Toxic Environmental Exposures and Energy Production

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Mitochondria—the beautifully delicate organelles that house the respiratory chain, provide cellular energy, and are the site of biosynthetic pathways—have become increasingly vulnerable to a vast array of environmental pollutants.1-3 Interestingly, the unique complexity of mitochondrial structure and function, which facilitates its diverse and essential role within the human body, also enhances its vulnerability.2 In the last decade, the adverse effects of air pollutants, including particulate matter (PM), on the central nervous system have been reported in epidemiological, animal, and post-mortem studies.4 Oxidative stress and inflammation resulting from exposure to PM is associated with deteriorating brain health; however, the mechanism for how air pollutants exact these effects remains elusive.4 In addition to air pollutants, other chemicals like heavy metals, pesticides, and microplastics, which all are capable of inducing mitochondrial impairment, can do so through multiple mechanisms, indicating there may not be a sole mechanism of mitochondrial toxicity.5 What are the most common environmental toxicants affecting the powerful yet fragile mitochondria, and how might they damage the body at the subcellular level?

Mitochondrial Toxins & Neurodegenerative Disorders

Mitochondrial dysfunction is a major source of cellular pathology and is often an early event in the disease process of neurodegeneration.3 Some environmental toxins that affect mitochondrial function have been linked epidemiologically to Parkinson’s disease (PD) and Alzheimer’s disease (AD) and, in animals, have at times been found to elicit neurodegeneration.2-3,5-6 Neuronal death is a common element in both PD and AD; proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction, and oxidative stress are the hallmark features.6 Ultimately, a major goal in the research on the role of neurotoxicant exposures in neurodegenerative disease is to identify potential risk factors.3 From this vantage point, clinicians can better assess a patient’s total toxic burden and develop practical steps for improving biotransformation and eliminating toxicants.

A large number of environmental toxicants, including heavy metals like lead and arsenic, as well as pesticides like chlorpyrifos (CPF), dichlorodiphenyltrichloroethane (DDT), and paraquat (PQ), are widely recognized as mitochondrial toxicants and, specifically, neurotoxins.2 A growing body of epidemiologic and animal model studies support a link between environmental exposure and neurologic toxicity in humans.2 It is generally accepted that the disease genesis of both AD and PD is likely to be multifactorial, with genetic and environmental factors at play.

Alzheimer’s Disease

In Alzheimer’s disease (AD), studies suggest that aluminum, the third most common metal element on earth, may cause cellular toxicity at low nanomolar concentrations; aluminum has a high affinity for the large pyramidal neurons in the brain’s hippocampus and has been shown to promote amyloid aggregation and accumulation, which is a key feature of AD neuropathology.2,6 Studies suggest that aluminum may increase protein and DNA oxidation, increase lipid peroxidation, decrease polyunsaturated fatty acids, generate free radicals, and decrease ATP synthesis in rat brains.2

Researchers have been hypothesizing about the connection between aluminum and AD since the 1980s, when metal was first reported in plaques and tangles; however, more recent data have not always supported this link.6 A 2020 study published in the Journal of Alzheimer’s Disease supports this growing body of research that links human exposure to aluminum with AD.7 Researchers found significant amounts of aluminum content in brain tissue from donors with familial AD. The aluminum content of the brain tissue from donors with a genetic mutation predisposing to AD was high, with 42% of tissues having a level considered pathologically significant, and the levels were significantly higher than those in the control group. The study also found a high degree of co-location with the amyloid-beta protein, which leads to early onset of AD.7 However, the question remains whether aluminum participates in the pathogenesis of AD or if plaques and tangles simply accumulate the metal due to increased affinity.6

As well, chronic, low-level exposures to methylmercury, which can cross the blood-brain barrier due to its ability to bind to cysteine, has been associated with the disruption of neurodevelopment, memory loss, and altered cognition in adults.2 Some studies suggest that exposure to methylmercury may increase reactive oxygen species (ROS) levels and decrease glutathione levels, directly affecting the mitochondria.2

Parkinson’s Disease

In Parkinson’s disease (PD), the second most common neurodegenerative disorder after AD, pesticides (including insecticides and herbicides), as well as heavy metals, have been studied the closest in their relation to the pathogenesis of PD.6,8-9 PD has been positively associated with two groups of pesticides: paraquat, a broad-spectrum herbicide, and rotenone, an insecticide, suggesting that these chemicals may impair mitochondrial function and increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology.10-11 The molecular links of proteinopathy and proteotoxicity with oxidative stress are varied and complex. Some research suggests that aggregated or oligomerized proteins—or even monomers of amyloid beta or alpha-synuclein—cause varied mitochondrial damages, such as impairment of bioenergetics, altered fusion/fission, and impaired mitophagy, as evident in studies with isolated mitochondria, cultured cells, and post-mortem brain samples.6 Dysfunctional mitochondria result from proteotoxicity and may produce excess ROS, triggering cellular death pathways.6

An alternative possibility, suggested in a 2020 study, is that free radicals, such as superoxide anions, which are known to result from mitochondrial inhibition, may be responsible for the damage to the brain.11 Oxidative damage is implicated in neurodegenerative diseases, and researchers suggest that it may be of particular importance in synucleinopathies, given the extensive and widespread oxidative modification of alpha-synuclein in the deposits characteristic of these diseases.11

Iron deposition has also long been implicated in the pathogenesis of PD, although the initial causes of PD are not clearly defined.8,12 Apart from the loss of dopamine-producing neurons in the substantia nigra, Parkinson’s is characterized by pronounced iron accumulation in that brain region, as well as the globus pallidus.13 A meta-analysis in 2015 suggests that the dietary intake of iron does not proliferate PD risk, lending more credibility to the hypothesis that environmental pathways may be vectors of susceptibility.14 In 2020, 100 patients with early-stage to mid-stage PD and no evidence of dementia underwent a Quantitative Susceptibility Mapping exam and had their cognitive and motor skills assessed.13 The exams found higher iron content in brain tissue of the prefrontal cortex and putamen of PD patients compared to controls. Higher brain iron levels in the hippocampus and in the thalamus were associated with poorer memory and thinking scores.13 As with aluminum, the question remains whether the excess iron in the brain that often accompanies PD actually causes the neurodegenerative disorder or is merely a product of it.15

Humans are exposed to numerous environmental toxicants in the course of a lifespan, and, as such, it is difficult to establish a clear link between individual toxicants and disease causation.3 However, epidemiology and laboratory-based science have identified environmental factors—like those illustrated above—that influence risk and have reproduced the key pathological features using animal models of the major neurodegenerative diseases.6

The Plasticene: Microplastics & Nanoplastics

Researchers have only just begun examining the health effects of some other pervasive environmental toxicants—micro and nanoplastics, which are appearing in our food and water supplies as well as in the bodies of other living organisms.16 While some scientists contend that consumption of microplastics from fish and other food poses little or no risk to human health, others say that more analysis is needed and that microplastics could harm bodily organs and, at the subcellular level, the mitochondria.17

Microplastics are defined as plastic particles smaller than 5 mm, whereas engineered nanomaterials are defined as having at least one dimension in the size range of 1-100 nm.17 In the first study to estimate human ingestion of plastic pollution, researchers found that the average American eats and drinks at least 50,000 particles of microplastic a year and breathes in a similar quantity.18 Microplastics are found in every sphere of the environment—in the air, soil, rivers, and oceans—and humans are exposed to them via ingestion, inhalation, and dermal absorption.16,18 Their worldwide distribution is so vast that many scientists are referring to this historical epoch as the Plasticene, meaning that plastic materials can be used as stratigraphic markers in the archaeological field by considering them as recent indicators of earth deposits.19

Several studies suggest that direct human contact with microplastic particles may have adverse effects at the cellular level;18-20 specifically, polystyrene particles of the size 50 nm may be associated with genotoxic and cytotoxic effects on pulmonary epithelial cells and macrophages.19 However, a great deal of uncertainty is associated with this issue, and research has only just begun.19,20-22 A 2021 study investigating the effects of polystyrene microplastics (PS-MPs) in kidney cells in in vitro and in vivo mice models suggests that PS-MPs caused mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, and autophagy-related proteins in kidney cells.23

A variety of different types of nanomaterials have been studied for their ability to induce toxic effects on mitochondria, including titanium oxide and silver nanoparticles.24-27 A study on titanium oxide nanoparticles in various in vitro models suggests that toxicity occurs through several different mechanisms, including reduced mitochondrial membrane potential (MMP), depolarization of the mitochondrial membrane, increased cytochrome C release, mitochondrial swelling, and mitophagy activation.25 Similarly, silver nanoparticles have also been shown to reduce MMP and ATP production, as well as promote mitochondrial fragmentation in several in vitro models.26 Lehner et al found that in vitro studies using human cell lines showed evidence that nanoparticles are taken up and induce oxidative stress or pro-inflammatory responses.17,27

A recent study predicts that 33 billion tons of plastic will be produced in 2050.28 This waste will be broken down into small fragments via physiochemical decomposition to join the other microplastics and nanoplastics infiltrating our environment every day and ultimately entering our human bodies. What does this mean for the future of our mitochondria? To be sure, there is considerable complexity involved in the study of microplastics and nanoplastics and their consequent effects on human health.

Clinical Applications

Understanding toxicity and taking practical steps to improve biotransformation and the elimination of toxicants are essential and critical pieces in any functional medicine approach to health and well-being. Functional medicine educates clinicians about the biochemistry and genetics of biotransformation pathways, the connection between organ system dysfunction and potential toxic exposures, the laboratory evaluations necessary in working up a toxin-exposed patient, and various treatment approaches. Treatments for patients concerned about toxic exposures may include support of mitochondrial health and concurrent consideration of multiple lifestyle factors, including nutrition and exercise.

For example, specific nutrients and dietary patterns have been investigated for their neuroprotective properties. From reducing inflammatory markers and severity of symptoms to improving outcomes and quality of life, nutrition is an essential part of a patient’s personalized clinical intervention for neurodegenerative diseases. A functional medicine strategy for prevention and treatment of neurodegeneration may include a therapeutic food plan such as IFM’s Mitochondrial Food Plan, which focuses on mitochondrial biogenesis, nutritional support through dietary patterns, and nutraceuticals that enhance specific antioxidant and anti-inflammatory agents, as well as patient-practitioner collaboration to help sustain lifestyle modifications.

Exercise is another strategy that has been shown to optimize both mitochondrial and cognitive function, potentially decelerating cognitive decline and attenuating neurodegeneration. It is an important part of a patient’s personalized clinical intervention. Appropriate exercise interventions for the treatment of neurodegenerative disorders may include low and moderate high-intensity exercise, short-term interval training and aerobic training, multimodal physical exercise, and mind-body exercises such as tai chi, yoga, and qigong. Gain additional insights and tools on mitochondrial health at IFM’s Bioenergetics Advanced Practice Module (APM).

Learn More About Mitochondrial Function

Learn more about human health and the environment by following the links provided below.


Exposure to Pesticides, Herbicides, & Insecticides: Human Health Effects

Low-Level Lead Exposure & Implications for Human Health

Neurodegenerative Disease: Improving Outcomes Through Nutrition


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