Search

The objective of the present review is to discuss epidemiological evidence demonstrating the association between toxic metal (Cd, Pb, Hg, As, Sn, Ti, Tl) exposure and retinal pathology, along with the potential underlying molecular mechanisms. Epidemiological studies demonstrate that Cd, and to a lesser extent Pb exposure, are associated with age-related macular degeneration (AMD), while the existing evidence on the levels of these metals in patients with diabetic retinopathy is scarce. Epidemiological data on the association between other toxic metals and metalloids including mercury (Hg) and arsenic (As), are limited. Clinical reports and laboratory in vivo studies have shown structural alterations in different layers of retina following metal exposure. Examination of retina samples demonstrate that toxic metals can accumulate in the retina, and the rate of accumulation appears to increase with age. Experimental studies in vivo and in vitro studies in APRE-19 and D407 cells demonstrate that toxic metal exposure may cause retinal damage through oxidative stress, apoptosis, DNA damage, mitochondrial dysfunction, endoplasmic reticulum stress, impaired retinogenesis, and retinal inflammation. However, further epidemiological as well as laboratory studies are required for understanding the underlying molecular mechanisms and identifying of the potential therapeutic targets and estimation of the dose-response effects. [Display omitted] • Cd, Pb, As, and Hg exposure is linked to retinal diseases in epidemiological studies. • Accumulation of toxic metals in retina increases with age. • Metal accumulation causes structural alterations in different retinal layers. • Toxic metals induce retinal damage through a variety of mechanisms. • Metal exposure was shown to interfere with retinogenesis regulation. [ABSTRACT FROM AUTHOR]

Methylmercury is a toxic environmental contaminant that elicits significant toxicity in humans. The central nervous system is the primary target of toxicity, and is particularly vulnerable during development. Rho-associated protein kinase 1 (ROCK-1) is a major downstream effector of the small GTPase RhoA and a direct substrate of caspase-3. The activation of ROCK-1 is necessary for membrane blebbing during apoptosis. In this work, we examined whether MeHg could affect the RhoA/ROCK-1 signaling pathway in primary cultures of mouse astrocytes. Exposure of cells with 10 μM MeHg decreased cellular viability after 24 h of incubation. This reduction in viability was preceded by a significant increase in intracellular and mitochondrial reactive oxygen species levels, as well as a reduced NAD + /NADH ratio. MeHg also induced an increase in mitochondrial-dependent caspase-9 and caspase-3, while the levels of RhoA protein expression were reduced or unchanged. We further found that MeHg induced ROCK-1 cleavage/activation and promoted LIMK1 and MYPT1 phosphorylation, both of which are the best characterized ROCK-1 downstream targets. Inhibiting ROCK-1 and caspases activation attenuated the MeHg-induced cell death. Collectively, these findings are the first to show that astrocytes exposed to MeHg showed increased cleavage/activation of ROCK-1, which was independent of the small GTPase RhoA. [ABSTRACT FROM AUTHOR]

The present study aims to review epidemiological and experimental toxicology studies published over the last two decades linking mercury (Hg) exposure and carcinogenesis, with a special emphasis on the potential underlying mechanisms. While some epidemiological studies have observed a strong association between environmental/occupational Hg exposure levels, measured in blood, toenail, and hair, and cancer risk and mortality, others failed to reveal any association. In experimental models, high-dose Hg exposure has been linked with cytotoxicity, whereas low-dose exposure was posited to induce proliferative responses in both normal and cancerous cells by interference with estrogen receptor, ERK1/2, JNK, NADPH-oxidase and, potentially, Nrf2 signaling. Combined with reduced apoptosis and pro-survival signaling upon low-dose Hg exposure, accumulation of DNA lesions in cells may predispose to an increased risk of malignant transformation. In addition, the pro-oxidant activity of Hg species may induce oxidative DNA modifications and inhibits DNA repair mechanisms. Furthermore, epigenetic effects of Hg exposure seem to contribute to the carcinogenic activity, although the particular mechanisms have yet to be characterized. Therefore, even after 20 years of research, one cannot consider Hg as a non-carcinogenic agent, whereas specific mechanisms of Hg-induced toxicity may promote carcinogenic risk. • Hg exposure is associated with cancer risk, although the data are contradictory. • Cancerous and healthy tissues differentially accumulate Hg. • Hg may promote carcinogenic risk through modulation of cell proliferation. • Hg affects estrogen receptor, ERK1/2, JNK, NADPH-oxidase, and Nrf2 signaling. • Oxidative DNA damage, genotoxicity, epigenetic effects of Hg may be involved in cancer. [ABSTRACT FROM AUTHOR]

Toxic stimuli (stressors) exposure limits are typically based on single toxic stimuli experiments, but are presently used for both toxic stimuli in isolation and in combination with other toxic stimuli (simultaneous co-exposure or exposures separated in time). In the combination case, typically less of each constituent of the combination is required to cause damage compared to the amount determined from single stressor experiments. Thus, exposure limits based on single toxic stimulus experiments are inadequate for setting limits for stressor combinations. This article presents a recommended simplified approach to improving regulatory exposure limits for toxic stimuli combinations, and a more expansive and expensive alternative to the recommended simplified approach. The recommended approach will partially compensate for the enhanced adverse effects of toxic stimuli combinations relative to adverse effects of toxic stimuli in isolation. The approach covers myriad categories of toxic stimuli reflective of real-life exposures due to lifestyle, iatrogenic, biotoxin, occupational/environmental, and psychosocial/socioeconomic conditions. The proposed approach 1) assumes that all potential toxic stimuli to which an individual might be exposed have the same mechanisms/modes of action on biological mechanisms, and are, thus, indistinguishable by the impacted organism; 2) normalizes the myriad stimuli by converting the doses of toxic stimuli exposures to the respective toxicity reference values (TRV) fractions; 3) sums all the TRVs fractions from these toxic stimuli exposures; and 4) divides all the single substance TRVs by the sum of fractions. While it is an additive approach conceptually, it differs from other additive approaches in the breadth of its inter-category coverage, in order to reflect true inter-category real-life simulation. The newly posited approach does not account for hormetic, antagonistic, or synergistic effects of toxic stimuli in combination. It does not adjust for 1) low-dose toxicants with adverse effects that have been under-reported, or 2) exposure limits like the Occupational Safety and Health Administration - Permissible Exposure Limits (OSHA PELs) that are orders of magnitude above levels shown by published single toxic stimuli studies to have caused adverse effects. Practical considerations for the application of this approach are presented. Image 1 • Presumable "safe" exposure limits based on single toxic stimulus experiments are inadequate for stressors' combinations. • A simplified approach to improving regulatory exposure limits for toxic stimuli combinations is presented. • The approach proposes conversion of exposures to TRVs fraction and division of single TRVs by the sum of these fractions. • Practical considerations for the application of this approach are presented. [ABSTRACT FROM AUTHOR]

Among epigenetic mechanisms, DNA methylation has been widely studied with respect to many environmental factors. Smoking is a common factor which affects both global and gene-specific DNA methylation. It is supported that smoking directly affects DNA methylation, and these effects contribute to the development and progression of various diseases, such as cancer, lung and cardiovascular diseases and male infertility. In addition, prenatal smoking influences the normal development of the fetus via DNA methylation changes. The DNA methylation profile and its smoking-induced alterations helps to distinguish current from former smokers and non-smokers and can be used to predict the risk for the development of a disease. This review summarizes the DNA methylation changes induced by smoking, their correlation with smoking behavior and their association with various diseases and fetus development. • Changes in the expression of specific genes, due to smoking-induced alterations in DNA methylation. • Identification of smoking behavior through DNA methylation patterns. • Smoking-induced hyper/hypo-methylation affects human health and is associated with diseases. • DNA methylation status of fetus is affected by maternal smoking. [ABSTRACT FROM AUTHOR]

Neurological illnesses are multifactorial incurable debilitating disorders that may cause neurodegeneration. These diseases influence approximately 30 million people around the world. Despite several therapies, effective management of such disorders remains a global challenge. Thus, natural products might offer an alternative therapy for the treatment of various neurological disorders. Polyphenols, such as curcumin, resveratrol, myricetin, mangiferin and naringin (NRG) have been shown to possess promising potential in the treatment of neurogenerative illness. In this review, we have targeted the therapeutic potential of naringin as a neuroprotective agent. The overall neuroprotective effects and different possible underlying mechanisms related to NRG are discussed. In light of the strong evidence for the neuropharmacological efficacy of NRG in various experimental paradigms, it is concluded that this molecule should be further considered and studied as a potential candidate for neurotherapeutics, focusing on mechanistic and clinical trials to ascertain its efficacy. • Neurological illnesses are multifactorial incurable debilitating disorders that may cause neurodegeneration. • Neurological illnesses affect approximately 30 million people around the world. • Effective management of such disorders remains a global challenge. • Naringin has been shown possess outstanding therapeutic potential as a neuroprotective agent. • Naringin affects multiple signaling pathways in its neuropharmacological efficacy. • Naringin might be a potential candidate for neurotherapeutics. [ABSTRACT FROM AUTHOR]

The therapeutic effect of the hot water infusion of Cola nitida against hyperglycemia-induced neurotoxicity, cerebellar neurodegeneration and elemental deregulations was investigated in fructose-streptozotocin induced rat model of type 2 diabetes (T2D). A diabetic group was administered drinking water, two other diabetic groups were treated with C. nitida at 150 and 300 mg/kg bodyweight respectively, while another group was administered metformin (200 mg/kg bodyweight). Two other groups consisting of normal rats, were administered drinking water and C. nitida (300 mg/kg bodyweight). After 6 weeks of treatment, their brains were collected. Treatment with C. nitida led to suppression of oxidative stress, significantly elevating reduced glutathione (GSH) levels, superoxide dismutase and catalase activities, concomitant with depletion of malondialdehyde (MDA) levels. Acetylcholinesterase and ATPase activities were significantly inhibited in C. nitida -treated diabetic rats. Histological and microscopic analysis also revealed a restorative effect of C. nitida on T2D-altered distribution of elements, neurons and axonal nodes. Treatment with C. nitida also led to significant inhibition of Nrf2 expression in the cerebellar cortex. These results suggest the therapeutic effects of C. nitida in maintenance of the neuronal integrity and antioxidant status of the brain in T2D. These neuroprotective activities can be attributed to the identified alkaloid, caffeine in the infusion. • Cola nitida suppressed oxidative stress biomarkers and enzyme activities in brain tissues of type 2 diabetic rats. • Cola nitida inhibited cholinesterase and ATPase activities in brain tissues of type 2 diabetic rats. • Cola nitida restored morphological changes in cerebellar cortices of type 2 diabetic rats. • Cola nitida suppressed the expression of nrf2 in cerebellar cortices of type 2 diabetic rats. [ABSTRACT FROM AUTHOR]

Abstract The current study aims to assess the long-term effects of very low dose exposures to a complex chemical mixture on motor performance and behavioural changes in rats. For twelve months (equivalent to thirty years in human terms), four groups of Sprague Dawley rats (five males and five females per group) were exposed to a thirteen chemical mixture (in drinking water) in doses of 0, 0.25, 1 and 5xADI/TDI (acceptable daily intake/tolerable daily intake) (mg/kg body weight/day). After twelve month exposure, the rats' motor performances were assessed by rotarod test, and their behavioural changes were assessed by open field exploratory test and elevated plus maze test. Exposure to the chemical mixture resulted in a statistically significant increase in the locomotor activity quantified by the number of crossings over external squares and in the spatial orientation activity quantified as the number of rearings in the lower dose group (0.25xADI/TDI) compared with the control group (p < 0.05). No significant changes were observed in the two higher dose groups (1xADI/TDI, 5xADI/TDI) compared with the control group. The administration of a very low doses of a cocktail of 13 chemicals led to a dose-dependent stimulation of the nervous system, rather than its inhibition. Graphical abstract Image 1 Highlights • Very low doses combined exposure to 13 chemicals revealed hormetic effects on nervous system. • Locomotor activity testing showed two phase dose-dependent effects in rats. • Spatial orientation activity showed non-monotonic response in rats. • Neurobehavioral tests disclose hormesis after exposure to chemical mixture in doses below NOAEL. [ABSTRACT FROM AUTHOR]

Atropa belladonna , commonly known as belladonna or deadly nightshade, ranks among one of the most poisonous plants in Europe and other parts of the world. The plant contains tropane alkaloids including atropine, scopolamine, and hyoscyamine, which are used as anticholinergics in Food and Drug Administration (FDA) approved drugs and homeopathic remedies. These alkaloids can be very toxic at high dose. The FDA has recently reported that Hyland's baby teething tablets contain inconsistent amounts of Atropa belladonna that may have adverse effects on the nervous system and cause death in children, thus recalled the product in 2017. A greater understanding of the neurotoxicity of Atropa belladonna and its modification of genetic polymorphisms in the nervous system is critical in order to develop better treatment strategies, therapies, regulations, education of at-risk populations, and a more cohesive paradigm for future research. This review offers an integrated view of the homeopathy and neurotoxicity of Atropa belladonna in children, adults, and animal models as well as its implications to neurological disorders. Particular attention is dedicated to the pharmaco/toxicodynamics, pharmaco/toxicokinetics, pathophysiology, epidemiological cases, and animal studies associated with the effects of Atropa belladonna on the nervous system. Additionally, we discuss the influence of active tropane alkaloids in Atropa belladonna and other similar plants on FDA-approved therapeutic drugs for treatment of neurological disorders. [ABSTRACT FROM AUTHOR]

The objective of the study was to evaluate the association between smoking and essential metal (Co, Cr, Cu, Fe, Mn, V, Zn) and metalloid (Se) levels in hair and serum of adult women using inductively coupled plasma-mass spectrometry (ICP-MS). In this cross-sectional study, a total of 344 women 20–70 years old including 199 smokers and 145 non-smoking women were enrolled. Serum Cu, Fe, and Zn levels in smoking women were found to be 6%, 8%, and 3% lower of levels in non-smokers, respectively. In contrast, circulating Mn, V, and especially Cr concentrations in smoking women exceeded the respective values in non-smoking women by 5%, 14%, and 54%. Hair Fe and Se levels in smoking women were 17% and 23% lower as compared to non-smoking controls, respectively. In multiple regression models, smoking severity was inversely associated with serum and hair Se concentrations, whereas the relationship to serum and hair Cr was positive. In addition, serum Zn and hair Fe levels were found to be inversely associated with the number of cigarettes per day. These findings hypothesize that health hazards of smoking may be at least in part be mediated by alteration in essential metal and metalloid metabolism. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

Highlights: [•] Se- and Te-xylofuranosides depicted low toxicity in C. elegans. [•] The compounds protected from toxicity-induced by Mn. [•] Se- and Te-xylofuranosides increased the expression SOD-3. [•] Compounds induced nuclear translocation of DAF-16/FOXO. [•] DAF-16 cascade modulation is a possible mechanism of organohalcogens. [Copyright &y& Elsevier]

Abstract: Methylmercury (MeHg) is a highly neurotoxic pollutant, whose mechanisms of toxicity are related to its pro-oxidative properties. A previous report showed under in vivo conditions the neuroprotective effects of plants of the genus Polygala against MeHg-induced neurotoxicity. Moreover, the flavonoid quercetin, isolated from Polygala sabulosa, displayed beneficial effects against MeHg-induced oxidative damage under in vitro conditions. In this study, we sought for potential beneficial effects of quercetin against the neurotoxicity induced by MeHg in Swiss female mice. Animals were divided into six experimental groups: control, quercetin low dose (5mg/kg), quercetin high dose (50mg/kg), MeHg (40mg/L, in tap water), MeHg+quercetin low dose, and MeHg+quercetin high dose. After the treatment (21 days), a significant motor deficit was observed in MeHg+quercetin groups. Biochemical parameters related to oxidative stress showed that the simultaneous treatment with quercetin and MeHg caused a higher cerebellar oxidative damage when compared to the individual exposures. MeHg plus quercetin elicited a higher cerebellar lipid peroxidation than MeHg or quercetin alone. The present results indicate that under in vivo conditions quercetin and MeHg cause additive pro-oxidative effects toward the mice cerebellum and that such phenomenon is associated with the observed motor deficit. [Copyright &y& Elsevier]

Hair is used as a biomarker of manganese (Mn) exposure, yet there is limited evidence to support its utility to quantify internal vs external Mn exposure. C57BL/6 J mice and Sprague-Dawley rats were exposed in two blocks of 3 subcutaneous injections every 3 days starting on day 0 or 20. The control group received two blocks of saline (vehicle); Treatment A received the first block as Mn (50 mg/kg MnCl 2 tetrahydrate), with the second block as either methylmercury (MeHg at 2.6 or 1.3 mg/kg) for mice or vehicle for rats; and Treatment B received Mn for both blocks. Hair was collected on days 0 and 60 from all treatment groups and Mn quantified by inductively coupled plasma-mass spectrometry (ICP-MS) and total Hg by Direct Mercury Analyzer (DMA). No correlation between internal Mn dose and hair Mn was observed, whereas hair Hg was significantly elevated in MeHg exposed vs non-exposed mice. Whole body Mn content at day 60 was quantified postmortem by neutron activation analysis, which detected significantly elevated Mn for Treatment B in mice and rats. Overall, we find no evidence to support the use of hair as a valid biomarker for internal exposure to Mn at a neurotoxic level. • Hair has potential to serve as a non-invasive biomarker for Mn exposure. • Mice and rats received sub-cutaneous Mn injections to examine accumulation in hair. • Whole body Mn was examined in mice and rats using NAA. • Sub-cutaneous MeHg exposures confirmed as a positive control. • No support for hair as a biomarker for internal Mn exposure at a neurotoxic level. [ABSTRACT FROM AUTHOR]

The developing human brain is uniquely vulnerable to methylmercury (MeHg) resulting in lasting effects especially in developing cortical structures. Here we assess by single-cell RNA sequencing (scRNAseq) persistent effects of developmental MeHg exposure in a differentiating cortical human-induced pluripotent stem cell (hiPSC) model which we exposed to in vivo relevant and non-cytotoxic MeHg (0.1 and 1.0 μM) concentrations. The cultures were exposed continuously for 6 days either once only during days 4–10, a stage representative of neural epithelial- and radial glia cells, or twice on days 4–10 and days 14–20, a somewhat later stage which includes intermediate precursors and early postmitotic neurons. After the completion of MeHg exposure the cultures were differentiated further until day 38 and then assessed for persistent MeHg-induced effects by scRNAseq. We report subtle, but significant changes in the population size of different cortical cell types/stages and cell cycle. We also observe MeHg-dependent differential gene expression and altered biological processes as determined by Gene Ontology analysis. Our data demonstrate that MeHg results in changes in gene expression in human developing cortical neurons that manifest well after cessation of exposure and that these changes are cell type-, developmental stage-, and exposure paradigm-specific. [ABSTRACT FROM AUTHOR]

Developmental methylmercury (MeHg) exposure selectively targets the cerebral and cerebellar cortices, as seen by disruption of cytoarchitecture and glutamatergic (GLUergic) neuron hypoplasia. To begin to understand the mechanisms of this loss of GLUergic neurons, we aimed to develop a model of developmental MeHg neurotoxicity in human-induced pluripotent stem cells differentiating into cortical GLUergic neurons. Three dosing paradigms at 0.1 μM and 1.0 μM MeHg, which span different stages of neurodevelopment and reflect toxicologically relevant accumulation levels seen in human studies and mammalian models, were established. With these exposure paradigms, no changes were seen in commonly studied endpoints of MeHg toxicity, including viability, proliferation, and glutathione levels. However, MeHg exposure induced changes in mitochondrial respiration and glycolysis and in markers of neuronal differentiation. Our novel data suggests that GLUergic neuron hypoplasia seen with MeHg toxicity may be due to the partial inhibition of neuronal differentiation, given the increased expression of the early dorsal forebrain marker FOXG1 and corresponding decrease in expression on neuronal markers MAP2 and DCX and the deep layer cortical neuronal marker TBR1. Future studies should examine the persistent and latent functional effects of this MeHg-induced disruption of neuronal differentiation as well as transcriptomic and metabolomic alterations that may mediate MeHg toxicity. • Human-induced pluripotent stem model of early developmental MeHg neurotoxicity. • Developmental MeHg causes changes in neuronal differentiation and energetics. • No Observed Adverse Effect Concentration (NOAEC) for MeHg cytotoxicity and GSH levels. • Neuron hypoplasia by MeHg may be due to inhibition of neuronal differentiation. [ABSTRACT FROM AUTHOR]

Lead is a heavy metal pollutant that is widely present in the environment. It affects every organ system, yet the nervous system appears to be the most sensitive and primary target. Although many countries have made significant strides in controlling Pb pollution, Pb poisoning continuous to be a major public health concern. Exposure to Pb causes neurotoxicity that ranges from neurodevelopmental disorders to severe neurodegenerative lesions, leading to impairments in learning, memory, and cognitive function. Studies on the mechanisms of Pb-induced nervous system injury have convincingly shown that this metal can affect a plethora of cellular pathways affecting on cell survival, altering calcium dyshomeostasis, and inducing apoptosis, inflammation, energy metabolism disorders, oxidative stress, autophagy and glial stress. This review summarizes recent knowledge on multiple signaling pathways associated with Pb-induced neurological disorders in vivo and in vitro. • Summarize Pb neural signal transduction in vivo and in vitro. • The pathways are concerned with Pb-induced neurological disorders. • Lead influence on calcium homeostasis can induce multiple neurological disorders. • Lead-induced neurological disorders are characterized by learning and memory disorders. [ABSTRACT FROM AUTHOR]

The objective of the present study was to assess the impact of cobalt (Co) exposure on tissue distribution of iron (Fe), copper (Cu), manganese (Mn), and zinc (Zn), as well as serum hepcidin levels in immature mice (18, 25, 30 days). Pregnant mice were exposed to 75 mg/kg b.w. cobalt chloride (CoCl 2 × 6H2O) with drinking water starting from 3 days before delivery and during lactation. At weaning (day 25) the offspring were separated and housed in individual cages with subsequent exposure to 75 mg/kg b.w. CoCl 2 until 30 days postnatally. Evaluation of tissue metal levels was performed by an inductively coupled plasma-mass spectrometry (ICP-MS). Serum hepcidin level was assayed by enzyme linked immunosorbent assay (ELISA). Cobalt exposure resulted in a time- and tissue-dependent increase in Co levels in kidney, spleen, liver, muscle, erythrocytes, and serum on days 18, 25, and 30. In parallel with increasing Co levels, CoCl 2 exposure resulted in a significant accumulation of Cu, Fe, Mn, and Zn in the studied tissues, with the effect being most pronounced in 25-day-old mice. Cobalt exposure significantly increased serum hepcidin levels only in day18 mice. The obtained data demonstrate that Co exposure may alter essential metal metabolism in vivo. Image 1 • The effects of Co on metal levels were studied in 18, 25, and 30-day old mice. • Co exposure resulted in a time- and tissue-dependent increase in Co levels. • Co exposure resulted in co-accumulation of Cu, Fe, Mn, and Zn in the studied tissues. • Co exposure significantly impacted hepcidin levels only in day18 mice. • Alterations in metal homeostasis may be considered a mechanism of Co-induced toxicity. [ABSTRACT FROM AUTHOR]

Several studies have demonstrated that heavy metals disrupt energy homeostasis. Leptin inhibits food intake and decreases body weight through activation of its receptor in the hypothalamus. The impact of heavy metals on leptin signaling in the hypothalamus is unclear. Here, we show that the environmental pollutant, methylmercury (MeHg), favors an anorexigenic profile in wild-type males. C57BL/6J mice were exposed to MeHg via drinking water (5 ppm) up to 30 days. Our data shows that MeHg exposure was associated with changes in leptin induced activation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in the hypothalamus. In males, the activation of JAK2/STAT3 signaling pathway was sustained by an increase in SOCS3 protein levels. In females, MeHg-activated STAT3 was inhibited by a concomitant increase in PTP1B. Taken together, our data suggest that MeHg enhanced leptin effects in males, favoring an anorexigenic profile in males, which notably, have been shown to be more sensitive to the neurological effects of this organometal than females. A better understanding of MeHg-induced molecular mechanism alterations in the hypothalamus advances the understanding of its neurotoxicity and provides molecular sites for novel therapies. • C57BL/6J female mice accumulated higher mercury concentrations in the hypothalamus than males. • MeHg potentiated leptin-induced appetite loss and body weight decrease. • In both males and females MeHg induced the hypothalamic JAK2/STAT3 signaling pathway. • Leptin induced anti-apoptotic proteins and restored antioxidant HO1 protein levels in males. [ABSTRACT FROM AUTHOR]

Methylmercury (MeHg) is a neurotoxic pollutant widely present in the environment. Initial symptoms of MeHg may include loss of body weight. However, the mechanisms by which MeHg induces body weight changes have yet to be fully elucidated. Body weight is regulated by multiple mechanisms. Whereas multiple peripheral peptides lead to food intake cessation, ghrelin is the only recognized peripheral hormone that stimulates food intake. It exerts its action on Neuropeptide Y/Agouti-related peptide neurons in the hypothalamus. To test if MeHg affects ghrelin signaling C57BL/6J mice (males and females) were exposed to 5 ppm MeHg via drinking water during a month. On days 15 and 30 of MeHg exposure ghrelin was administered intraperitoneally and changes in body weight and food intake were recorded. In addition, changes in ghrelin-induced signaling pathways in hypothalamus were also analyzed. Here, we show that in males, MeHg enhanced ghrelin-induced body weight gain by activating the AMP-activated Kinase (AMPK)/Uncoupled protein 2 (UCP2) signaling pathway. In contrast, in females, MeHg inhibited ghrelin-induced mTOR signaling activation and decreased Npy mRNA expression, thus mitigating the ghrelin-induced weight gain. Combined, our novel results demonstrate, for the first time, that MeHg disrupts the physiological functions of ghrelin differently in males and females. • MeHg mitigated ghrelin-induced body weight gain in females by disrupting mTOR signaling pathways in the hypothalamus. • MeHg mediated its anorexigenic/catabolic effects decreasing Npy mRNA in females, whereas no changes were observed in males. • MeHg exacerbated ghrelin effects by enhancing AMPK signaling pathways in the hypothalamus. • Ghrelin displayed several anti-apoptotic and antioxidant properties in males. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders are characterized by progressive loss of neurons. To date, no efficacious therapies exist for these disorders, and current therapies provide only symptomatic relief. The neuroprotective effects of natural compounds have been reported in several neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) amyotrophic lateral sclerosis (ALS), cerebral ischemia and brain tumors. Flavonoids are the most widely studied natural products for the prevention and treatment of neurodegenerative disorders. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) represents a complex gene regulated cytoprotective pathway. Several natural compounds have been identified as Nrf2 regulators in various chronic disorders, including carcinogenic, liver ailments, inflammatory conditions, neurodegeneration, diabetes and cardiotoxicities. The current review focuses on Nrf2 targeting by flavonoids in the prevention and treatment of neurodegenerative disorders, addressing the most contemporary information available on this timely subject. Image 1 • Neurodegenerative disorders are characterized by progressive loss of neurons, lacking efficacious therapies. • The Nrf2 represents a complex gene regulated cytoprotective pathway. • Flavonoids are the most widely studied natural products for the prevention and treatment of neurodegenerative disorders. • Nrf2 targeting by flavonoids showed outstanding therapeutic effects in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Multiple medical, lifestyle, and environmental conditions, including smoking and particulate pollution, have been considered as risk factors for CO rona VI rus D isease 2019 (COVID-19) susceptibility and severity. Taking into account the high level of toxic metals in both particulate matter (PM2.5) and tobacco smoke, the objective of this review is to discuss recent data on the role of heavy metal exposure in development of respiratory dysfunction, immunotoxicity, and severity of viral diseases in epidemiological and experimental studies, as to demonstrate the potential crossroads between heavy metal exposure and COVID-19 severity risk. The existing data demonstrate that As, Cd, Hg, and Pb exposure is associated with respiratory dysfunction and respiratory diseases (COPD, bronchitis). These observations corroborate laboratory findings on the role of heavy metal exposure in impaired mucociliary clearance, reduced barrier function, airway inflammation, oxidative stress, and apoptosis. The association between heavy metal exposure and severity of viral diseases, including influenza and respiratory syncytial virus has been also demonstrated. The latter may be considered a consequence of adverse effects of metal exposure on adaptive immunity. Therefore, reduction of toxic metal exposure may be considered as a potential tool for reducing susceptibility and severity of viral diseases affecting the respiratory system, including COVID-19. Image 1 [ABSTRACT FROM AUTHOR]

Common manifestations of COVID-19 are respiratory and can extend from mild symptoms to severe acute respiratory distress. The severity of the illness can also extend from mild disease to life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions, leading to gastrointestinal symptoms. Moreover, SARS-CoV-2 can cause central and peripheral neurological manifestations, affect the cardiovascular system and promote renal dysfunction. Epidemiological data have indicated that cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. Considering the multitude of clinical symptoms of COVID-19, the objective of the present review was to summarize their pathophysiology in previously healthy patients, as well as in those with comorbidities. The present review summarizes the current, though admittedly fluid knowledge on the pathophysiology and symptoms of COVID-19 infection. Although unclear issues still remain, the present study contributes to a more complete understanding of the disease, and may drive the direction of new research. The recognition of the severity of the clinical symptoms of COVID-19 is crucial for the specific therapeutic management of affected patients. Image 1 • Respiratory system is the main target of SARS-CoV-2. • SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions. • SARS-CoV-2 can cause central and peripheral neurological manifestations. • SARS-CoV-2 can affect the cardiovascular system and promote renal dysfunction. • Cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) and previous pandemics have been viewed almost exclusively as virology problems, with toxicology problems mostly being ignored. This perspective is not supported by the evolution of COVID-19, where the impact of real-life exposures to multiple toxic stressors degrading the immune system is followed by the SARS-CoV-2 virus exploiting the degraded immune system to trigger a chain of events ultimately leading to COVID-19. This immune system degradation from multiple toxic stressors (chemical, physical, biological, psychosocial stressors) means that attribution of serious consequences from COVID-19 should be made to the virus-toxic stressors nexus, not to any of the nexus constituents in isolation. The leading toxic stressors (identified in this study as contributing to COVID-19) are pervasive, contributing to myriad chronic diseases as well as immune system degradation. They increase the likelihood for comorbidities and mortality associated with COVID-19. For the short-term, tactical/reactive virology-focused treatments are of higher priority than strategic/proactive toxicology-focused treatments, although both could be implemented in parallel to reinforce each other. However, for long-term pandemic prevention, toxicology-based approaches should be given higher priority than virology-based approaches. Since current COVID-19 treatments globally ignore the toxicology component almost completely, only limited benefits can be expected from these treatments. • Toxicology contributions to COVID-19 are mostly ignored relative to virology contributions. • Exposure to myriad toxic substances degrades the immune system, whose resulting dysfunction is then exploited by SARS-CoV-2 to result in COVID-19. • Attribution of serious consequences from COVID-19 should be made to the virus-toxic stressors combination nexus, not to any of the nexus constituents in isolation. • Effective treatments need to address toxicology and virology interactions. [ABSTRACT FROM AUTHOR]

Occupational, residential, dietary and environmental exposures to mixtures of synthetic anthropogenic chemicals after World War II have a strong relationship with the increase of chronic diseases, health cost and environmental pollution. The link between environment and immunity is particularly intriguing as it is known that chemicals and drugs can cause immunotoxicity (e.g., allergies and autoimmune diseases). In this review, we emphasize the relationship between long-term exposure to xenobiotic mixtures and immune deficiency inherent to chronic diseases and epidemics/pandemics. We also address the immunotoxicologic risk of vulnerable groups, taking into account biochemical and biophysical properties of SARS-CoV-2 and its immunopathological implications. We particularly underline the common mechanisms by which xenobiotics and SARS-CoV-2 act at the cellular and molecular level. We discuss how long-term exposure to thousand chemicals in mixtures, mostly fossil fuel derivatives, exposure toparticle matters, metals, ultraviolet (UV)–B radiation, ionizing radiation and lifestyle contribute to immunodeficiency observed in the contemporary pandemic, such as COVID-19, and thus threaten global public health, human prosperity and achievements, and global economy. Finally, we propose metrics which are needed to address the diverse health effects of anthropogenic COVID-19 crisis at present and those required to prevent similar future pandemics. Image 1 • Developmental exposure to environmental factors can disrupt the immune system. • Long-term low-dose exposure to chemical mixtures is linked to imunodeficiency • Immunodeficiency contributes to chronic diseases and the current Covid-19 pandemics. • Environmental chemicals and microorganisms share similar molecular pathomechanisms (AhR pathway). • Understanding the underlying pathomechanisms helps to improve public health. [ABSTRACT FROM AUTHOR]

It appears that electronic cigarettes (EC) are a less harmful alternative to conventional cigarette (CC) smoking, as they generate substantially lower levels of harmful carcinogens and other toxic compounds. Thus, switching from CC to EC may be beneficial for smokers. However, recent accounts of EC- or vaping-associated lung injury (EVALI) has raised concerns regarding their adverse health effects. Additionally, the increasing popularity of EC among vulnerable populations, such as adolescents and pregnant women, calls for further EC safety evaluation. In this state-of-the-art review, we provide an update on recent findings regarding the neurological effects induced by EC exposure. Moreover, we discuss possible neurotoxic effects of nicotine and numerous other chemicals which are inherent both to e-liquids and EC aerosols. We conclude that in recognizing pertinent issues associated with EC usage, both government and scientific researchers must address this public health issue with utmost urgency. • Electronic cigarettes (EC) are marketed as alternatives to conventional cigarette (CC) smoking. • Recent accounts of EC- or vaping-associated lung injury (EVALI) have raised concerns regarding their adverse health effects. • The increased popularity of EC among adolescents and pregnant women calls for further safety evaluation. • EC may have neurotoxic effects due to nicotine and other chemicals inherent both to e-liquids and EC aerosols. [ABSTRACT FROM AUTHOR]