Toxic substances for the brain

Long-term exposure to the same environmental pollutant, even in small amounts, leads to bioaccumulation, i.e. small amounts accumulate in organs and tissues over a lifetime and can lead to adverse health consequences. Some studies show that such accumulation can trigger inflammation in the central nervous system (neuroinflammation) and cause a chain of neuropathological changes leading to the development of Alzheimer’s disease and other neurodegenerative diseases.

In addition, there are a growing number of studies looking at the impact of early childhood exposure to pollutants on neurological disorders such as Alzheimer’s disease, Parkinson’s disease, as well as developmental neurological disorders such as autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). It is already known that early life is critical for brain maturation and that numerous environmental factors that occur during this time can significantly affect the long-term functionality of the brain, which in turn has strong implications for lifelong health.

Through the concept of Developmental Origins of Health and Disease (DOHaD), it is now clear that adverse circumstances in early childhood influence disease risk throughout life. For example, environmental factors from conception to age 2 (the very important first 1000 days of life) play a critical role in a person’s susceptibility to developing chronic diseases later in life, including Alzheimer’s disease. Persistent organic pollutants, such as many pesticides used, can affect epigenetic DNA methylation and thus neurodevelopment increasing the risk of neurodegenerative diseases.

• Anatomical limitations: The human brain is protected by a hard layer of bone – the cranial box – that does not allow for a major increase in volume, e.g., due to edema. Toxins that alter intracranial pressure can dramatically alter neuron function and be potentially fatal.
• Energy supply: The human brain has a high metabolic rate, consuming about 20% of the oxygen and 25% of the glucose in the entire body. However, it has low energy reserves and very low anaerobic activity (it cannot function effectively without oxygen and nutrients). Toxins that interfere with energy production have devastating consequences for the nervous system.
• Chemical transmission in the space between cells: Communication between the cells of the nervous system occurs through the release of chemical signals, the so-called Neurotransmitters. The release, reuptake, and metabolism of neurotransmitters are highly regulated, and any disruption in this system can impair neuron function and lead to neurodegeneration.
• Limited cellular regenerative capacity: the brain’s ability to compensate for cell loss is much lower than other organ systems, making it particularly sensitive to toxic stress, which can lead to permanent consequences.
• Lipid-rich environment: The high lipid content of the nervous system is highly susceptible to lipid peroxidation – a severe form of oxidative stress – and facilitates the spread of lipid-soluble toxins.

• Destruction of the blood-brain barrier: Some toxins, such as heavy metals, increase the permeability of the blood-brain barrier and can trigger the entire neurodegeneration process observed in Alzheimer’s disease.
• Oxidative stress: the vast majority of toxic agents act through oxidative stress, i.e., a sharp increase in free radical production in the absence of adequate antioxidants. Signs of oxidative damage precede other pathological events in AD and are an early event in the pathogenesis of the disease
• Protein aggregation: Environmental neurotoxicants can disrupt protein processing and lead to neurodegeneration. Amyloid beta and tau protein deposition can be triggered by the presence of certain toxins in the nervous system.
• Mitochondrial dysfunction: environmental toxins can impair mitochondrial function, disrupting the energy supply to nerve cells and leading to neuro-degeneration.

The link between exposure to environmental pollutants and Alzheimer’s disease, although not fully proven, has been confirmed in studies for many years. Individuals who are exposed to pollutants (through occupational exposure or by living in regions with high levels of environmental pollutants) or who have higher blood levels of toxic substances have a higher risk of developing dementia. Most of these studies are published in environmental or toxicology journals, while they are (curiously) rarely covered in medical journals.

Some in vitro studies and studies using animal models have identified toxic effects of environmental pollutants at the cellular level and have revealed alterations in metabolic processes and responses that have been associated with AD pathology. This warrants further investigation. However, even if there is solid evidence of the negative impact of toxins on cognitive health, studies in this area are scarce.

A major difficulty in studying the environmental factors that cause Alzheimer’s disease is the long latency period of the disease, i.e., the time between exposure and the onset of symptoms. Environmental studies of Alzheimer’s disease often examine exposures at the time of onset of clinical symptoms, although relevant exposures may have occurred years or decades earlier or possibly even during early life. For example, some brain changes are due to exposures during neurodevelopment (in the womb and infancy) but manifest later in life.

Another limitation is the fact that it is not possible for ethical reasons to conduct an interventional case-control study, as we do with pharmaceuticals, because the compounds are known or suspected to be toxic to humans. Research with toxins in humans could cause great harm to health.

These are some of the reasons we have used to try to justify the limited number of studies on aggressive agents and Alzheimer’s disease. In this context, however, we already know the following:

• Epidemiological studies should be more prominent when addressing the issue of toxicity
• “The absence of evidence of harm (due to lack of information!) is not evidence of the absence of harm.” – This maxim fits very well here.
• We should strive to reduce exposure to all toxic substances that can potentially promote neurodegeneration as much as possible throughout life.
• Collective health policy must be directed toward greater control of the use of toxic substances in the environment

In the following pages, the most important toxins associated with Alzheimer’s disease will again be discussed individually and their respective modes of action will be described.

References

1. Cannon JR, Greenamyre JT. The role of environmental exposures in neurodegeneration and neurodegenerative diseases. Toxicol Sci. 2011 Dec;124(2):225-50. doi: 10.1093/toxsci/kfr239. Epub 2011 Sep 13. PMID: 21914720; PMCID: PMC3216414.

1. Cohen A, Vom Saal F. Non-Toxic: A guide to living healthy in a chemical world, Oxford University Press 2020

1. Dekosky ST, Gandy S. Environmental exposures and the risk for Alzheimer disease: can we identify the smoking guns? JAMA Neurol. 2014 Mar;71(3):273-5. doi: 10.1001/jamaneurol.2013.6031. PMID: 24473699; PMCID: PMC4847540.

1. Grova N, Schroeder H, Olivier JL, Turner JD. Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants. Int J Genomics. 2019 Jan 14;2019:2085496. doi: 10.1155/2019/2085496. PMID: 30733955; PMCID: PMC6348822.