三维结构。MFI芯片将把我们的老鼠数据转换成人类早期怀孕的模型。我们提出如下建议：具体目标1：确定暴露于TCDD的雄性小鼠睾丸内与胎盘-蜕膜功能改变相关的炎症相关生物标志物，从而使其对照交配伴侣发生早产。具体目标2：研究具有与环境相关的TCDD身体负担的男性，在有和没有二次成人接触的情况下，对妊娠结局的影响。具体目标3：使用独特的人类母胎芯片接口(MFIChip)系统，将我们在体内的小鼠研究转化为人类条件。发生在战区内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。由于在战时减少暴露是不现实的，本研究项目专注于确定使我们能够保护我们的退伍军人免受某些环境毒物未来生殖风险的策略。

 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.