PROJECT SUMMARY/ABSTRACT Periods of fetal, infant, and early childhood development are remarkably venerable to environmental hazards, and exposures to toxic chemicals during these critical windows of susceptibility have been linked with disease, disabilities, and adverse health in childhood and across the entire life span. Consequently, the timing of exposure during early-life is a critical factor to consider when investigating environmental causes of disease. As a complement to the human genome, the concept of the exposome—representing the totality of human exposures occurring from conception onward— has become increasingly salient in the field of environmental health sciences for investigating disease etiologies. While it is currently not possible to measure all chemicals in blood samples using single experiments (analogous to gene-wide association studies for measuring genes), important classes of chemicals can be investigated during critical period of development. One important class of chemicals is electrophiles, which are highly reactive compounds that have been linked to a vast majority of cancers and chronic diseases. Electrophiles have both exogenous (e.g., environmental pollutants and diet) and endogenous (e.g., oxidative stress and inflammation) sources, and thus reflect a broad spectrum of important molecules ranging across the entire exposure-disease continuum. However, because electrophiles tend to have very short life spans in vivo, they normally cannot be measured directly in blood samples. This has motivated the use of protein addition products (adducts) as biomarkers for estimating exposures to reactive electrophilic chemicals, which reflect an integration of exposure to short-lived electrophiles over the residence time of the protein (e.g., weeks to months). In this proposal we will apply a two-stage approach that directly aligns with the NIEHS 2012-2017 Strategic Plan. First, we will apply a new omics strategy called adductomics to map the early-life exposome from before birth onward to age 21. Using data from these experiments, as well as data collected from collaborating laboratories, we will then crate a library of all detectable HSA-Cys34 adducts. Finally, we will develop and validate a high-throughput muiltiplexed assay for quantifying panels of targeted adducts in dried blood samples—drops of blood collected on filter paper using a simple and minimally-invasive heel or finger prick. Given the overwhelming lack of human in vivo data on early-life environmental exposures and their impacts on children’s health, this proposal offers a unique opportunity to bridge this critical gap in scientific knowledge. The biomarker approaches developed in this proposal will provide the first maps of the early-life adductome, and will provide specific tools for investigating environmental causes of diseases and disorders in future studies.
|Effective start/end date||9/1/16 → 2/29/20|
- National Institute of Environmental Health Sciences (5R21ES026776-02)
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