The role of environmental exposures in neurodegeneration and neurodegenerative diseases

Abstract

Neurodegeneration describes the loss of neuronal structure and function. Numerous neurodegenerative diseases are associated with neurodegeneration. Many are rare and stem from purely genetic causes. However, the prevalence of major neurodegenerative diseases is increasing with improvements in treating major diseases such as cancers and cardiovascular diseases, resulting in an aging population. The neurological consequences of neurodegeneration in patients can have devastating effects on mental and physical functioning. The causes of most cases of prevalent neurodegenerative diseases are unknown. The role of neurotoxicant exposures in neurodegenerative disease has long been suspected, with much effort devoted to identifying causative agents. However, causative factors for a significant number of cases have yet to be identified. In this review, the role of environmental neurotoxicant exposures on neurodegeneration in selected major neurodegenerative diseases is discussed. Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis were chosen because of available data on environmental influences. The special sensitivity the nervous system exhibits to toxicant exposure and unifying mechanisms of neurodegeneration are explored.

FIG. 1.

Toxicant entry into the CNS and interactions with diverse cell types. To gain access to the CNS, a toxicant may enter through a specific transporter if it has structural similarities to endogenous molecules that are selectively transported across the BBB. Highly lipophilic molecules may pass directly through biological membranes gaining access to the CNS. A damaged or dysfunctional BBB could potentially allow toxicants that would normally be excluded to enter the CNS. Once in the CNS, toxicants may interact and influence the physiology of a variety of very different cell types, including neurons, astrocytes, microglia, and oligodendrocytes. Toxicant action on each of these cell types may adversely affect neurological function.

FIG. 2.

Selective sensitivity of the nigrostriatal dopamine system to toxicant insults. (A) Neuronal morphology and physiology vary dramatically based on the anatomical region and neurotransmitter system. Specific populations of neurons may exhibit selective or heightened sensitivity to environmental insults based upon their anatomical features. As an example, the nigrostriatal dopamine system is selectively sensitive to several environmental toxicants. Long, poorly myelinated processes (average ∼500 mm in rat—due to convolution) terminating in ∼75,000 synapses result in a system with enormous energy and transport (antero- and retrograde) requirements (Braak et al., 2004; Matsuda et al., 2009). Such a system may be particularly sensitive to specific toxic insults. (B) Specific neurotransmitter systems may produce endogenous oxidative stress. These cell populations have an inherent oxidative burden and may be especially sensitive to additional oxidative insults elicited by exposure to environmental toxicants. Dopamine metabolism mediated by monoamine oxidase-B (MAO-B) produces hydrogen peroxide. The Fenton reaction occurring in the presence of Fe2+ may then result in the production of the highly reactive hydroxyl radical. This population is especially sensitive to additional oxidative stress insults.