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The majority of the heme-binding proteins possess a “heme-pocket” that stably binds to heme. Usually known as housekeeping heme-proteins, they participate in a variety of metabolic reactions (e.g., catalase). Heme also binds with lower affinity to the “Heme-Regulatory Motifs” (HRM) in specific regulatory proteins. This type of heme binding is known as exchangeable or regulatory heme (RH). Heme binding to HRM proteins regulates their function (e.g., Bach1). Although there are well-established methods for assaying total cellular heme (e.g., heme-proteins plus RH), currently there is no method available for measuring RH independent of the total heme (TH). The current study describes and validates a new method to measure intracellular RH. This method is based on the reconstitution of apo-horseradish peroxidase (apoHRP) with heme to form holoHRP. The resulting holoHRP activity is then measured with a colorimetric substrate. The results show that apoHRP specifically binds RH but not with heme from housekeeping heme-proteins. The RH assay detects intracellular RH. Furthermore, using conditions that create positive (hemin) or negative (N-methyl protoporphyrin IX) controls for heme in normal human fibroblasts (IMR90), the RH assay shows that RH is dynamic and independent of TH. We also demonstrated that short-term exposure to subcytotoxic concentrations of lead (Pb), mercury (Hg), or amyloid-β (Aβ) significantly alters intracellular RH with little effect on TH. In conclusion the RH assay is an effective assay to investigate intracellular RH concentration and demonstrates that RH represents ∼6% of total heme in IMR90 cells.

It is estimated that 5.5 Million North Americans suffer from varying degrees of Alzheimer’s disease (AD) and by the year 2050 it may be one in 85 people globally (100 Million). It will be shown that heavy metal toxicity plays a significant role in sporadic AD. Although current literature speaks to involvement of metal ions (via Fenton reaction), studies and reviewers have yet to link cellular events including known structural changes such as amyloid plaque development to this metal toxicity the way it is proposed here. Contrary to the current AD model which positions BACE1 (β-secretase) as an aberrant or AD-advancing enzyme, it is proposed herein that the neuron’s protective counteraction to this metal toxicity is, in fact, a justified increase in BACE1 activity and amyloid precursor protein (APP) processing to yield more secreted APP (sAPP) and β-amyloid peptide in response to metal toxicity. This new perspective which justifies a functional role for APP, BACE1 enzyme activity and the peptide products from this activity may at first appear to be counterintuitive. Compelling evidence, however, is presented and a mechanism is shown herein that validate BACE1 recruitment and the resulting β-amyloid protein as strategic countermeasures serving the cell effectively against neuro-impeding disease.

In addition, the more recent understanding of how TREM-2 mutations factor into inflammatory response has shed new light on how chronic inflammatory activity can escalate to uncontrolled systemic levels in a variety of inflammatory diseases from neurodegenerative, auto-inflammatory and autoimmune diseases. TREM-2 mutations represent yet another complicating element in these multigenic disease pathologies. This review takes us one step back to discuss basic pathological features of these neurodegenerative diseases known to us for some time. However, the objective is to discuss the possibility of related or linked mechanisms that may exist through these basic disease hallmarks that we often classify as absolute signatures of one disease. These new perspectives will be discussed in the context of a new paradigm for Alzheimer’s disease that implicates heavy metals as a primary cause. Plausible links between these distinctly different pathologies are presented showing intersections of their distinct pathologies that hinge on metal interactions.

“BACKGROUND:
The effects of chronic occupational exposure to elemental mercury (Hg(0)) are largely unknown. The objective was to evaluate the association of occupational Hg(0) exposure with multiple sclerosis (MS) and tremor.

METHODS:
The study included 13,906 dentists who attended the American Dental Association’s annual meeting over 24 years (1986-2007 and 2011-2012). Participants reported MS and tremor and provided urine specimens for Hg(0) analysis. The authors estimated mean Hg(0) exposures over time and used logistic regression to estimate the associations of 3 Hg(0) exposure measures with MS or tremor.

RESULTS:
Among participants, 0.18% reported MS and 1.24% reported tremor. Hg(0) exposure was not associated with MS (odds ratio [OR] per 191 micrograms per liter in cumulative Hg(0) exposure, 0.85; 95% confidence interval [CI], 0.39-1.85). Increased prevalent risk of tremor was found with exposure to both urinary Hg(0) exposure (OR, 1.10 [95% CI, 1.00-1.22]) and cumulative Hg(0) exposure among younger dentists (< 51 years; OR, 1.13 [95% CI, 1.05-1.22]). CONCLUSIONS: Occupational Hg(0) exposure in US dentists decreased over time and now is approaching that of the general population. Our results suggest a positive association between Hg(0) exposure and tremor."

According to an earlier SDPI study, reported in 2013, alarmingly high mercury levels were observed
in air (indoor as well as outdoor) at 11 of the 34 visited dental sites (17 dental teaching institutions, 7
general hospitals & 10 dental clinics) in five main cities of Pakistan. 88% of the sites indicated indoor
mercury levels in air above the USA EPA reference level of 300ng/m3. These very high levels of
mercury vapors in air were thought to be due to more than one reasons, including the use of liquid
mercury & non-mechanical mixing for mercury amalgam making and lack of environmentally sound
best practices for mercury emissions/releases control. SDPI study also showed general unawareness
among dental professionals regarding appropriate handling of mercury/mercury amalgam and
careless/care free use of mercury/mercury amalgam by the undergraduate students. A follow up
study was carried out in 2014, to review and evaluate the contents of Bachelor of Dental Surgery
(BDS) curriculum, offered to undergraduate students at dental teaching institutions in the country.
The objective of this study was to see whether or not, the curriculum provided adequate information
& training to upcoming dental professionals, regarding hazardous mercury/mercury amalgam use in
dentistry and mercury related issues.

High-level exposures to a number of agents are known to have direct nephrotoxic effects in children. A growing body of literature supports the hypothesis that chronic, relatively low-level exposure to various nephrotoxicants may also increase the risk for chronic kidney disease (CKD) or accelerate its progression. In this review we highlight several environmental nephrotoxicants and their association with CKD in children and adolescents. We also discuss unique epidemiological challenges in the use of kidney biomarkers in environmental nephrotoxicology.

The microbiome of dental clinic wastewater and its impact on mercury methylation remains largely unknown. Waste generated during dental procedures enters the sewer system and contributes a significant fraction of the total mercury (tHg) and methyl mercury (MeHg) load to wastewater treatment facilities. Investigating the influence of geochemical factors and microbiome structure is a critical step linking the methylating microorganisms in dental wastewater (DWW) ecosystems. DWW samples from a dental clinic were collected over eight weeks and analyzed for geochemical parameters, tHg, MeHg and bacterio-toxic heavy metals. We employed bacterial fingerprinting and pyrosequencing for microbiome analysis. High concentrations of tHg, MeHg and heavy metals were detected in DWW. The microbiome was dominated by Proteobacteria, Actinobacteria, Bacteroidetes, Chloroflexi and many unclassified bacteria. Significant correlations were found between the bacterial community, Hg levels and geochemical factors including pH and the predicted total amount (not fraction) of neutral Hg-sulfide species. The most prevalent known methylators included Desulfobulbus propionicus, Desulfovibrio desulfuricans, Desulfovibrio magneticus and Geobacter sulfurreducens. This study is the first to investigate the impact of high loads of Hg, MeHg and other heavy metals on the dental clinic wastewater microbiome, and illuminates the role of many known and unknown sulfate-reducing bacteria in Hg methylation.

A total of 1016 healthy Saudi mothers and their respective infants (aged 3–12 months) were recruited from 57 Primary Health Care Centers (PHCCs) in Riyadh, Saudi Arabia, to evaluate the extent of mercury (Hg) exposure and predict its sources in the healthy Saudi population. Total Hg levels were measured in maternal urine, breast milk, blood, and hair and in the infants’ urine and hair. Only 1.9 % of the mothers had urinary Hg (UHg) >10 μg/l, the limit for asymptomatic adults recommended by the World Health Organization, but the median (0.99 μg/l) was higher than in other countries. Also, 49.3 % of the mothers had UHg >1 μg/l, the German reference value for adults. Median infant UHg was 0.729 μg/l, and 77 and 93 % of the infants had levels higher than 0.4 and 0.1 μg/l, the reference values of the Centers for Disease Control and Prevention and for Germany, respectively. The median Hg level in breast milk was 0.884 μg/l. Even though 43.2 % of the milk samples were above the background level for Hg in human milk (1 μg/l), our results were lower than those reported from other countries. Median maternal total Hg in blood was 0.637 μg/l, and only 0.4 and 6.9 % of samples were higher than the Hg reference levels of 5.8 μg/l of the Environmental Protection Agency (EPA) and of 2 μg/l for Germany, respectively. Total Hg levels in hair (HHg) varied widely among mothers and infants, but only 3.9 % of the mothers and 2.8 % of the infants had HHg >1 μg/g (the EPA reference level). Median HHg values were 0.117 μg/g dry weight in mothers and 0.1 μg/g dry weight in infants; both were lower than in other countries. The Hg levels in mothers and their respective infants were relatively low, but our results were consistent with other studies indicating that dental amalgam fillings and fish consumption were the main predictors of maternal Hg exposure. Among the several biomarkers of Hg exposure, Hg levels in maternal hair and urine were the strongest predictors of infant exposure. The lack of an association between Hg in breast milk and Hg in infant urine and hair suggested that the infants were exposed to Hg predominately during pregnancy rather than during breastfeeding. We expect that our data can serve as a baseline for further biomonitoring and follow-up studies, particularly of the long-term impact of Hg on childhood neurodevelopment.