DESCRIPTION (provided by applicant): Experimental animal studies have shown that fetal exposure to low levels of environmental toxicants can produce measurable neurologic impairments and other health disorders. Translating this research to humans is hampered by the lack of methods to objectively measure two principle components in the exposure-disease pathway: (i) fetal exposure and (ii) fetal homeostatic disruptions. The greatest challenges in feta exposure assessment are the lack of biomarkers that directly measure fetal exposure at specific intrauterine developmental periods and the inability to objectively reconstruct past exposure timing. Blood assays are most commonly used for determining environmental toxicant exposure in adults. However, it is not possible to routinely sample fetal blood in human studies. Furthermore, while maternal blood may be collected during pregnancy, chemicals in mother's blood are not a direct measure of fetal exposure because of the marked variability in placental transfer. The inability to retrospectively measure fetal exposure is particularly relevant to the study of diseases that occur at a lower frequency. As a consequence, establishing prospective cohort studies becomes essential to generate high-quality evidence but such an approach is not feasible for low frequency diseases. Fetal homeostatic disruptions remain understudied, but are crucial for a comprehensive understanding of how early life toxicant exposures affect different body systems. It is now recognized that measuring exposure in itself is not sufficient to study health risks but rather it is important to measure whether exposure to a toxicant is accompanied by disruption of key physiological pathways that would ultimately increase the risk of a clinically detectable disease. We propose a fundamentally new methodology to study the fetal environment and homeostatic disruptions based on the laboratory methods we have developed. First, we will develop an analytical methodology to provide detailed temporal information on toxicant exposure at 5 to 10 day resolution to capture exposure events that occur over a narrow timescale. For this we will utilize newly developed laser ablation- and synchrotron radiation-based techniques and use a combination of human and animal studies. Second, we propose a novel method to uncover the imprint of homeostatic disruptions over the pre- and postnatal periods, and we provide preliminary data to support our proposition. By studying disruption of physiologic pathways in conjunction with environmental exposures we will be able to more accurately study the fetal determinants of disease. Third, we propose to develop a novel method of multi-dimensional mathematical modeling that will allow us to study complex mixtures over time, allowing us to translate our work to population studies.

PUBLIC HEALTH RELEVANCE: We propose to develop a fundamentally new methodology to study fetal programming by environmental toxicants and stress, and the associated risks of long-term health disorders. The most important aspect of the proposed methodology is that it can retrospectively reconstruct fetal environmental and homeostatic insults at different stages of intrauterine development. This is a paradigm shift in the study of rare diseases because, for the first time, case-control studies will be able to obtain time-series data on early life environmenta exposures. Not only do we aim to develop the laboratory analytical techniques, but as part of this project we will also develop a novel mathematical modeling approach that will allow rapid translation of our work to the study of fetal determinants of disease in population based studies.