Endocrine Disruptors, Ahr Signaling, and Placentation

University Of Kansas Medical Center, Kansas City KS

Investigators

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Abstract

The placenta is a vital organ critical for a successful pregnancy. Placental development involves differentiation of trophoblast stem cells into various specialized trophoblast cell lineages with endocrine, transport, and uterine vascular remodeling functions. Formation of the placenta is a result of an orchestrated crosstalk between maternal and fetal tissues. The process of placentation also exhibits plasticity. Placental structure and function can be influenced by environmental challenges. These environmental exposures include chemicals known as endocrine disruptors that interfere with signaling pathways generating adverse effects on developmental, reproductive, and immunological processes. The role of the placenta as physiological barrier makes it a vulnerable target for the detrimental effects of endocrine disruptors. The effects of endocrine disruptors on regulatory processes controlling placental development are largely unknown. We hypothesize that exposure to endocrine disruptors at sensitive and critical windows of development will affect placental development, impacting growth and maturation of the fetus, and lifelong postnatal health. In the proposed experimentation, we will utilize the rat as a model of hemochorial placentation and 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and benzo[a]pyrene (BaP) as a model endocrine disruptor. TCDD and BaP affect cellular function through activation of the aryl hydrocarbon receptor pathway. We will explore the impact of endocrine disruptors such as TCDD and BaP and Ahr signaling on establishment of the hemochorial placenta using the rat as an animal model. We propose two aims: 1) To investigate the actions of TCDD and BaP during placental development. 2) To evaluate maternal versus placental-fetal sites of TCDD and BAP action impacting placental development. These efforts will further our understanding of the etiology of placentation-related diseases and provide a paradigm for developing translational approaches to mitigate the detrimental effects of endocrine disruptors on reproductive health.