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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
4DP2ES025453-02
Application #
9696042
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Cui, Yuxia
Project Start
2014-09-30
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Claus Henn, Birgit; Austin, Christine; Coull, Brent A et al. (2018) Uncovering neurodevelopmental windows of susceptibility to manganese exposure using dentine microspatial analyses. Environ Res 161:588-598
Horton, Megan K; Hsu, Leon; Claus Henn, Birgit et al. (2018) Dentine biomarkers of prenatal and early childhood exposure to manganese, zinc and lead and childhood behavior. Environ Int 121:148-158
Curtin, Paul; Austin, Christine; Curtin, Austen et al. (2018) Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder. Sci Adv 4:eaat1293
Morris-Schaffer, Keith; Sobolewski, Marissa; Allen, Joshua L et al. (2018) Effect of neonatal hyperoxia followed by concentrated ambient ultrafine particle exposure on cumulative learning in C57Bl/6J mice. Neurotoxicology 67:234-244
Zheng, Laura Y; Sanders, Alison P; Saland, Jeffrey M et al. (2017) Environmental exposures and pediatric kidney function and disease: A systematic review. Environ Res 158:625-648
Chiu, Yueh-Hsiu Mathilda; Claus Henn, Birgit; Hsu, Hsiao-Hsien Leon et al. (2017) Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor function in adolescents. Environ Res 159:458-465
Austin, Christine; Richardson, Cardius; Smith, Donald et al. (2017) Tooth manganese as a biomarker of exposure and body burden in rats. Environ Res 155:373-379
Smith, Tanya M; Austin, Christine; Hinde, Katie et al. (2017) Cyclical nursing patterns in wild orangutans. Sci Adv 3:e1601517
Velthorst, Eva; Smith, Lauren; Bello, Ghalib et al. (2017) New Research Strategy for Measuring Pre- and Postnatal Metal Dysregulation in Psychotic Disorders. Schizophr Bull 43:1153-1157
Morishita, Hirofumi; Arora, Manish (2017) Tooth-Matrix Biomarkers to Reconstruct Critical Periods of Brain Plasticity. Trends Neurosci 40:1-3

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