Towards a Human Exposome Cell Atlas

In December, the first session of the webinar series ‘ Towards a Human Exposome Cell Atlas’, co-hosted by UNESCO, the Global Exposome Forum, and the Human Cell Atlas took place to explore how connecting the Exposome and the Human Cell Atlas can advance global health understanding and impact. This session focused on endocrine disruptors and examined opportunities and challenges in combining single cell mapping (HCA) and exposomics to advance the Human Exposome Project and human health in general. The meeting brought together a wide range of experts for lightning talks and a panel discussion.

Fenna Sillé, PhD, Johns Hopkins University, co-organized and helped facilitate the event. Her presentation introduced audiences, who may have been otherwise unfamiliar, to the concept of the exposome and the role the Global Exposome Forum is playing in building global engagement by supporting regional efforts. Dr. Sillé emphasized the importance of facilitating exchange between science, policy, and precision medicine initiatives and detailed GEF’s strategy to support strong regional engagement combined with shared data systems to allow for information exchange and collaboration. In her presentation and closing remarks, Dr. Sillé also discussed the importance of approaching exposomics research from multiple levels and locals. Understanding how the exposome operates, not only at the individual level but also at the local, regional, and national level enables insights into population-wide health trends while informing strategies for prevention and intervention.

NEXUS MPI Chirag Patel, PhD, Harvard University was another panelist who spoke about integration of exposomics in single cell experiments.

Interrogating the standard model with functional exposomics with single cell ‘omics

The standard model for understanding disease variation is often summarized as P = G + E where our phenotype (P) is the result of both our genome (G) and our exposome (E). While the scientific community has made immense strides in mapping the “G,” there is a significant opportunity to gain new insights by looking closer at the “E”—the integrated compilation of physical, chemical, biological, and psychosocial influences that impact our biology. Rather than relying solely on population-level data, we can now look toward single-cell analysis as a powerful alternative for uncovering the mechanisms of environmental health.

Moving Beyond Bulk Data: An Alternative Perspective

Traditionally, researchers have looked at “bulk” tissue or blood samples to understand environmental impacts. However, single-cell exposomics offers a different path forward for identifying the biological impact of the world around us:

• Distinguishing Signal from Noise: While bulk analysis averages data across many cells, single-cell resolution helps determine what is truly transcriptional “noise” versus a genuine biological signal from an exposure.
• Cell-Type Specificity: This approach allows us to see how different cell types have distinct susceptibilities and adaptive strategies when faced with environmental stressors.
• Mapping Internal Architecture: Instead of just measuring an exposure in the blood, we can use spatial mass spectrometry to observe how molecular compositions are organized within individual cells.

Connecting the Dots: From Expression to Disease Mechanism

The most critical advantage of single-cell analysis is its ability to bridge the gap between exposure and the actual disease mechanism. While we can see associations between an exposure and a phenotype in large cohorts, single-cell expression data provides the “how”:

• Perturbing Pathways: If the exposome is causal, it must perturb specific biological pathways. Single-cell data allows us to observe these perturbations in the exact tissue and cells where the disease begins—such as the basal ganglia in cases of heavy metal exposure.
• Identifying Mediators: By examining the Human Exposome Architecture of the Proteome (HEAP), we can identify how lifestyle factors like diet and smoking impact biological mediators that lead to future disease.
• Uncovering Cellular Dynamics: We can move from static “snapshots” of exposure to understanding the cellular responses to environmental stimuli that ultimately drive disease progression.

Deciphering “Noise” as an Exposomic Signal

One of the most provocative shifts in this field is rethinking the concept of developmental noise. Work by Arjun Raj and others has demonstrated that while gene expression is heritable, a significant portion may be stochastic, leading to significant cell-to-cell variability even in genetically identical populations. What often appears to be “noise” may actually be a “primed” cellular state—a non-genetic fluctuation that dictates how a cell will later respond to environmental triggers.

In this view, the “chance” variation we see at the single-cell level is not just random error but potentially the fingerprint of subtle exposomic differences. For instance, certain cells may “remember” prior environmental stressors through non-genetic heritability, effectively rewiring their response to future challenges. Single-cell analysis allows us to decode this “noise,” revealing how the environment pushes a cell past a critical threshold into a disease-prone state.

How ExWAS Informs Single-Cell Testing

A common question in this field is which specific exposures to test—a question that can seem at odds with the agnostic goals of exposomics. However, Exposome-Wide Association Studies (ExWAS) act as a vital discovery engine that systematically filters environmental data to prioritize high-value candidates for single-cell interrogation.

Rather than contradicting the goal of discovery, this approach uses data-driven results to identify which exposures exhibit the strongest phenotypic or proteomic signatures, such as the pleiotropic effects observed with heavy metals or lifestyle markers in diet and smoking. By grounding subsequent single-cell experiments in these “ExWAS-prioritized” hits, researchers can move from broad population-level snapshots to mechanistic testing, pinpointing exactly how specific stressors perturb biological pathways within tissue-specific cell types.

From Target II to NEXUS

This transition to cellular resolution is a natural evolution of past work. Programs like the NIEHS Target II provided a vital starting point by focusing on how environmental insults impact genomic and epigenomic regulators. We are now building upon that legacy by:

• Expanding the Atlas: Current research has already mapped an “Exposome-Phenome Atlas” consisting of 619 targeted exposures against 278 clinical phenotypes. This research is in the press.
• Integrating Multi-Omics: By combining environmental insights with the proteome, we can see how factors like exercise or diet impact biological pathways independently of genetics.

The Vision: From Discovery to Intervention

The potential for a Human Exposome Single-Cell Atlas isn’t just about discovery; it’s about finding new ways to intervene. We have already seen that exposome-associated protein signatures are concordant with the results of clinical interventions, such as exercise training or GLP1-RA treatments. By viewing health through the lens of the single cell, we gain a more precise alternative for predicting, preventing, and eventually reversing the biological impacts of the world around us.

References

• NEXUS Network Portal: https://www.nexus-exposomics.org/
• Chirag Patel Group Research: https://www.chiragjpgroup.org/
• Science (2025) - Integrating Exposomics into Biomedicine: https://www.science.org/doi/10.1126/science.adr0544
• HEAP: Human Exposome Architecture of the Proteome: https://heap.bio/
• XWAS Resource (Multidimensionality of Aging): https://www.multidimensionality-of-aging.net/xwas
• CaTCH: Claims Analysis of Twin Correlation and Heritability: http://apps.chiragjpgroup.org/catch/

Appendix: Priority Pleiotropic Exposures (ExWAS)

Based on recent ExWAS findings, the following exposure domains show significant broad-spectrum (pleiotropic) associations with clinical phenotypes:

• Watch the webinar here: https://www.youtube.com/watch?v=4qQJwR_J7d8
• Learn more about the webinar series: https://events.humancellatlas.org/exposome/9816712