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March/April 2024
March/April 2024 Issue Neurology: Environmental Exposure and Neurodegeneration In 2005, the US Environmental Protection Agency (EPA) published a report titled “Aging and Toxic Response: Issues Relevant to Risk Assessment” that was compiled to “better understand the age-related toxicokinetic and toxicodynamic impacts of environmental agents.”1 The report notes that the geriatric population is more susceptible to the risks and side effects associated with exposure to environmental substances. Specifically, “age-altered physiological processes,” as well as common age-related diseases (eg, heart failure, COPD), may increase reactions to environmental exposure, such as air pollution, pesticides, and metals.1 The recent media coverage of the extensive wildfires in Canada and the United States has made clear to the general public the link between exposure to air pollutants and poor air quality and the exacerbation of respiratory diseases such as asthma and COPD. It is also commonly known that prolonged exposure to toxic chemicals, especially in infancy and childhood, can cause cancer. Less commonly known is the connection between environmental exposure and the development of neurological diseases. The EPA report flags the risk of continued exposure to certain agents that act on the neurological system as a potential contributing factor to neurodegeneration—the loss of neuron structure and function over time.1 Since the publication of the 2005 EPA report, a growing research specialty in neuroscience and aging focuses on the effects of environmental exposure to toxic and synthetic chemicals on neurological health—in particular, the development of neurological disorders such as Parkinson’s and Alzheimer’s disease. Also in 2005, the term “exposome” was first proposed to characterize lifetime environmental exposures. In 2013, to better capture the physiological response to exposure, the definition was refined to “the cumulative measure of environmental influences and associated biologic responses throughout the life span, including exogenous exposures and endogenous processes.”2 High interest in the exposome and neurological health led to an American Neurological Association (ANA) symposium in October 2022 dedicated to environmental neurotoxicology.3 The ANA symposium highlighted the importance of exposome research due to the ever-increasing amount of chemicals and other toxic materials that humans are exposed to every day, including pesticides, microplastics, industrial products, building materials, household chemicals, and pollution in the air and water. A key issue is that current environmental regulations do not sufficiently address the cumulative effect of lifelong exposure to multiple agents and their potential interactions in the human body and living environment.3 The ANA notes that continued research is needed to ascertain the impact of the exposome on neurological health. Published research over the last decade has sought to shed light on the role of environmental exposures in the development of neurodegenerative diseases. A 2011 comprehensive review4 notes that hundreds of chemicals, both naturally occurring and synthetic, are considered to be neurotoxicants and have direct or indirect effects on the function of the human nervous system. A well-known example is lead, which occurs naturally but was common in paints in buildings built before the late 1970s. Lead is known to affect the central and peripheral nervous systems by causing myelin and axonal degeneration; children are highly sensitive to lead exposure. Research suggests that adults born in the years when lead paint was common in houses may be at greater risk of neurodegenerative disease as they age.4,5 Lead is absorbed via the gastrointestinal and respiratory tracts but redistributes to bone after being processed in the liver and kidneys. Up to 90% of the body’s lead accumulation ends up in the bones; due to the half-life of lead in bone being years or decades, exposure continues throughout life. The EPA report notes that as bone loss occurs with aging, especially in women with osteoporosis, release into the blood stream occurs, once again exposing the body to the neurotoxic effects of lead and potentially the development of neurodegenerative diseases.1 Exposure to lead and other heavy metals has been linked to the development of Alzheimer’s disease, the most common neurodegenerative disease. Although genetics and the presence of the apolipoprotein allele are a known cause, in the majority of Alzheimer’s disease cases, the cause is unknown. A direct causal relationship has not been confirmed between metal exposure and Alzheimer’s disease, but research suggests it could be a factor. Aluminum, copper, and zinc overconsumption from drinking water and foods with higher concentrations may result in a higher brain metal ion concentration that could contribute to Alzheimer’s disease. However, researchers suspect that disruptions in metal transport or regulation in the body may also need to be present to cause neurologic degeneration.4,6 Exposure to heavy metals other than lead, such as manganese, have also been linked to neurodegenerative diseases. Manganese is an essential mineral for the body, but an excess, usually from occupational exposures, can be toxic. After ingestion or inhalation, manganese is absorbed into the blood and uptake to the brain occurs. Lead, manganese, aluminum, mercury, and cadmium have all been linked to the growth of amyloid plaques and neurofibrillary tangles found in Alzheimer’s disease.4-7 Considered a potent neurotoxin, manganese has also been linked to Parkinson’s disease, the second most common neurodegenerative disease.1,4,6 Parkinson’s disease is caused by genetics in roughly 10% of cases. Like Alzheimer’s disease, in most Parkinson’s cases, the cause is unknown. However, environmental exposure to metals and certain chemicals has been definitively linked to the development of Parkinson’s disease. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a synthetic organic compound that’s lipid-soluble and easily crosses the blood-brain barrier, was found to cause Parkinson-like symptoms in the 1980s when it was identified as a contaminant in street drugs. MPTP oxidizes in the body to MPP, 1-methyl-4-phenylpyridinium, which is a neurotoxin that causes selective destruction of dopaminergic neurons. The chemical structure of MPTP and MPP is very similar to that found in a common herbicide/pesticide, paraquat.4,8 Since the discovery of MPTP, several other types of environmental agents have been linked to Parkinson’s disease, including pesticides (organochlorines, organophosphates) and industrial solvents. In particular, trichloroethylene (TCE), commonly used in dry cleaning, paint removers, and industrial cleaning materials, has been suspected of contributing to the development of Parkinson’s disease by inducing oxidative stress and causing loss of dopamine neurons. TCE is one of the most commonly identified groundwater contaminants in the United States.4 Despite TCE’s known widespread contamination and being linked to Parkinsonlike symptoms since 1969, clinical research into the links between TCE exposure and the development of Parkinson’s disease are lacking.9 Pesticide exposure has been linked to both Parkinson’s and Alzheimer’s disease due to its negative effect on the cholinergic system, part of the autonomic nervous system that has an important role in memory, digestion, and control of blood pressure, movement, and other physiologic functions. Cholinergic function gradually declines with normal aging. It’s been speculated that the additional adverse effects on cholinergic function caused by pesticide exposure can exacerbate neurodegenerative decline.1,7 Although researchers are still debating the exact mechanisms by which environmental exposure causes neurodegeneration, after more than a decade of research, exposure to environmental agents are now regarded as primary factors in the development of neurodegenerative disease. And the adverse effects begin early in life, with prenatal and early infancy/childhood exposure being a critical contributor.7 The increasing prevalence of neurodegenerative diseases such as Alzheimer’s and Parkinson’s has been linked to the escalation in environmental pollution worldwide. Despite occupational and environmental safety efforts, it’s challenging to monitor prolonged hazardous exposure and its health effects. And the interactions of environmental exposure with individual genetics, lifestyle, and diet make it difficult to quantify the contribution of long-term exposure to medical conditions commonly associated with aging.7,10 The research summarized previously is just the tip of the iceberg for toxic environmental agents. In addition to negatively affecting the nervous system, environmental toxicants may also damage mitochondrial DNA and cellular function, leading to accelerated aging. Collaborative research is ongoing to better elucidate the relationship of the exposome, neurological health and neurodegeneration, and aging.10 — J.E. Whilldin is a medical research analyst and writer from the Reading, Pennsylvania, area.
References 2. Miller GW. The Exposome: A Primer. 1st edition. Academic Press; 2013. 3. American Neurological Association. Environmental exposures key to neurologic disease. Newswise website. https://www.newswise.com/articles/environmental-exposures-key-to-neurologic-disease. Published October 25, 2022. 4. Cannon JR, Greenamyre JT. The role of environmental exposures in neurodegeneration and neurodegenerative diseases. Toxicol Sci. 2011;124(2):225-250. 5. Reuben A. Childhood lead exposure and adult neurodegenerative disease. J Alzheimers Dis. 2018;64(1):17-42. 6. Bakulski KM, Seo YA, Hickman RC, et al. Heavy metals exposure and Alzheimer's disease and related dementias. J Alzheimers Dis. 2020;76(4):1215-1242. 7. Nabi M, Tabassum N. Role of environmental toxicants on neurodegenerative disorders. Front Toxicol. 2022;4:837579. 8. Langston JW. The MPTP story. J Parkinsons Dis. 2017;7(s1):S11-S19. 9. Dorsey ER, Zafar M, Lettenberger SE, et al. Trichloroethylene: an invisible cause of Parkinson's disease? J Parkinsons Dis. 2023;13(2):203-218. 10. Pandics T, Major D, Fazekas-Pongor V, et al. Exposome and unhealthy aging: environmental drivers from air pollution to occupational exposures. Geroscience. 2023;45(6):3381-3408. |
