Citation:

Schymanski, E., N. Baker, A. Williams, R. Singh, J. Trezzi, P. Wilmes, P. Kolber, R. Kruger, N. Paczia, C. Linster, AND R. Balling. Connecting environmental exposure and neurodegeneration using cheminformatics and high resolution mass spectrometry: potential and challenges. Environmental Science: Processes & Impacts. RSC Publishing, Cambridge, Uk, 21:1426-1445, (2019). https://doi.org/10.1039/c9em00068b

Impact/Purpose:

Rapid developments in analytical techniques over the last decades have opened up new opportunities such as non-target high resolution mass spectrometry (NT-HR-MS) to explore the impact of humans on the environment, as well as the effect of environmental contamination on humans and other organisms. With growing accessibility and maturity in analytical methods, these are being applied to increasingly complex research questions and hypotheses. In this perspective article, we take a close look at the challenges in identifying “neurotoxicants” in the context of chronic neurodegenerative diseases and use this case study to explore the potential and limitations of NT-HR-MS to support answering these questions. Ultimately, solving complex challenges such as these will need a systems approach, requiring knowledge that crosses many disciplines. While the main focus of this article, determining which (relevant) chemicals are present in environmental or biological samples (let alone their mode of action), is already a daunting task, it is a necessary foundation to enable the elucidation of functional effects and generation of hypotheses for a greater understanding of the causes of complex diseases and environmental impacts.

Description:

Connecting chemical exposures over a lifetime to complex chronic diseases with multifactorial causes such as neurodegenerative diseases is an immense challenge requiring a long-term, interdisciplinary approach. Rapid developments in analytical and data technologies, such as non-target high resolution mass spectrometry (NT-HR-MS), have opened up new possibilities to do this, inconceivable 20 years ago. While NT-HR-MS is being applied to increasingly complex research questions, there are still many unidentified chemicals and uncertainties in linking exposures to human health outcomes and environmental impacts. In this perspective, we explore the possibilities and challenges involved in using NT-HR-MS to answer complex questions that cross many scientific disciplines, taking the identification of potential (small molecule) neurotoxicants in environmental or biological matrices as a case study. We explore capturing literature knowledge and patient exposure information in a form amenable to highthroughput data mining, and the related cheminformatic challenges. We then briefly cover which samples are available, which method(s) could potentially be used to detect these chemicals in various matrices and what remains beyond the reach of NT-HR-MS. We touch on the potential for biological validation systems to contribute to mechanistic understanding of observations and explore which sampling and data archiving strategies may be required to form an accurate, sustained picture of small molecule signatures on extensive cohorts of patients with chronic neurodegenerative disorders. Finally, we reflect on how NT-HR-MS can support unravelling the contribution of the environment to complex diseases. The views expressed are those of the authors and do not necessary reflect the view or policy of the US Environmental Protection Agency.

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