Mercury is present in neurons and oligodendrocytes in regions of the brain affected by Parkinson's disease and co-localises with Lewy bodies.

OBJECTIVE: Environmental toxicants are suspected to play a part in the pathogenesis of idiopathic Parkinson's disease (PD) and may underlie its increasing incidence. Mercury exposure in humans is common and is increasing due to accelerating levels of atmospheric mercury, and mercury damages cells via oxidative stress, cell membrane damage, and autoimmunity, mechanisms suspected in the pathogenesis of PD. We therefore compared the cellular distribution of mercury in the tissues of people with and without PD who had evidence of previous mercury exposure by mercury being present in their locus ceruleus neurons. MATERIALS AND METHODS: Paraffin sections from the brain and general organs of two people with PD, two people without PD with a history of mercury exposure, and ten people without PD or known mercury exposure, were stained for inorganic mercury using autometallography, combined with immunostaining for a-synuclein and glial cells. All had mercury-containing neurons in locus ceruleus neurons. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to confirm the presence of mercury and to look for other potentially toxic elements. Autometallography-stained locus ceruleus paraffin sections were examined to compare the frequency of previous mercury exposure between 20 PD and 40 non-PD individuals. RESULTS: In PD brains, autometallography-detected mercury was seen in neurons affected by the disease, such as those in the substantia nigra, motor cortex, striatum, thalamus, and cerebellum. Mercury was seen in oligodendrocytes in white and grey matter. Mercury often co-localised with Lewy bodies and neurites. A more restricted distribution of brain mercury was seen in people without PD (both with or without known mercury exposure), with no mercury present in the substantia nigra, striatum, or thalamus. The presence of autometallography-detected mercury in PD was confirmed with LA-ICP-MS, which demonstrated other potentially toxic metals in the locus ceruleus and high iron levels in white matter. Autometallography-detected mercury was found in locus ceruleus neurons in a similar proportion of PD (65%) and non-PD (63%) individuals. CONCLUSIONS: In people with PD, mercury was found in neurons and oligodendrocytes in regions of the brain that are affected by the disease, and often co-localised with aggregated a-synuclein. Mercury in the motor cortex, thalamus and striatum could result in bradykinesia and rigidity, and mercury in the cerebellum could cause tremor. People without PD had a restricted uptake of mercury into the brain. The similar frequency of mercury in the locus ceruleus of people with and without PD suggests these two groups have had comparable previous mercury exposures but that PD brains have a greater predisposition to take up circulating mercury. While this post mortem study does not provide a direct link between mercury and idiopathic PD, it adds to the body of evidence that metal toxicants such as mercury play a role in the disease. A precautionary approach would be to reduce rising mercury levels in the atmosphere by limiting the burning of fossil fuels, which may be contributing to the increasing incidence of PD

Mercury in the human thyroid gland: Potential implications for thyroid cancer, autoimmune thyroiditis, and hypothyroidism

Objective Mercury and other toxic metals have been suggested to be involved in thyroid disorders, but the distribution and prevalence of mercury in the human thyroid gland is not known. We therefore used two elemental bio-imaging techniques to look at the distribution of mercury and other toxic metals in the thyroid glands of people over a wide range of ages. Materials and methods Formalin-fixed paraffin-embedded thyroid tissue blocks were obtained from 115 people aged 1–104 years old, with varied clinicopathological conditions, who had thyroid samples removed during forensic/coronial autopsies. Seven-micron sections from these tissue blocks were used to detect intracellular inorganic mercury using autometallography. The presence of mercury was confirmed using laser ablation-inductively coupled plasma-mass spectrometry which can detect multiple elements. Results Mercury was found on autometallography in the thyroid follicular cells of 4% of people aged 1–29 years, 9% aged 30–59 years, and 38% aged 60–104 years. Laser ablation-inductively coupled plasma-mass spectrometry confirmed the presence of mercury in samples staining with autometallography, and detected cadmium, lead, iron, nickel and silver in selected samples. Conclusions The proportion of people with mercury in their thyroid follicular cells increases with age, until it is present in over one-third of people aged 60 years and over. Other toxic metals in thyroid cells could enhance mercury toxicity. Mercury can trigger genotoxicity, autoimmune reactions, and oxidative damage, which raises the possibility that mercury could play a role in the pathogenesis of thyroid cancers, autoimmune thyroiditis, and hypothyroidism

The Prevalence of Inorganic Mercury in Human Kidneys Suggests a Role for Toxic Metals in Essential Hypertension

The kidney plays a dominant role in the pathogenesis of essential hypertension, but the initial pathogenic events in the kidney leading to hypertension are not known. Exposure to mercury has been linked to many diseases including hypertension in epidemiological and experimental studies, so we studied the distribution and prevalence of mercury in the human kidney. Paraffin sections of kidneys were available from 129 people ranging in age from 1 to 104 years who had forensic/coronial autopsies. One individual had injected himself with metallic mercury, the other 128 were from varied clinicopathological backgrounds without known exposure to mercury. Sections were stained for inorganic mercury using autometallography. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used on six samples to confirm the presence of autometallography-detected mercury and to look for other toxic metals. In the 128 people without known mercury exposure, mercury was found in: (1) proximal tubules of the cortex and Henle thin loops of the medulla, in 25% of kidneys (and also in the man who injected himself with mercury), (2) proximal tubules only in 16% of kidneys, and (3) Henle thin loops only in 23% of kidneys. The age-related proportion of people who had any mercury in their kidney was 0% at 1–20 years, 66% at 21–40 years, 77% at 41–60 years, 84% at 61–80 years, and 64% at 81–104 years. LA-ICP-MS confirmed the presence of mercury in samples staining with autometallography and showed cadmium, lead, iron, nickel, and silver in some kidneys. In conclusion, mercury is found commonly in the adult human kidney, where it appears to accumulate in proximal tubules and Henle thin loops until an advanced age. Dysfunctions of both these cortical and medullary regions have been implicated in the pathogenesis of essential hypertension, so these findings suggest that further studies of the effects of mercury on blood pressure are warranted

Assessing the efficacy of dietary selenomethionine supplementation in the setting of cardiac ischemia/reperfusion injury

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. article distributed under the terms and conditions of the Cr. Oxidative stress is a major hallmark of cardiac ischemia/reperfusion (I/R) injury. This partly arises from the presence of activated phagocytes releasing myeloperoxidase (MPO) and its production of hypochlorous acid (HOCl). The dietary supplement selenomethionine (SeMet) has been shown to bolster endogenous antioxidant processes as well as readily react with MPO-derived oxidants. The aim of this study was to assess whether supplementation with SeMet could modulate the extent of cellular damage observed in an in vitro cardiac myocyte model exposed to (patho)-physiological levels of HOCl and an in vivo rat model of cardiac I/R injury. Exposure of the H9c2 cardiac myoblast cell line to HOCl resulted in a dose-dependent increase in necrotic cell death, which could be prevented by SeMet supplementation and was attributed to SeMet preventing the HOCl-induced loss of mitochondrial inner trans-membrane potential, and the associated cytosolic calcium accumulation. This protection was credited primarily to the direct oxidant scavenging ability of SeMet, with a minor contribution arising from the ability of SeMet to bolster cardiac myoblast glutathione peroxidase (GPx) activity. In vivo, a significant increase in selenium levels in the plasma and heart tissue were seen in male Wistar rats fed a diet supplemented with 2 mg kg−1 SeMet compared to controls. However, SeMet-supplementation demonstrated only limited improvement in heart function and did not result in better heart remodelling following I/R injury. These data indicate that SeMet supplementation is of potential benefit within pathological settings where excessive HOCl is known to be generated but has limited efficacy as a therapeutic agent for the treatment of heart attack

Mercury in Pancreatic Cells of People with and without Pancreatic Cancer.

Toxic metals have been implicated in the pathogenesis of pancreatic cancer. Human exposure to mercury is widespread, but it is not known how often mercury is present in the human pancreas and which cells might contain mercury. We therefore aimed to determine, in people with and without pancreatic cancer, the distribution and prevalence of mercury in pancreatic cells. Paraffin-embedded sections of normal pancreatic tissue were obtained from pancreatectomy samples of 45 people who had pancreatic adenocarcinoma, and from autopsy samples of 38 people without pancreatic cancer. Mercury was identified using two methods of elemental bio-imaging: (1) With autometallography, inorganic mercury was seen in islet cells in 14 of 30 males (47%) with pancreatic cancer compared to two of 17 males (12%) without pancreatic cancer (p = 0.024), and in 10 of 15 females (67%) with pancreatic cancer compared to four of 22 females (19%) without pancreatic cancer (p = 0.006). Autometallographic mercury was present in acinar cells in 24% and in periductal cells in 11% of people with pancreatic cancer, but not in those without pancreatic cancer. (2) Laser ablation-inductively coupled plasma-mass spectrometry confirmed the presence of mercury in islets that stained with autometallography and detected cadmium, lead, chromium, iron, nickel and aluminium in some samples. In conclusion, the genotoxic metal mercury is found in normal pancreatic cells in more people with, than without, pancreatic cancer. These findings support the hypothesis that toxic metals such as mercury contribute to the pathogenesis of pancreatic cancer

Elemental analysis of aging human pituitary glands implicates mercury as a contributor to the somatopause

Copyright © 2019 Pamphlett, Kum Jew, Doble and Bishop. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Background: Growth hormone levels often decline on aging, and this “somatopause” is associated with muscle and bone loss, visceral adiposity and impaired cardiovascular function. Mercury has been detected in human pituitary glands, so to see if mercury could play a part in the somatopause we measured the proportion of people at different ages who had mercury in their anterior pituitary cells. Materials and methods: Paraffin sections of pituitary glands taken at autopsy from 94 people between the ages of 2 and 99 years were stained for inorganic mercury using autometallography. Pituitary mercury content was classified as none, low (30% of cells) in increasing two-decade age groups. Autometallography combined with immunohistochemistry determined which hormone-producing cells contained mercury. Laser ablation-inductively coupled plasma-mass spectrometry was used to confirm the presence of mercury. Results: The proportion of people with low-content pituitary mercury remained between 33 and 42% at all ages. The proportion of people with high-content mercury increased with increasing age, from 0% of people in the 2-20 year group to a peak of 50% of people in the 61-80 years group, followed by a fall to 35% of people in the 81-99 years group. Mercury, when present, was found always in somatotrophs, occasionally in corticotrophs, rarely in thyrotrophs and gonadotrophs, and never in lactotrophs. Laser ablation-inductively coupled plasma-mass spectrometry detected mercury in regions of pituitaries that stained with autometallography. Conclusions: The proportion of people with mercury in their anterior pituitary cells, mostly somatotrophs, increases with aging, suggesting that mercury toxicity could be one factor contributing to the decline in growth hormone levels found in advancing age

Age-related accumulation of toxic metals in the human locus ceruleus

© 2018 Pamphlett et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Damage to the locus ceruleus has been implicated in the pathogenesis of a number of neurological conditions. Locus ceruleus neurons accumulate toxic metals such as mercury selectively, however, the presence of toxic metals in locus ceruleus neurons of people of different ages, and with a variety of disorders, is not known. To demonstrate at what age toxic metals are first detectable in the locus ceruleus, and to evaluate whether their presence is more common in certain clinicopathological conditions, we looked for these metals in 228 locus ceruleus samples. Samples were taken at coronial autopsies from individuals with a wide range of ages, pre-existing conditions and causes of death. Paraffin sections of pons containing the locus ceruleus were stained with silver nitrate autometallography, which indicates inorganic mercury, silver and bismuth within cells (termed autometallography-detected toxic metals, or AMG™). No locus ceruleus AMG neurons were seen in 38 individuals aged under 20 years. 47% of the 190 adults (ie, aged 20 years and over) had AMG locus ceruleus neurons. The proportion of adults with locus ceruleus AMG neurons increased during aging, except for a decreased proportion in the 90-plus years age group. No differences were found in the proportions of locus ceruleus AMG neurons between groups with different neurological, psychiatric, or other clinicopathological conditions, or among various causes of death. Elemental analysis with laser ablation-inductively coupled plasma-mass spectrometry was used to cross-validate the metals detected by AMG, by looking for silver, gold, bismuth, cadmium, chromium, iron, mercury, nickel, and lead in the locus ceruleus of ten individuals. This confirmed the presence of mercury in locus ceruleus samples containing AMG neurons, and showed cadmium, silver, lead, iron, and nickel in the locus ceruleus of some individuals. In conclusion, toxic metals stained by AMG (most likely inorganic mercury) appear in locus ceruleus neurons in early adult life. About half of adults in this study had locus ceruleus neurons containing inorganic mercury, and elemental analysis found a range of other toxic metals in the locus ceruleus. Locus ceruleus inorganic mercury increased during aging, except for a decrease in advanced age, but was not found more often in any single clinicopathological condition or cause of death

Elemental imaging shows mercury in cells of the human lateral and medial geniculate nuclei.

OBJECTIVE:Interference with the transmission of sensory signals along visual and auditory pathways has been implicated in the pathogenesis of hallucinations. The relay centres for vision (the lateral geniculate nucleus) and hearing (the medial geniculate nucleus) appear to be susceptible to the uptake of circulating mercury. We therefore investigated the distribution of mercury in cells of both these geniculate nuclei. MATERIALS AND METHODS:Paraffin-embedded tissue sections containing the lateral geniculate nucleus were obtained from 50 adults (age range 20-104 years) who at autopsy had a variety of clinicopathological conditions, including neurological and psychiatric disorders. The medial geniculate nucleus was present in seven sections. Sections were stained for mercury using autometallography. Laser ablation-inductively coupled plasma-mass spectrometry was used to confirm the presence of mercury. RESULTS:Ten people had mercury in cells of the lateral geniculate nucleus, and in the medial geniculate nucleus of three of these. Medical diagnoses in these individuals were: none (3), Parkinson disease (3), and one each of depression, bipolar disorder, multiple sclerosis, and mercury self-injection. Mercury was distributed in different groups of geniculate capillary endothelial cells, neurons, oligodendrocytes, and astrocytes. Mass spectrometry confirmed the presence of mercury. CONCLUSION:Mercury is present in different combinations of cell types in the lateral and medial geniculate nuclei in a proportion of people from varied backgrounds. This raises the possibility that mercury-induced impairment of the function of the geniculate nuclei could play a part in the genesis of visual and auditory hallucinations. Although these findings do not provide a direct link between mercury in geniculate cells and hallucinations, they suggest that further investigations into the possibility of toxicant-induced hallucinations are warranted

Mercury in the human adrenal medulla could contribute to increased plasma noradrenaline in aging

Plasma noradrenaline levels increase with aging, and this could contribute to the sympathetic overactivity that is associated with essential hypertension and the metabolic syndrome. The underlying cause of this rise in noradrenaline is unknown, but a clue may be that mercury increases noradrenaline output from the adrenal medulla of experimental animals. We therefore determined the proportion of people from 2 to 104 years of age who had mercury in their adrenal medulla. Mercury was detected in paraffin sections of autopsied adrenal glands using two methods of elemental bioimaging, autometallography and laser ablation-inductively coupled plasma-mass spectrometry. Mercury first appeared in cells of the adrenal medulla in the 21–40 years group, where it was present in 52% of samples, and increased progressively in frequency in older age groups, until it was detected in 90% of samples from people aged over 80 years. In conclusion, the proportion of people having mercury in their adrenal medulla increases with aging. Mercury could alter the metabolism of catecholamines in the adrenal medulla that leads to the raised levels of plasma noradrenaline in aging. This retrospective autopsy study was not able to provide a definitive link between adrenal mercury, noradrenaline levels and hypertension, but future functional human and experimental studies could provide further evidence for these associations

A guide to integrating immunohistochemistry and chemical imaging

© 2018 The Royal Society of Chemistry. Chemical imaging provides new insight into the fundamental atomic, molecular, and biochemical composition of tissue and how they are interrelated in normal physiology. Visualising and quantifying products of pathogenic reactions long before structural changes become apparent also adds a new dimension to understanding disease pathogenesis. While chemical imaging in isolation is somewhat limited by the nature of information it can provide (e.g. peptides, metals, lipids, or functional groups), integrating immunohistochemistry allows simultaneous, targeted imaging of biomolecules while also mapping tissue composition. Together, this approach can provide invaluable information on the inner workings of the cell and the molecular basis of diseases