Unlocking the Exposome with Metabolon’s Comprehensive Metabolomics Platform

4.0 Introduction

4.1 Reliable Metabolomics for Assessing Exposures

As discussed in the last chapter, some of the major challenges in exposome research are accurately annotating biochemicals, achieving sufficient pathway coverage, and limitations inherent to sample matrices themselves. As an industry leader, Metabolon has developed innovations that may offer solutions to these challenges.

Multiple methods of chromatography. To grant the highest possible confidence to the identity of metabolites, especially isomers and biochemicals that are structurally similar, samples are subjected to multiple chromatography methods that are optimized to separate hydrophilic, hydrophobic, basic, and acidic compounds. Using multiple methods results in superior compound separation and builds analytic redundancy into the method to allow compounds with overlapping chemical characteristics to be identified with the highest confidence.

Data acquisition and analysis tools. Metabolon’s proprietary software addresses the issue of inadequate pathway coverage by allowing thousands of biochemicals from 70+ pathways to be rapidly annotated and then aligned with data from the scientific literature. These tools also allow merging of metabolomics data from studies run at different times as well as integration with other -omics datasets to maximize biological insight and interpretability. Furthermore, these tools maximize the reproducibility of results.

Experience with diverse sample types. In some cases, understanding the biological context of exposures requires more than one sample type to be analyzed. Metabolon has extensive experience with a variety of sample matrices including plasma, serum, urine, feces, saliva, and multiple types of tissue. In other cases, generating impactful exposome data calls for samples from remote groups or groups in low resource settings to be collected and analyzed. Metabolon also has extensive experience with dried blood spots (DBS), which can be easily and cost-effectively collected, stored, and shipped, enabling a potential solution to this logistical challenge.

Highest accuracy metabolite identification, confirmed with authentic reference standards (MSI Level 1², see Chapter 5 for further detail on metabolite annotation). This provides confidence in metabolite identifications, which is essential for deriving correct biological conclusions and for generating reproducible data that can drive discovery and inform policy.

Another challenge faced in exposome research is the reliability of annotation and quantification of untargeted approaches. Metabolon’s rich library of authentic reference standards, combined with rigorous quality controls, enables our Global Discovery Panel to demonstrate the capacity to capture the complexity of the exposome with high reliability. A study conducted at Uppsala University showed a strong correlation between PFAS metabolites identified using Metabolon’s Discovery Panel and results from an independent targeted assay (Figure 3.1)³. This concordance illustrates that broad, untargeted metabolomics can deliver data with the same dependability as traditional targeted methods. Such validation confirms that Metabolon’s approach is both expansive and precise, ensuring that discoveries across the exposome are biologically meaningful and quantitatively trustworthy. This analytical strength reinforces the platform’s role as a cornerstone for comprehensive exposome coverage.

Figure 4.1: MCorrelation of a targeted method (x-axis) for measuring PFOS (left) and PFHxS (right) versus Metabolon’s Global Discovery Panel (y-axis). Figure adapted and modified from Salihovic 2024 et al³

4.2 Coverage of the Exposome

Metabolon’s Global Discovery platform is well suited for assessing both the internal and specific external exposome (see Chapter 1). The Global Discovery Panel detects diverse xenobiotics, environmental contaminants and microbial products categorized by source:

• • Industrial Applications
    Research chemicals, plastics, metals, pharmaceutical intermediates, industrial chemicals, polymers, flame retardants, and PAHs.
  • Consumer Products
    Colorants, flavorants, preservatives, natural product additives, caffeine, tobacco-related compounds, cosmetics, and food additives.
  • Anthropogenic Activities
    Signatures from agriculture (e.g., pesticides, herbicides, fungicides), cooking byproducts, water runoff, waste management, and urban pollution.
  • Persistent and Halogenated Chemicals
    PFAS, halogenated organics, and other long-lived pollutants.
  • Diet Derived Metabolites
    Polyphenols, flavonoids, and caffeine metabolites.
  • Pharmaceuticals
    Analgesics, antibiotics, anti-inflammatory, antineoplastic, antiviral, cardiometabolic, and other drug classes.
  • Microbiome-mediated metabolism
    Tryptophan/indole metabolism, aromatic amino acids, and bile acids.

In addition to our Global Discovery Panel, Metabolon has a suite of targeted panels that enable absolute quantification of exposome metabolites:

A person’s diet, their gut microbiota composition, and their systemic response to these biological factors are important components of both the internal and external exposome. Formation of short chain fatty acids (SCFAs) occurs through a complex interaction between the diet, gut microbiota, and host. SCFAs influence the physiology of the colon by serving as energy sources for host cells and the intestinal microbiota and by participating in various host-signaling mechanisms. The Short Chain Fatty Acids Targeted Panel provides absolute quantitation of 9 metabolites and is available for research use only (RUO) or good clinical practice (GCP) use, depending on sample type.

4.3 Detection History Across Matrices

Decades of performing metabolic profiling studies have allowed Metabolon to amass significant knowledge about the identity of various classes of exposome molecules. The exposome is particularly challenging to annotate because in biological samples environmental chemicals are typically present in lower (trace or sub-nanomolar) concentrations compared to endogenous metabolites. Also, unlike endogenous compounds, which are consistently produced and regulated by metabolic pathways, environmental chemicals enter the body sporadically and vary based on exposure frequency, route, and individual metabolism. Furthermore, many environmental chemicals undergo rapid biotransformation and clearance, resulting in transient presence or conversion into diverse, low-abundance metabolites. Thus, having a long detection history can significantly aid in the accurate identification of exposome metabolites.

Table 4.1 demonstrates the detection history of environmental exposures in plasma using Metabolon’s biochemical reference library. Metabolon works with a variety of matrices. It is important to note that metabolite detection patterns are matrix- dependent because depending on the biology, bioaccumulation may occur in specific tissues. Metabolon frequently adds new metabolites to the library as our understanding of exposure and its impact grows.

The breadth of coverage provided by Metabolon’s library ensures robust detection of both common and rare exposure biomarkers in diverse biological contexts.  

Table 4.1: A summary of how frequently certain classes of molecules in the exposome are detected with the highest MSI confidence (Level 1). Total LIB = Total metabolites in the library for each category.

4.4 Consequences of Exposure: Downstream Biological Insights

Although directly measuring exposures such as chemicals, diet, drugs, and behaviors (the specific external exposome) provides valuable insight into environmental influences, it is essential to also understand their biological consequences if the true health impact (the internal exposome) is to be known. Many exogenous metabolites are volatile, unstable, or rapidly cleared, making them difficult to consistently detect across timepoints or individuals. In contrast, the downstream metabolic responses they trigger including inflammation, oxidative stress, or disrupted energy metabolism, are often more persistent and measurable. By capturing both the exposure and its biological fingerprint, researchers gain a more comprehensive and actionable view of risk, resilience, and disease mechanisms. Metabolon’s profiling enables detailed examination of the physiological consequences of environmental exposure through:

4.4.1 Pathway Disruption Analysis

Exposures often perturb critical biochemical networks, including:

• • Lipid metabolism
  • Amino acid metabolism
  • Mitochondrial energy production

Air pollutants like PM2.5, NO2, PM10, and O3 are known to exacerbate asthma through oxidative stress, inflammation, and immune activation. In the Children’s Health Study cohort, the metabolic and transcriptomic impact of short and long-term pollutant exposures were assessed4. Dysregulated beta-alanine and glycine metabolism was correlated to poor asthma control following PM2.5 and NO2 exposure. Increases in oxidative stress were observed following PM10 and O3 exposure. Additionally, poor asthma control was negatively associated with aspartate, choline, and carnosine. This study demonstrates how metabolomics provides insights into how exposures disrupt pathways. Understanding the consequences of air pollutants in asthmatics enables the development of preventative and therapeutic modalities.

4.4.2 Biological Response Profiling

Exposure-associated dysfunctions include:

• • Oxidative stress and redox imbalance
  • Mitochondrial dysfunction
  • Immune system modulation
  • Hormonal disturbances

In a skin study by the Sino-German Cosmetics Institute, metabolomics and 16S metagenomics were combined to explore how chronic air pollution impacts human skin health by affecting both the skin barrier and microbiota5. Researchers examined women from two cities with differing pollution levels to identify associations between environmental exposure, skin microbiota composition, metabolite profiles, and visible skin signs. They found that pollution aggravated skin disorders including eczema, acne, lentigines, and wrinkles, with changes in the microbiome contributing to these effects. Untargeted metabolomic profiling revealed disruptions in lipid and amino acid metabolism, including elevated levels of pyrrolidone carboxylic acid (PCA), a key moisturizing factor that results from filaggrin proteolysis, which may be a compensatory response to environmental pollutants. Ultimately, the study showed that metabolomics provides a functional lens to directly observe how pollution biochemically shapes skin chemistry and appearance.

4.4.3 Health Outcome Associations

Exposure-related metabolite profiles are linked to disease progression in large cohort studies. For example, in the COPSAC cohort, prenatal and early-life exposure signatures correlated with childhood inflammation and metabolic disease risk6. Longitudinal untargeted metabolomics performed on serum samples from mothers (pregnant and postpartum) and their children demonstrated that asthma risk correlated to higher maternal PFOS exposure independent of inflammation, immune response, and epigenetic alterations. Evaluating metabolic changes over time enabled researchers to draw a clear line between exposure and long-term asthma outcomes providing actionable prevention strategies.

Summary

Metabolon’s platform enables researchers to decode the exposome by providing:

• Specific detection of diverse environmental exposures.
• Biological interpretation through validated, untargeted metabolomics.
• Translational insight linking exposure to disease biology.

As metabolomics becomes central to exposome science, Metabolon’s tools are uniquely positioned to enable precision environmental health research and population-wide risk stratification especially because Metabolon offers solutions to some of the most challenging aspects of exposome research. These challenges and Metabolon’s approach to addressing them are summarized in Table 4.2.

Table 4.2