Building the Environmental Chemical-Protein Interaction Network (eCPIN): An Exposome-Wide Strategy for Bioactive Chemical Contaminant Identification

Abstract

Although advancements in nontargeted analysis have made it possible to detect hundreds of chemical contaminants in a single run, the current environmental toxicology approaches lag behind, precluding the transition from analytical chemistry efforts to health risk assessment. We herein highlighted a recently developed “top-down” bioanalytical method, protein Affinity Purification with Nontargeted Analysis (APNA), to screen for bioactive chemical contaminants at the “exposome-wide” level. To achieve this, a tagged functional protein is employed as a “bait” to directly isolate bioactive chemical contaminants from environmental mixtures, which are further identified by nontargeted analysis. Advantages of this protein-guided approach, including the discovery of new bioactive ligands as well as new protein targets for known chemical contaminants, were highlighted by several case studies. Encouraged by these successful applications, we further proposed a framework, i.e., the environmental Chemical-Protein Interaction Network (eCPIN), to construct a complete map of the 7 billion binary interactions between all chemical contaminants (>350,000) and human proteins (∼20,000) via APNA. The eCPIN could be established in three stages through strategically prioritizing the ∼20,000 human proteins, such as focusing on the 48 nuclear receptors (e.g., thyroid hormone receptors) in the first stage. The eCPIN will provide an unprecedented throughput for screening bioactive chemical contaminants at the exposome-wide level and facilitate the identification of molecular initiating events at the proteome-wide level.

Disclosing Environmental Ligands of L-FABP and PPARγ: Should We Re-evaluate the Chemical Safety of Hydrocarbon Surfactants?

“…To identify environmental contaminants binding to L-FABP and PPARγ in indoor dust and sewage sludge, APNA was employed. − In this study, indoor dust and sewage sludge were selected for testing because they represent important reservoirs for commercial chemicals and have long been used as promising sources to measure the collective consumption or chemical exposure of humans. , To prepare the indoor dust or sewage sludge extracts, approximately 0.5 g of indoor dust or freeze-dried sewage sludge was extracted twice with 5 mL of methanol, and the extracts were blown down and reconstituted to a final volume of 1 mL before use. His-tagged full length L-FABP or His-tagged PPARγ ligand binding domain (LBD) were overexpressed in E. coli cells.…”

“…A bioanalytical method “protein A ffinity P urification with N ontargeted A nalysis (APNA)” has been proposed in our previous studies for the screening of protein ligands in the environment, on the exposome-wide level. − Distinct from the conventional EDA method relying on LC fractionation, APNA uses a tagged protein (e.g., NR) as a “bait” to directly isolate ligands from environmental mixtures consisting of thousands of chemicals . This overcomes the major challenge of coelution in EDA and largely reduces false discovery rates.…”

“…25−29 Distinct from the conventional EDA method relying on LC fractionation, APNA uses a tagged protein (e.g., NR) as a "bait" to directly isolate ligands from environmental mixtures consisting of thousands of chemicals. 29 This overcomes the major challenge of coelution in EDA and largely reduces false discovery rates. This method has been employed in our recent studies to identify chemical contaminants binding to multiple human 25−27 and bacterial proteins.…”

Amino Acid Transporter as a Potential Carrier Protein for the Root-to-Shoot Translocation of Polybrominated Diphenyl Ethers in Rice

“…Conventional chemical approaches, such as fluorescence spectra, circular dichroism (CD), and sorption equilibrium studies, can uncover the quenching mechanisms, changes in secondary structures, and ligand–receptor maximal binding capacity. − Functional genomic approaches, such as CRISPR/Cas9 gene editing, can reveal the direct links between the genes of interest and the corresponding loss of function ( e.g. , increased resistance or susceptibility to the chemical exposure). − The combined use of chemical and gene editing techniques offers a comprehensive approach to examining PBDE translocation in plants, shedding light on both biological and chemical mechanisms underlying this behavior. Additionally, computational simulation ( e.g.…”

Exploring Single-Cell Exposomics by Mass Spectrometry

“…This approach can provide insights into how these exposures influence health and disease at the molecular level, leading to the development of novel biomarkers and prevention strategies. For example, single-cell exposomics can be combined with proteomics to investigate the protein binding effects of exposure to a specific environmental carcinogen on individual lung cells . This approach could reveal a diverse range of individual cellular responses, driven by complex molecular pathways, that would have been obscured in traditional bulk analysis.…”