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

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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.