Getting the right exposure

Understanding the totality of environmental exposures from conception onward and what that might do to our health. That is the ambition of exposomics and it is an incredibly tough undertaking – but, says Benedikt Warth, it is absolutely key to understanding chronic disease

Tell us a bit about your work at the global exposomics and biomonitoring group.

In one sentence, we try to understand the impact of environmental molecules on human health.

Our lab applies a multi-disciplinary approach to better understand the impact of chemicals in food and the environment on health and disease from a global perspective. This includes contaminants that can cause adverse effects but also food constituents with potential protective properties as well as their complex interactions at various levels. We combine mass spectrometry, in vitro toxicology and systems-based approaches to investigate exposure, metabolism, and toxicity.

The concept of the ‘exposome’ aims towards the holistic investigation of lifetime exposures and their biological/toxicological consequences. The untargeted assessment of exposure towards xenobiotics in human bio-fluids is currently entering center stage in the field of exposure science and public health research. We work on establishing new exposomics technology based on high-resolution mass spectrometry (HR-MS) to allow for global exposure assessment. Thereby we generate new hypotheses regarding environmental causes of chronic disease and deciphering combinatory toxic effects and drug-exposome interactions. Besides, we develop targeted biomonitoring assays to accurately quantify exposure towards different classes of food contaminants including mycotoxins and xenoestrogens in urine, plasma, and breast milk.

The exposomics approach seems very ambitious – almost dauntingly so. What are the main challenges?

It is challenging although we have already had some very notable successes, our recent study on xenoestrogens for example¹. And while it is true that the concept is highly ambitious and there is also some controversy on its utility, I am convinced it will be of great value. In my opinion, a key challenge is the establishment and thorough evaluation of suitable analytical workflows covering both, a wide array of molecules with different chemical properties and a broad range of different concentrations. Also, the identification of metabolites in untargeted mass spectrometry-based analyses is still an issue. Finally, it is highly complex to link chemical exposures with a specific biological effect or disease phenotype.

Interestingly, these challenges are very similar to those the field of metabolomics faced about a decade ago. I believe exposomics research can significantly benefit from the lessons learnt in global metabolomics and the advances in high-end instrumentation and new bioinformatics approaches. We were able to demonstrate this in a couple of proof-of-principle experiments in which we developed a global exposure metabolomics workflow and created the largest exposome database for the identification of xenobiotics (METLIN Exposome)².

So it certainly could yield a lot of data and, potentially, knowledge – but do we really need another 'omic?

This is an interesting question as I am personally also very critical regarding many of the proposed ‘pseudo-omics’ disciplines. However, in the case of the exposome I am convinced that the high degree of complexity as well as its unique challenges and tremendous impact on human health fully justify it as an own scientific discipline. It is also noteworthy to mention that the ‘exposome’ was first proposed in 2005 by Christopher Wild, a leading cancer epidemiologist³. That was only seven years after the first paper on ‘metabolomics’ was published. Due to its complexity it just took more time to truly take off.

The most critical point will be to apply an interdisciplinary approach involving exposure scientists, analytical chemists, bioinformaticians, epidemiologists, and toxicologists. There is a realistic risk we will strangle ourselves in complexity if we are not able to combine complementary expertise and extract meaningful conclusions. While I assume many of the new ‘omics’ will disappear in the future, I expect that we will deal with the ‘exposome’ for at least a couple of decades. Personally, I am glad to be pretty young and have at least four decades to work in this exciting field.

How have the scientific community reacted to the kind of 'meta-omic' approach of exoposomics?

On the one hand the community is enthusiastic as it is well-known that genetics can explain only a relatively small fraction of chronic disease. The impact of the environment (exposome) on disease susceptibility is far more relevant though clearly under-researched.

On the other hand there is skepticism since some researchers are afraid that toxicants, very low in abundance but highly biologically potent, may escape global screening approaches. This is certainly a valid point that needs to be addressed. Hence, in our lab we propose a dual approach comprising untargeted HR-MS screening as well as highly accurate quantitative biomonitoring of all these toxicants, natural contaminants, drugs etc.

Food contaminants are clearly a focus for you ­– how important is this as many populations continue to rely on heavily processed food?

Our diet is a very important contributor to our exposome. In food many bio-active molecules may be found, some with potentially beneficial properties such as polyphenols, some with adverse effects like mycotoxins. Investigating their combinatory biological/toxicological effects is currently a hot topic. Since these interactions are again highly complex our approach is to investigate them in human cell models to understand the metabolic pathways affected by combined exposure.

In our most recent work we could also demonstrate that these food bio-actives have the potential to modulate drug action¹. Specifically, we showed that estrogen-mimicking molecules occurring in our food heavily modify the metabolic effect of a combined breast cancer therapy. This area of drug-exposome interactions calls for more investigations as it is likely that many food-related metabolites may not only be associated with disease but also with drug efficacy.

References

1. Warth, B. et al. (2018) Dietary xenoestrogens significantly alter cellular metabolism induced by palbociclib/letrozole combination cancer therapy. Cell Chemical Biology 25, 291-300
2. Warth, B. et al. (2017) Exposome-Scale Investigations Guided by Global Metabolomics, Pathway Analysis, and Cognitive Computing. Analytical Chemistry 89, 11505-11513
3. Wild, C. P. (2005) Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiology Biomarkers and Prevention 14, 1847-1850

 Benedikt Warth is Assistant Professor at the Department of Food Chemistry and Toxicology, Global Exposomics & Biomonitoring Group based at the University of Vienna

http://exposomics.univie.ac.at