Assessing the Risks of Chemical Exposures for Neurodegenerative Diseases

Introduction

In recent years, many environmental chemicals, from solvents to pesticides, have been implicated in the development and progression of neurodegenerative diseases. However, a systematic approach akin to genome-wide association studies, which have identified dozens of genes associated with Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative disorders, has been lacking thus far. Fortunately, it is now possible to study hundreds to thousands of chemical features within an exposome framework. This emerging approach leverages advances in mass spectrometry techniques to generate exposomic data that can complement genomic data, thereby better elucidating the underpinnings of neurodegenerative diseases.

As human lifespan increases, age-related neurodegenerative diseases have become leading causes of disability and death. The two most common neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD), affect over 45 million and 6 million people worldwide, respectively. Although clinically distinct, these diseases share common pathogenic mechanisms, such as misfolded protein aggregation, disruption of protein degradation systems, mitochondrial dysfunction, increased blood-brain barrier (BBB) permeability, and neuroinflammation. These processes ultimately lead to neuronal death.

Despite sharing similar pathogenic processes, a common etiology beyond aging has yet to be identified for these diseases. Both AD and PD (in their vast majority of sporadic cases) are multifactorial diseases caused by a combination of genetic and environmental risk factors. Multiple susceptibility loci identified to date are disease-specific and explain only a fraction of cases. Hence, exploring the relationship between environmental exposures and neurodegenerative diseases is of paramount importance.

Paper Source

This paper is authored by S. Lefèvre-Arbogast (University of Bordeaux), J. Chaker (University of Rennes), F. Mercier (University of Rennes), R. Barouki (Paris City University), X. Coumoul (Paris City University), G.W. Miller (Columbia University), A. David (University of Rennes), and C. Samieri (University of Bordeaux).

The paper was published in Volume 27 of Nature Neuroscience, issued in May 2024.

Research Content and Findings

Epidemiological evidence for chemical exposures and neurodegenerative diseases

Most research has focused on pesticides, metals, solvents, and fine particulate matter (PM2.5). The most consistent evidence to date is for occupational pesticide exposure being associated with increased risk of PD, followed by increased risk of AD. Some biomarker studies have also linked low-level exposures to increased disease risk. Evidence for metals, solvents, and PM2.5 is more limited and inconsistent. As for synthetic additives (such as flame retardants, plasticizers, etc.), there is almost no epidemiological evidence.

Effects of chemical toxicity on pathways relevant to neurodegenerative diseases

Abundant experimental studies have shown that various chemicals can impact multiple molecular pathways implicated in neurodegenerative diseases, such as oxidative stress, mitochondrial dysfunction, neurotransmitter dysregulation, misfolded protein aggregation, neuroinflammation, and altered BBB permeability. Metals, pesticides, organic solvents, and combustion pollutants have been most studied, while new insecticides and synthetic additives have received less attention.

Research gaps and challenges

1. Integrating exposure sources, expanding chemical lists of interest Current research has overlooked many emerging chemical exposures, such as new insecticides, flame retardants, perfluorinated compounds, plasticizers, etc., despite their potential neurotoxic effects. The impacts of microplastics and nanomaterials on the nervous system have also been rarely studied.

2. Challenges in extrapolating from animal models to human health Animal models often employ unrealistic dosing regimens and seldom consider the toxicity of metabolites; cell or tissue models also struggle to recapitulate real-world exposure patterns.

3. Improving predictive neurotoxicology methods Limited toxicokinetic data on the absorption, distribution, metabolism, and excretion of chemicals hinders the prediction of their ability to reach and adversely affect the brain.

4. Elucidating mixed exposure effects Existing studies largely focus on single chemicals, overlooking potential additive or synergistic effects from co-exposure to multiple chemicals in complex environments.

Delineating the endogenous chemical exposome through high-throughput molecular approaches

The exposome concept integrates environmental exposures with biological responses within a unified framework. Advances in high-resolution mass spectrometry (HRMS) now enable the simultaneous measurement of thousands of exogenous chemicals and their metabolites in biological samples, providing unprecedented opportunities to explore the association between the chemical exposome and neurodegenerative diseases.

While HRMS faces technical challenges such as limited detection capabilities, restricted chemical space coverage, and complex annotation processes, it represents an innovative and powerful approach overall. Some preliminary HRMS studies have already identified chemical species associated with AD and PD, paving the way for larger-scale epidemiological investigations.

Summary

Chemical exposures may represent important environmental risk factors for neurodegenerative diseases, but current research efforts are clearly lacking. Developing emerging techniques such as HRMS could break through existing bottlenecks, enabling a systematic evaluation of the entire chemical exposome and its potential links to neurodegenerative diseases. Future progress will require close interdisciplinary collaboration among genetics, environmental sciences, and biology to comprehensively understand this complex cross-disciplinary field.

Keywords: chemical exposome, exposomics, neurodegenerative diseases, high-resolution mass spectrometry (HRMS), Alzheimer’s disease, Parkinson’s disease