Revisiting Genetic Influence on Mercury Exposure and Intoxication in Humans: A Scoping Review.

Human intoxication to mercury is a worldwide health problem. In addition to the type and length of exposure, the genetic background plays an important role in mercury poisoning. However, reviews on the genetic influence in mercury toxicity are scarce and not systematic. Therefore, this review aimed to systematically overview the most recent evidence on the genetic influence (using single nucleotide polymorphisms, SNPs) on human mercury poisoning. Three different databases (PubMed/Medline, Web of Science and Scopus) were searched, and 380 studies were found that were published from 2015 to 2022. After applying inclusion/exclusion criteria, 29 studies were selected and data on characteristics (year, country, profile of participants) and results (mercury biomarkers and quantitation, SNPs, main findings) were extracted and analyzed. The largest number of studies was performed in Brazil, mainly involving traditional populations of the Tapajós River basin. Most studies evaluated the influence of the SNPs related to genes of the glutathione system (GST, GPx, etc.), the ATP-binding cassette transporters and the metallothionein proteins. The recent findings regarding other SNPs, such as those of apolipoprotein E and brain-derived neurotrophic factor genes, are also highlighted. The importance of the exposure level is discussed considering the possible biphasic behavior of the genetic modulation phenomena that could explain some SNP associations. Overall, recommendations are provided for future studies based on the analysis obtained in this scoping review.

What We Know about Euterpe Genus and Neuroprotection: A Scoping Review.

The Euterpe genus (mainly Euterpe oleracea Martius, Euterpe precatoria Martius, and Euterpe edulis Martius) has recently gained commercial and scientific notoriety due to the high nutritional value of its fruits, which are rich in polyphenols (phenolic acids and anthocyanins) and have potent antioxidant activity. These characteristics have contributed to the increased number of neuropharmacological evaluations of the three species over the last 10 years, especially açaí of the species Euterpe oleracea Martius. The fruits of the three species exert neuroprotective effects through the modulation of inflammatory and oxidative pathways and other mechanisms, including the inhibition of the mTOR pathway and protection of the blood-brain barrier, all of them intimately involved in several neuropathologies. Thus, a better understanding of the neuropharmacological properties of these three species may open new paths for the development of therapeutic tools aimed at preventing and treating a variety of neurological conditions.

Global Human Threat: The Potential Synergism between Mercury Intoxication and COVID-19.

The COVID-19 pandemic affected billions of people worldwide, and exposure to toxic metals has emerged as an important risk factor for COVID-19 severity. Mercury is currently ranked as the third toxic substance of global concern for human health, and its emissions to the atmosphere have increased globally. Both COVID-19 and mercury exposure present a high prevalence in similar regions: East and Southeast Asia, South America and Sub-Saharan Africa. Since both factors represent a multiorgan threat, a possible synergism could be exacerbating health injuries. Here, we discuss key aspects in mercury intoxication and SARS-CoV-2 infection, describing the similarities shared in clinical manifestations (especially neurological and cardiovascular outcomes), molecular mechanisms (with a hypothesis in the renin-angiotensin system) and genetic susceptibility (mainly by apolipoprotein E, paraoxonase 1 and glutathione family genes). Literature gaps on epidemiological data are also highlighted, considering the coincident prevalence. Furthermore, based on the most recent evidence, we justify and propose a case study of the vulnerable populations of the Brazilian Amazon. An understanding of the possible adverse synergism between these two factors is crucial and urgent for developing future strategies for reducing disparities between developed and underdeveloped/developing countries and the proper management of their vulnerable populations, particularly considering the long-term sequelae of COVID-19.

Contributing to Understand the Crosstalk between Brain and Periphery in Methylmercury Intoxication: Neurotoxicity and Extracellular Vesicles.

Human exposure to methylmercury (MeHg) is currently high in regions such as the Amazon. Understanding the molecular changes associated with MeHg-induced neurotoxicity and the crosstalk with the periphery is essential to support early diagnoses. This work aimed to evaluate cellular and molecular changes associated with behavioral alterations in MeHg acute exposure and the possible changes in extracellular vesicles (EVs) number and S100ß content. Adults male Wistar rats were orally treated with 5 mg/kg for four days. Behavioral performance, molecular and histological changes in the cerebellum, and plasma EVs were assessed. MeHg-intoxicated animals performed significantly worse in behavioral tests. MeHg increased the number of GFAP+ cells and GFAP and S100ß mRNA expression in the cerebellum but no change in NeuN+ or IBA-1+ cells number was detected. The number of exosomes isolated from plasma were decreased by the metal. S100B mRNA was detected in circulating plasma EVs cargo in MeHg exposure. Though preliminary, our results suggest astrocytic reactivity is displaying a protective role once there was no neuronal death. Interestingly, the reduction in exosomes number could be a new mechanism associated with MeHg-induced neurotoxicity and plasma EVs could represent a source of future biomarkers in MeHg intoxication.

Eating in the Amazon: Nutritional Status of the Riverine Populations and Possible Nudge Interventions.

The Amazon is the largest tropical forest in the world and a source of healthy food, such as fruits and fish. Surprisingly, the Amazonian riverine population present an increased prevalence (as high as 58%) of non-communicable diseases, such as hypertension and insulin resistance, even higher than that described for the urban population of the Amazon. Therefore, this work aimed to analyze the nutritional status and associated risk of the riverine population. Body mass index, waist circumference (WC), waist-to-hip ratio, and neck circumference (NC) were evaluated, and risk analysis was assayed. Furthermore, data about occupation and the prevalence of consumers of the different groups of food were analyzed. All anthropometric parameters revealed high proportions of individuals at risk, WC and NC being the factors that had more high-risk women and men, respectively. Our data confirmed the characteristic profile of the riverine communities with a high number of fish consumers, but also observed different patterns probably associated to a phenomenon of nutrition transition. Based on our data, some nudge interventions that take into account the principles of behavior analysis are discussed and proposed for these populations, aiming to improve the nutritional status and avoid the long-term consequences of the results showed by this work.

Salivary biomarkers and neuropsychological outcomes: A non-invasive approach to investigate pollutants-associated neurotoxicity and its effects on cognition in vulnerable populations.

The occurrence of neurotoxicity caused by xenobiotics such as pesticides (dichlorodiphenyltrichloroethane, organophosphates, pyrethroids, etc.) or metals (mercury, lead, aluminum, arsenic, etc.) is a growing concern around the world, particularly in vulnerable populations with difficulties on both detection and symptoms treatment, due to low economic status, remote access, poor infrastructure, and low educational level, among others features. Despite the numerous molecular markers and questionnaires/clinical evaluations, studying neurotoxicity and its effects on cognition in these populations faces problems with samples collection and processing, and information accuracy. Assessing cognitive changes caused by neurotoxicity, especially those that are subtle in the initial stages, is fundamentally challenging. Finding accurate, non-invasive, and low-cost strategies to detect the first signals of brain injury has the potential to support an accelerated development of the research with these populations. Saliva emerges as an ideal pool of biomarkers (with interleukins and neural damage-related proteins, among others) and potential alternative diagnostic fluid to molecularly investigate neurotoxicity. As a source of numerous neurological biomarkers, saliva has several advantages compared to blood, such as easier storage, requires less manipulation, and the procedure is cheaper, safer and well accepted by patients compared with drawing blood. Regarding cognitive dysfunction, neuropsychological batteries represent, with their friendly interface, a feasible and accurate method to evaluate the eventual cognitive deficits associated with neurotoxicity in people from diverse cultural and educational backgrounds. The association of these two tools, saliva and neuropsychological batteries, to cover the molecular and cognitive aspects of neurotoxicity in vulnerable populations, could potentially increase the prevalence of early intervention and successful treatment.

Revisiting Astrocytic Roles in Methylmercury Intoxication.

Intoxication by heavy metals such as methylmercury (MeHg) is recognized as a global health problem, with strong implications in central nervous system pathologies. Most of these neuropathological conditions involve vascular, neurotransmitter recycling, and oxidative balance disruption leading to accelerated decline in fine balance, and learning, memory, and visual processes as main outcomes. Besides neurons, astrocytes are involved in virtually all the brain processes and perform important roles in neurological response following injuries. Due to astrocytes' strategic functions in brain homeostasis, these cells became the subject of several studies on MeHg intoxication. The most heterogenous glial cells, astrocytes, are composed of plenty of receptors and transporters to dialogue with neurons and other cells and to monitor extracellular environment responding tightly through fluctuation of cytosolic ions. The overall toxicity of MeHg might be determined on the basis of the balance between MeHg-mediated injury to neurons and protective responses from astrocytes. Although the role of neurons in MeHg intoxication is relatively well-established, the role of the astrocytes is only beginning to be understood. In this review, we update the information on astroglial modulation of the MeHg-induced neurotoxicity, providing remarks on their protective and deleterious roles and insights for future studies.

Towards Therapeutic Alternatives for Mercury Neurotoxicity in the Amazon: Unraveling the Pre-Clinical Effects of the Superfruit Açaí (Euterpe oleracea, Mart.) as Juice for Human Consumption.

Methylmercury (MeHg) exposure is a serious problem of public health, especially in the Amazon. Exposure in riverine populations is responsible for neurobehavioral abnormalities. It was hypothesized that consumption of Amazonian fruits could protect by reducing mercury accumulation. This work analyzed the effects of commercial samples of Euterpe oleracea (EO) for human consumption (10 µL/g) against MeHg i.p. exposure (2.5 mg/Kg), using neurobehavioral (open field, rotarod and pole tests), biochemical (lipid peroxidation and nitrite levels), aging-related (telomerase reverse transcriptase (TERT) mRNA expression) and toxicokinetic (MeHg content) parameters in mice. Both the pole and rotarod tests were the most sensitive tests accompanied by increased lipid peroxidation and nitrite levels in brains. MeHg reduced TERT mRNA about 50% demonstrating a strong pro-aging effect. The EO intake, similar to that of human populations, prevented all alterations, without changing the mercury content, but avoiding neurotoxicity and premature aging of the Central Nervous System (CNS). Contrary to the hypothesis found in the literature on the possible chelating properties of Amazonian fruits consumption, the effect of EO would be essentially pharmacodynamics, and possible mechanisms are discussed. Our data already support the regular consumption of EO as an excellent option for exposed Amazonian populations to have additional protection against MeHg intoxication.

Role for apolipoprotein E in neurodegeneration and mercury intoxication.

Mercury intoxication is a serious public health problem and a worldwide concern. The Minamata Convention on Mercury has been signed by 128 countries and endorsed by the World Health Organization with the recommendation of promoting the management of epidemiological information. The Central Nervous System is the main target organ for mercury. Symptoms of intoxication include altered motor coordination, visual and tactile dysfunction and paralysis, caused by neurodegeneration with a key role for oxidative damage. Recently, some studies have demonstrated a correlation between mercury intoxication and isoforms of apolipoprotein E (ApoE). In this review, epidemiological data and hypotheses about the possible molecular mechanisms underlying the association between ApoE and mercury intoxication are assessed. Based on the evidence and the neuropathological changes that the presence of ApoE4 and mercury neurotoxicity have in common, we propose a convergent action of both factors. ApoE4 seems to potentiate the damage caused by mercury. Increased knowledge of this interaction using epidemiological and pre-clinical studies is essential to improve prevention strategies to adequately manage intoxicated patients.