X-Ray Fluorescence Imaging: A New Tool for Studying Manganese Neurotoxicity

Abstract

The neurotoxic effect of manganese (Mn) establishes itself in a condition known as manganism or Mn induced parkinsonism. While this condition was first diagnosed about 170 years ago, the mechanism of the neurotoxic action of Mn remains unknown. Moreover, the possibility that Mn exposure combined with other genetic and environmental factors can contribute to the development of Parkinson's disease has been discussed in the literature and several epidemiological studies have demonstrated a correlation between Mn exposure and an elevated risk of Parkinson's disease. Here, we introduce X-ray fluorescence imaging as a new quantitative tool for analysis of the Mn distribution in the brain with high spatial resolution. The animal model employed mimics deficits observed in affected human subjects. The obtained maps of Mn distribution in the brain demonstrate the highest Mn content in the globus pallidus, the thalamus, and the substantia nigra pars compacta. To test the hypothesis that Mn transport into/distribution within brain cells mimics that of other biologically relevant metal ions, such as iron, copper, or zinc, their distributions were compared. It was demonstrated that the Mn distribution does not follow the distributions of any of these metals in the brain. The majority of Mn in the brain was shown to occur in the mobile state, confirming the relevance of the chelation therapy currently used to treat Mn intoxication. In cells with accumulated Mn, it can cause neurotoxic action by affecting the mitochondrial respiratory chain. This can result in increased susceptibility of the neurons of the globus pallidus, thalamus, and substantia nigra pars compacta to various environmental or genetic insults. The obtained data is the first demonstration of Mn accumulation in the substantia nigra pars compacta, and thus, can represent a link between Mn exposure and its potential effects for development of Parkinson's disease.

Epidemiological Approaches to Metal Toxicology

“…For some metals, such as lead, the blood concentration may reflect cumulated exposures, although assessment of the lead concentration in bone tissue by X-ray fluorescence may better reflect the body burden (Hu et al, 2007). For manganese, X-ray fluorescence imaging of manganese retained in the brain may be a useful marker of past exposures (Robison et al, 2012). Still, irregular exposure, discontinuation of occupational exposure, or other sources of variation may render such measures unreliable.…”

“…This conclusion may be correct, but it does not follow that the change can be ignored. Thus, from a population viewpoint, even a small average increase in blood pressure may push a substantial number of subjects into the hypertension range, with its associated increased risks of disease and mortality (Rose and Day, 1990). For a full interpretation of the findings, one therefore also needs to consider the possible effects at the extremes of the distributions.…”

Imaging Modalities for Manganese Toxicity

“…To date XRF has found its applications in the study of Mn neurotoxicity in single cell imaging, [129][130][131][132] as well as in high-resolution (order of microns) elemental imaging of ex vivo brain slices of rats exposed to Mn. [133][134][135] The generation of an XRF signal begins with the expulsion of a core electron (e.g. 1s) from the atomic shell by an incoming X-ray.…”

“…[133][134][135] The penetrating nature of X-rays allows for relatively thick sections (e.g. 30 mm), and the technique is sensitive to the total metal content regardless of the binding environment.…”

Mutual Neurotoxic Mechanisms Controlling Manganism and Parkisonism

“…18 This is especially remarkable because Mn has also been reported to accumulate both in the substantia nigra [19][20][21][22] and the striatum. 23 The fact that these neurons survive and that the dopamine content in the striatum is largely unaffected 16 implies that the action of Mn on dopamine release is likely to be a local response occurring within the presynaptic nerve terminal.…”