I seek funding to extend my training in epidemiology in two new directions-namely, human placental biologyand mass spectrometry. Learning these laboratory-based methods will move me closer to accomplishing mylong-term goals of becoming an independent academic investigator and offering new insights and methods toresearch on low dose chronic exposures to endocrine disrupting compounds and their role in health disordersthat originate in early pregnancy. During the K99 phase, under the primary mentorship of Dr. Susan Fisher, Iwill receive training in trophoblast (Tb) stem cell biology, state-of-the-art microarray-based methodologies thatare used to analyze gene expression at a global level, including bioinformatics approaches for data analysis.Building on the results of my initial post-doctoral research, I theorize that Tbs, the specialized cells that carryout many of the placenta's most important functions, are exposed to phthalates early in pregnancy withadverse consequences on placental development and function. We will test hypotheses regarding clinicaloutcomes and biological parameters that include molecular, cellular, and morphologic measures of humanplacental development and function. Specifically, I will conduct experiments to test the hypothesis that culturedhuman Tb stem cells will show dose-dependent changes in patterns of gene expression when they areexposed to environmentally relevant doses of di-(2-ethylhexyl) phthalate and di-n-butyl phthalate (Aim 1).During the R00 phase, I will test the theory, in a longitudinal study of pregnant women, that placental genesthat are differentially expressed as a consequence of phthalate exposure in vitro are similarly regulated, in adose-dependant manner, in vivo (Aim 2). As part of this aim, I will evaluate the correlation between theconventional dosimeter of prenatal exposure, urinary phthalate metabolite concentrations, and the dose to thetarget placental tissue. My primary mentor and co-mentors in obstetrics/gynecology, mass spectrometry,biostatistics, and epidemiology will guide the process whereby I learn the methods that are required toaccomplish the goals set forth in this proposal. At the conclusion of this training program I will have developednew methodologies and tools that I and other investigators can use to ask more directed questions about theconsequences of phthalate exposures during pregnancy in terms of alterations in placental function andconsequently, human development. This work is important because phthalates, which can disrupt cell andtissue differentiation, are well established as reproductive and developmental toxicants in rodents; yet therelevance of these finding to humans is not well understood. With biomarkers specific to phthalate-inducedplacental damage, it will become possible to identify high-risk pregnancies and provide opportunities forprevention, at the population level, and possibly intervention at the level of health care delivery systems toimprove placental and fetal outcomes.
The goal of this project is to prepare Dr. Jennifer Adibi to transition to a position as an independent academicinvestigator in environmental health sciences focusing on the consequences of phthalate exposures duringhuman pregnancy. She will conduct experiments using in vitro and in vivo models to test the hypothesis thatthis toxicant disrupts trophoblast differentiation; and therefore placental development and function; therebycompromising human development in utero.