Impact of endocrine disrupting chemicals on innate immune cell-mediated tissue remodeling in reproductive events

在过去的几十年里，人们认为免疫细胞具有免疫之外的多种复杂功能。先天免疫细胞参与生殖过程中的关键过程。特别是它们1)调节黄体发育，从而促进排卵和胚胎着床；2)分泌对滋养细胞迁移和子宫螺旋动脉重塑至关重要的介质，因此对胎盘和胎儿生长至关重要；最后3)它们是乳腺转化分支的调节剂，对哺乳至关重要。巨噬细胞、嗜酸性细胞、肥大细胞、嗜碱性细胞和自然杀伤细胞均存在这三个过程。这些细胞表达激素受体，即雌激素、黄体酮和雄激素受体。因此，在怀孕和围产期发生的复杂过程中，它们迅速适应不断变化的环境条件并不奇怪。内分泌干扰化学物质（EDCs）是有可能干扰由激素控制的过程的物质。我们特别感兴趣的是了解EDCs如何影响生殖过程。这对生育和繁殖具有直接的重要性，因此对物种的维持具有长期的相关性。特别是，EDCs对免疫介导的生殖步骤的影响及其潜在机制尚未得到研究。本项目的总体目标是阐明EDCs是否、在何种程度上以及通过何种机制影响先天免疫细胞调节生殖功能组织变化的上级功能。具体地说，我们将采用复杂的体内模型，包括免疫细胞特异性激素受体敲除和体外模型，包括类器官培养来解决这个相关的生物学问题。利用德国和阿根廷团队的互补专业知识，我们试图分析免疫介导的EDC对a)卵泡发生，排卵，黄体形成，b)胚胎着床，胎盘和胎儿生长以及c)对哺乳至关重要的终末芽（TEB）形成的影响。通过这样做，我们希望对了解EDC对生殖健康的影响作出长期贡献。

Over the last decades, multiple and complex functions that go beyond immunity have been attributed to immune cells. Innate immune cells are involved in critical processes during reproduction. In particular they 1) regulate corpus luteum development and thus contribute to ovulation and embryo implantation, 2) secrete mediators that are critical for trophoblast migration and the remodeling of uterine spiral artery and are therefore pivotal for placentation and fetal growth and finally 3) they are regulators of branching in mamma transformation and are crucial for lactation. For all three processes evidences were found for macrophages, eosinophils, mast cells, basophils and also for natural killer cells. These cells express hormone receptors, namely estrogen, progesterone and androgen receptors. It is therefore not surprising that they rapidly adapt to the changing environment conditions during the complex processes taking place in pregnancy and the perinatal period. Endocrine disrupting chemicals (EDCs) are substances that have the potential to interfere with processes that are controlled by hormones. Our particular interest is the understanding of how EDCs affect reproductive processes. This has immediate importance for fertility and reproduction and thus long-term relevance for the maintenance of the species. In particular, the impact of EDCs on immune-mediated reproductive steps and the underlying mechanisms have not been studied at all. The overall aim of this project is to elucidate if, to which extent and through which mechanisms EDCs affect innate immune cells in their superordinate function of modulating tissue changes for reproductive functions. Concretely, we will employ sophisticated in vivo models including immune cell specific hormone receptor knockouts and in vitro models including organoid cultures to tackle this relevant biological question. Taking advantage from the complementary expertise of the German and Argentinean groups we seek to analyze the immune mediated EDC effect on a) folicullogenesis, ovulation, corpus luteum formation, b) embryo implantation, placentation and fetal growth and c) terminal end buds (TEB) formation that is critical for lactation. By doing so we hope to contribute long term to the understanding of EDC impact on reproductive health.