Environmental Exposures, AHR Activation, and Placental Origins of Development

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Hemochorial placentation occurs in many mammalian species including primates and rodents. It ensures the most intimate contact between maternal and embryonic compartments and requires specialized adjustments during gestation. Disruptions in placental development and function affect fetal health and contribute to the origins of adult disease. Our environment is a source of chemicals and toxicants that can affect cellular and molecular processes, including those controlling the morphogenesis and function of the hemochorial placenta. Timing of environmental exposures are likely critical in determining their effects on placentation and postnatal health. Chemical properties of environmental exposures are wide-ranging and dictate cellular and molecular responses. Polychlorinated biphenyls (PCBs) are released into the environment as a byproduct of industry and when introduced prenatally have the capacity to influence embryonic and placental development. The aryl hydrocarbon receptor (AHR) is a key component of a molecular pathway sensitive to a wide range of xenobiotic exposures (including PCBs) and operative at the placentation site. AHR interacts with the AHR nuclear translocator (ARNT) to regulate transcription of an expansive cadre of genes encoding enzymes, transporters, etc. important in the biotransformation, metabolism, and detoxification of environmental pollutants. Among the AHR target genes is cytochrome P450 1A1 (CYP1A1). CYP1A1 can catalyze the biotransformation of both exogenous and endogenous substrates, which may contribute to the overall mechanism of xenobiotic action on placenta development. The impact of environmental exposures on placental development has received limited experimental attention. The foundation of our approach is that there is conservation in the actions of environmental exposures on placentation. Our efforts in this research proposal include complementary and interactive efforts with a relevant animal model, the rat, and with tissue specimens from human pregnancies. We will apply our expertise in developmental biology, toxicology, toxicogenomics, and perinatology to investigate the effects of environmental exposures on development of the hemochorial placenta. Our focus is on a signaling pathway responsive to xenobiotic action (AHR) rather than any one specific exposure. Aim No.1 utilizes rat models and trophoblast stem cells to investigate mechanisms associated with xenobiotic activated AHR signaling on rat placental development and will be performed at the University of Kansas Medical Center, Kansas City, whereas Aim No. 2 utilizes human placental tissue specimens and pregnant human subjects to investigate mechanisms associated with xenobiotic activated AHR signaling on human placental development and will be conducted at Children’s Mercy Kansas City. Understanding molecular mechanisms critical for placental development in a “physiological context” is a key to identifying relevant developmentally sensitive events that are susceptible to dysregulation by environmental exposures.