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Manganese (Mn) overexposure has been associated with the development of neurological damage reminiscent of Parkinson's disease, while the underlying mechanisms have yet to be fully characterized. This study aimed to investigate the mechanisms leading to injury in dopaminergic neurons induced by Mn and identify novel treatment approaches. In the in vivo and in vitro models, ICR mice and dopaminergic neuron-like PC12 cells were exposed to Mn, respectively. We treated them with anti-ferroptotic agents ferrostatin-1 (Fer-1), deferoxamine (DFO), HIF-1α activator dimethyloxalylglycine (DMOG) and inhibitor LW6. We also used p53-siRNA to verify the mechanism underlying Mn-induced neurotoxicity. Fe and Mn concentrations increased in ICR mice brains overexposed to Mn. Additionally, Mn-exposed mice exhibited movement impairment and encephalic pathological changes, with decreased HIF-1α, SLC7A11, and GPX4 proteins and increased p53 protein levels. Fer-1 exhibited protective effects against Mn-induced both behavioral and biochemical changes. Consistently, in vitro , Mn exposure caused ferroptosis-related changes and decreased HIF-1α levels, all ameliorated by Fer-1. Upregulation of HIF-1α by DMOG alleviated the Mn-associated ferroptosis, while LW6 exacerbated Mn-induced neurotoxicity through downregulating HIF-1α. p53 knock-down also rescued Mn-induced ferroptosis without altering HIF-1α protein expression. Mn overexposure resulted in ferroptosis in dopaminergic neurons, mediated through the HIF-1α/p53/SLC7A11 pathway. [Display omitted] • Overexposure to manganese leads to dopaminergic injury through ferroptosis. • The ferroptosis inhibitor Fer-1 alleviates the injury. • HIF-1α activator DMOG relieves the manganese-induced ferroptosis. • Manganese-induced dopaminergic injury is mediated by HIF-1α/P53/SLC7A11 pathway. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common, aggressive, and fatal primary malignant brain tumor in adults. The therapeutic efficacy of temozolomide (TMZ) is limited owing to frequent treatment resistance. The latter is in part related to the overexpression of redox systems such as the thioredoxin system. This system is fundamental for cell survival and proliferation, regulating hypoxia inducible factor-1alpha (HIF-1α) activity, in turn controlling vascular endothelial growth factor (VEGF), which is indispensable for tumor invasiveness, angiogenesis and microenvironment maintenance. HIF-1α can also be regulated by the signal transducer and activator of transcription 3 (STAT3), an oncogene stimulated by pro-inflammatory cytokines and growth factors. The thioredoxin system has several known inhibitors including mercury compounds such as Thimerosal (TmHg) which readily crosses the blood-brain barrier (BBB) and accumulates in the brain. Though previously used in various applications epidemiological evidence on TmHg's neurotoxicity is lacking. The objective of this study was to verify whether thimerosal is a suitable candidate for hard repurposing to control glioblastoma; therefore, the effects of this molecule were evaluated in human GBM (U87) cells. Our novel results show that TmHg decreased cellular viability (>50%) and migration (up to 90% decrease in wound closure), reduced thioredoxin reductase (TrxR/TXNRD1) and thioredoxin (Trx) activity, and increased reactive oxygen species (ROS) generation. Moreover, TmHg reduced HIF-1α expression (35%) as observed by immunofluorescence. Co-exposure of U87 cells to TmHg and TMZ reduced HIF-1α, VEGF, and phosphorylated STAT3. Consequently, TmHg alone or combined with chemotherapeutic drugs can reduce neoangiogenesis and ameliorate glioblastoma progression and treatment. [Display omitted] • Thioredoxin system inhibition by thimerosal increases ROS and cancer cell death; • Thimerosal strongly affects glioblastoma (U87) cells viability and migration; • Thimerosal hinders HIF-1α expression and angiogenesis signaling pathways; • Co-exposure of U87 cells to thimerosal and temozolamide reduces HIF-1α, VEGF, and pSTAT3; • Thimerosal kills human resistant glioblastoma cells and reduces treatment resistance. [ABSTRACT FROM AUTHOR]

Since the discovery of manifest Zn deficiency in 1961, the increasing number of studies demonstrated the association between altered Zn status and multiple diseases. In this chapter, we provide a review of the most recent advances on the role of Zn in health and disease (2010-20), with a special focus on the role of Zn in neurodegenerative and neurodevelopmental disorders, diabetes and obesity, male and female reproduction, as well as COVID-19. In parallel with the revealed tight association between ASD risk and severity and Zn status, the particular mechanisms linking Zn2+ and ASD pathogenesis like modulation of synaptic plasticity through ProSAP/Shank scaffold, neurotransmitter metabolism, and gut microbiota, have been elucidated. The increasing body of data indicate the potential involvement of Zn2+ metabolism in neurodegeneration. Systemic Zn levels in Alzheimer's and Parkinson's disease were found to be reduced, whereas its sequestration in brain may result in modulation of amyloid β and α-synuclein processing with subsequent toxic effects. Zn2+ was shown to possess adipotropic effects through the role of zinc transporters, zinc finger proteins, and Zn-α2-glycoprotein in adipose tissue physiology, underlying its particular role in pathogenesis of obesity and diabetes mellitus type 2. Recent findings also contribute to further understanding of the role of Zn2+ in spermatogenesis and sperm functioning, as well as oocyte development and fertilization. Finally, Zn2+ was shown to be the potential adjuvant therapy in management of novel coronavirus infection (COVID-19), underlining the perspectives of zinc in management of old and new threats. [ABSTRACT FROM AUTHOR]

Manganese (Mn) and iron (Fe) are essential trace elements for humans, yet excessive exposure to Mn or Fe can accumulate in the central nervous system (CNS) and cause neurotoxicity. The purpose of this study was to investigate the effects of Mn and Fe exposure, alone or in combination, on inducing oxidative stress-induced neurological damage in rat cortical and SH-SY5Y cells, and to determine whether combined exposure to these metals increases their individual toxicity. SH-SY5Y cells and male Sprague-Dawley rats were used to observe the effects of oxidative stress-induced neurological damage induced by exposure to manganese and iron alone or in combination. To detect the expression of anti-oxidative stress-related proteins, Nrf2, HO-1, and NQO1, and the apoptosis-related proteins, Bcl2 and Bax, and the neurological damage-related protein, α-syn. To detect reactive oxygen species generation and apoptosis. To detect the expression of the rat cortical protein Nrf2. To detect the production of proinflammatory cytokines. We demonstrate that juvenile developmental exposure to Mn and Fe and their combination impairs cognitive performance in rats by inducing oxidative stress causing neurodegeneration in the cortex. Mn, Fe, and their combined exposure increased the expression of ROS, Bcl2, Bax, and α-syn, activated the inflammatory factors IL-6 and IL-12, inhibited the activities of SOD and GSH, and induced oxidative stress-induced neurodegeneration both in rats and SH-SY5Y cells. Combined Mn-Fe exposure attenuated the oxidative stress induced by Mn and Fe exposure alone by increasing the expression of antioxidant factors Nrf2, HO-1, and NQO1. In both in vivo and in vitro studies, manganese and iron alone or in combination induced oxidative stress, leading to neuronal damage. In contrast, combined exposure to manganese and iron mitigated the oxidative stress induced by exposure to manganese and iron alone by increasing the expression of antioxidant factors. Therefore, studies to elucidate the main causes of toxicity and establish the molecular mechanisms of toxicity should help to develop more effective therapeutic modalities in the future. • We investigated the effects of manganese and iron and their combined exposure on neurological damage. • We investigated the effects of manganese, iron, and their combined exposure on oxidative stress. • We investigated the effects of manganese, iron, and their combined exposure on the expression of the Nrf2/HO-1/NQO1. • We investigated the antagonistic effect between manganese and iron in vivo and in vitro [ABSTRACT FROM AUTHOR]

The objective of the present study was to review the existing epidemiological and laboratory findings supporting the role of toxic metal exposure in non-alcoholic fatty liver disease (NAFLD). The existing epidemiological studies demonstrate that cadmium (Cd), lead (Pb), arsenic (As), and mercury (Hg) exposure was associated both with an increased risk of NAFLD and altered biochemical markers of liver injury. Laboratory studies demonstrated that metal exposure induces hepatic lipid accumulation resulting from activation of lipogenesis and inhibition of fatty acid β-oxidation due to up-regulation of sterol regulatory element-binding protein 1 (SREBP-1), carbohydrate response element binding protein (ChREBP), peroxisome proliferator-activated receptor γ (PPARγ), and down-regulation of PPARα. Other metabolic pathways involved in this effect may include activation of reactive oxygen species (ROS)/extracellular signal-regulated kinase (ERK) and inhibition of AMP-activated protein kinase (AMPK) signaling. The mechanisms of hepatocyte damage during development of metal-induced hepatic steatosis were shown to involve oxidative stress, endoplasmic reticulum stress, pyroptosis, ferroptosis, and dysregulation of autophagy. Induction of inflammatory response contributing to progression of NAFLD to non-alcoholic steatohepatitis (NASH) upon toxic metal exposure was shown to be mediated by up-regulation of nuclear factor κB (NF-κB) and activation of NRLP3 inflammasome. Moreover, epigenetic effects of the metals, as well as their effect on gut microbiota and gut wall integrity were also shown to mediate their role in NAFLD development. Despite being demonstrated for Cd, Pb, and As, the contribution of these mechanisms into Hg-induced NAFLD is yet to be estimated. Therefore, further studies are required to clarify the intimate mechanisms underlying the relationship between heavy metal and metalloid exposure and NAFLD/NASH to reveal the potential targets for treatment and prevention of metal-induced NAFLD. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Reproductive epidemiological studies have suggested associations between perinatal exposure to fine particulate matter (PM 2.5) and adverse birth outcomes. To explore the effects of early prenatal exposure to PM 2.5 on subsequent generations, pregnant mice were exposed to PM 2.5 or filtered clean air in whole body dynamic exposure chambers for 14 consecutive days from gestation day (GD) 1.5 to GD15.5. Neurobehavioral tests showed that spontaneous locomotion and exploratory behaviors in the offspring were significantly enhanced in the open field test. Meanwhile, metabolomics analysis suggested activation of dopamine pathway while inhibition of glycine pathway in murine brains. Administration of the DRD4 antagonist, clozapine; or supplementation of glycine receptor agonist, taurine, to mice offspring attenuated the locomotor hyperactivities to levels indistinguishable from controls. These data provide strong evidence that maternal exposure to air pollution might increase the risk for neural disorders in the offspring during critical periods of brain development. Highlights • Maternal PM 2.5 exposure led to locomotor hyperactivities in murine offspring. • Metabolomics analysis identified the metabolic pathway involved in PM 2.5 exposure. • Taurine can effectively rescue the PM 2.5 -induced hyperactivities to control level. [ABSTRACT FROM AUTHOR]

Abstract Epidemiological studies have associated ambient fine particulate matter (PM 2.5) exposure with lung cancer, in which epithelial-mesenchymal transition (EMT) is an initial process. Thus, it is important to identify the key molecule or pathway involved in the PM 2.5 induced EMT. Human bronchial epithelial (HBE) cells were exposed to PM 2.5 (100 or 500 μg/ml) for 30 passages and analyzed by metabolomics to identify the alteration of metabolites related to PM 2.5 exposure. The expression levels of EMT markers were evaluated by qRT-PCR and Western blot assays in HBE cells and murine lung tissues. Reduced epithelial markers, increased mesenchymal markers expression levels and increased capacity of metastasis were observed in PM 2.5 -exposed HBE cells. Metabolomics analysis suggested upregulation of citrate acid with fold change (FC) of 2.89 or 4.18 in 100 or 500 μg/ml PM 2.5 treated HBE cells. For both of the in vitro and in vivo study, the up-regulation of ATP citrate lyase (ACLY) was confirmed following PM 2.5 exposure. Importantly, ACLY knockdown in HBE cells reversed EMT, migration and invasion capacities in HBE cells induced by PM 2.5. Taken together, our data suggest that inhibition of ACLY demonstrates a protection against PM 2.5 -induced EMT, providing a concern on the molecular mechanisms of PM 2.5 -associated pulmonary disorders. Highlights • Long-term exposure of PM 2.5 leads to changes of phenotypes in HBE cells. • The malignant transformed HBE cells show metastasis capacity targeting to liver. • Citric acid plays a key role in the pathways enriched of modulated metabolites. • Knockdown of ACLY demonstrates protection effect against PM 2.5 exposure. [ABSTRACT FROM AUTHOR]

Lead contamination is a major public health concern. Previous studies have demonstrated that lead exposure could affect the hippocampus, which is a complex and heterogeneous structure composed of 12 subregions. Here, we explored volumetric and functional changes in hippocampal subfields and neuropsychological alterations after lead exposure. We performed a cross-sectional study at a smelting company between September 2020 and December 2021. Blood lead level was recorded, and neuropsychological functions were assessed by Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS). The hippocampus was segmented into 12 subfields in each hemisphere in magnetic resonance images (MRIs). Then, the effect of altered hippocampal subfield volumes on brain functions were studied by seed-based functional connectivity (FC) analysis. Finally, the relationships between the lead level with hippocampal subfield volumes and neuropsychological functions were investigated. Baseline characteristics, hippocampal subfield volumes, and FC analysis were compared between lead-exposed (≥ 300 μg/L) and the control group (≤ 100 μg/L). In 76 participants, lead level positively correlated with SDS(r = 0.422) and negatively correlated with MoCA(r = −0.414), MMSE(r = −0.251), Concentration(r = −0.331), Recall(r = −0.319), Orientation(r = −0.298) and Executive Function/Visuospatial abilities(r = −0.231). Lead group (26 participants) had lower MoCA and MMSE and higher SDS than control group (23 participants). A significantly decreased volume in the left CA4 and GC-ML-DG subfields was found in the lead group compared with the control group. The left GC-ML-DG of the lead group showed a decreased FC with the bilateral postcentral gyrus. The left CA4(r = −0.409) and left GC-ML-DG (r = −0.383) volumes negatively correlated with lead level. The FC between left GC-ML-DG and left postcentral gyrus positively correlated with MoCA(r = 0.318), MMSE(r = 0.379) and Recall(r = 0.311). The FC between left GC-ML-DG and right postcentral gyrus positively correlated with MoCA(r = 0.326), Executive Function/Visuospatial abilities(r = 0.307) and Concentration(r = 0.297). High blood lead level was associated with neuropsychological alterations, hippocampal structural and functional changes. The left GC-ML-DG and CA4 atrophy might serve as predictive imaging markers for neurological damage associated with high lead exposure. [Display omitted] • High blood lead level was associated with impaired neuropsychological functions. • Lead exposure decreases volumes of left GC-ML-DG and CA4 subfields in hippocampus. • Hippocampal subfield shrinkage as sensitive imaging marker for lead induced brain damage. [ABSTRACT FROM AUTHOR]

Lead (Pb) is a naturally occurring heavy metal, which can damage the brain and affect learning and memory. Sodium para-aminosalicylic acid (PAS-Na), a non-steroidal anti-inflammatory drug, can readily cross the blood-brain barrier. Our previous studies have found that PAS-Na alleviated Pb-induced hippocampal ultrastructural damage and neurodegeneration, but the mechanism has yet to be defined. Here, we investigated the molecular mechanisms that mediate Pb-induced apoptosis in hippocampal neurons, and the efficacy of PAS-Na in alleviating its effects. This work showed that juvenile developmental Pb exposure impaired rats cognitive ability by inducing apoptotic cell death in hippocampal neurons. Pb-induced neuronal apoptosis was accompanied by increased inositol 1,4,5-trisphosphate receptor (IP 3 R) expression and enhanced intracellular calcium [Ca2+] i levels, which resulted in increased phosphorylation of neuronal apoptosis signal-regulating kinase 1 (ASK1) and p38. Activation of ASK1 and p38 was blocked by IP 3 R inhibitor and a Ca2+ chelator. Importantly, PAS-Na treatment improved the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. In addition, PAS-Na reduced the expression of IP 3 R and the ensuing increase in intracellular Ca2+ and decreased the phosphorylation of ASK1 and p38 in Pb-exposed neurons. Taken together, this study demonstrates that the IP 3 R-Ca2+-ASK1-p38 signaling pathway mediates Pb-induced apoptosis in hippocampal neurons, and that PAS-Na, at a specific dose-range, ameliorates these changes. Collectively, this study sheds novel light on the cellular mechanisms that mediate PAS-Na efficacy, laying the groundwork for future research to examine the treatment potential of PAS-Na upon Pb poisoning. • Juvenile developmental Pb exposure impaired rat cognitive ability and induced apoptotic cell death in hippocampal neurons. • Pb-induced apoptosis in hippocampal neurons was secondary to IP 3 R-Ca2+-ASK1-p38 signaling pathway activation. • PAS-Na attenuated the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. • PAS-Na ameliorates the Pb-induced hippocampal neuronal apoptosis by suppressing IP 3 R-Ca2+-ASK1-p38 pathway activation. [ABSTRACT FROM AUTHOR]

Abstract: Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have been reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg-exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically studied agents. [Copyright &y& Elsevier]

Abstract: Research has demonstrated the toxic effects of methylmercury (MeHg), yet molecular mechanisms underlying its toxicity are not completely understood. Caenorhabditis elegans (C. elegans) offers a unique biological model to explore mechanisms of MeHg toxicity given many advantages associated with its ease of use and genetic power. Since our previous work indicated neurotoxic resistance of C. elegans to MeHg, the present study was designed to examine molecular mechanisms associated with this resistance. We hypothesized MeHg would induce expression of gst, hsp or mtl in vivo since glutathione (GSH), heat shock proteins (HSPs), and metallothioneins (MTs) have shown involvement in MeHg toxicity. Our studies demonstrated a modest, but significant increase in fluorescence in gst-4::GFP and mtl-1::GFP strains at an acute, low L1 MeHg exposure, whereas chronic L4 MeHg exposure induced expression of gst-4::GFP and hsp-4::GFP. Knockout gst-4 animals showed no alterations in lethality sensitivity compared to wildtype animals whereas mtl knockouts displayed increased sensitivity to MeHg exposure. GSH levels were increased by acute MeHg treatment and depleted with chronic exposure. We also demonstrate that MeHg induces hormesis, a phenotype whereby a sublethal exposure to MeHg rendered C. elegans resistant to subsequent exposure to the organometal. The involvement of gst-4, hsp-4, mtl-1, and mtl-2 in hormesis was examined. An increase in gst-4::GFP expression after a low-dose acute exposure to MeHg indicated that gst-4 may be involved in this response. Our results implicate GSH, HSPs, and MTs in protecting C. elegans from MeHg toxicity and show a potential role of gst-4 in MeHg-induced hormesis. [ABSTRACT FROM AUTHOR]

An increasing body of literature has demonstrated that armed conflicts and military activity may contribute to environmental pollution with metals, although the existing data are inconsistent. Therefore, in this paper, we discuss potential sources of military-related metal emissions, environmental metal contamination, as well as routes of metal exposure and their health hazards in relation to military activities. Emission of metals into the environment upon military activity occurs from weapon residues containing high levels of particles containing lead (Pb; leaded ammunition), copper (Cu; unleaded), and depleted uranium (DU). As a consequence, military activity results in soil contamination with Pb and Cu, as well as other metals including Cd, Sb, Cr, Ni, Zn, with subsequent metal translocation to water, thus increasing the risk of human exposure. Biomonitoring studies have demonstrated increased accumulation of metals in plants, invertebrates, and vertebrate species (fish, birds, mammals). Correspondingly, military activity is associated with human metal exposure that results from inhalation or ingestion of released particles, as well as injuries with subsequent metal release from embedded fragments. It is also notable that local metal accumulation following military injury may occur even without detectable fragments. Nonetheless, data on health effects of military-related metal exposures have yet to be systematized. The existing data demonstrate adverse neurological, cardiovascular, and reproductive outcomes in exposed military personnel. Moreover, military-related metal exposures also result in adverse neurodevelopmental outcome in children living within adulterated territories. Experimental in vivo and in vitro studies also demonstrated toxic effects of specific metals as well as widely used metal alloys, although laboratory data report much wider spectrum of adverse effects as compared to epidemiological studies. Therefore, further epidemiological, biomonitoring and laboratory studies are required to better characterize military-related metal exposures and their underlying mechanisms of their adverse toxic effects. • Military activity results in soil contamination with Pb, Cu, Cd, Sb, Cr, Ni, Zn. • Biomonitoring studies have demonstrated increased metals accumulation in biota. • Human metal exposure results from inhalation, ingestion, or embedded fragments. • Metals mediate adverse effects in military personnel and exposed civilian population. • Experimental studies demonstrated mechanisms of military-related metal toxicity. [ABSTRACT FROM AUTHOR]

Abstract: The present review is based on presentations from the meeting of the Society of Toxicology in San Diego, CA (March 2006). It addresses recent developments in the understanding of the transport of manganese (Mn) into the central nervous system (CNS), as well as brain imaging and neurocognitive studies in non-human primates aimed at improving our understanding of the mechanisms of Mn neurotoxicity. Finally, we discuss potential therapeutic modalities for treating Mn intoxication in humans. [Copyright &y& Elsevier]

Abstract: Historically, amino acids were studied in the context of their importance in protein synthesis. In the 1950s, the focus of research shifted as amino acids were recognized as putative neurotransmitters. Today, many amino acids are considered important neurochemicals. Although many amino acids play a role in neurotransmission, glutamate (Glu), glycine (Gly), and ¿-aminobutyric acid (GABA) are among the more prevalent and better understood. Glu, the major excitatory neurotransmitter, and Gly and GABA, the major inhibitory neurotransmitters, in the central nervous system, are known to be tightly regulated. Prolonged exposure to environmental toxicants, such as manganese (Mn), mercury (Hg), or lead (Pb), however, can lead to dysregulation of these neurochemicals and subsequent neurotoxicity. While the ability of these metals to disrupt the regulation of Glu, Gly and GABA have been studied, few articles have examined the collective role of these amino acids in the respective metal''s mechanism of toxicity. For each of the neurotransmitters above, we will provide a brief synopsis of their regulatory function, including the importance of transport and re-uptake in maintaining their optimal function. Additionally, the review will address the hypothesis that aberrant homeostasis of any of these amino acids, or a combination of the three, plays a role in the neurotoxicity of Mn, Hg, or Pb. [Copyright &y& Elsevier]

The concept of brain barriers or a brain barrier system embraces the blood–brain interface, referred to as the blood–brain barrier, and the blood–cerebrospinal fluid (CSF) interface, referred to as the blood–CSF barrier. These brain barriers protect the CNS against chemical insults, by different complementary mechanisms. Toxic metal molecules can either bypass these mechanisms or be sequestered in and therefore potentially deleterious to brain barriers. Supportive evidence suggests that damage to blood–brain interfaces can lead to chemical-induced neurotoxicities. This review article examines the unique structure, specialization, and function of the brain barrier system, with particular emphasis on its toxicological implications. Typical examples of metal transport and toxicity at the barriers, such as lead (Pb), mercury (Hg), iron (Fe), and manganese (Mn), are discussed in detail with a special focus on the relevance to their toxic neurological consequences. Based on these discussions, the emerging research needs, such as construction of the new concept of blood–brain regional barriers, understanding of chemical effect on aged or immature barriers, and elucidation of the susceptibility of tight junctions to toxicants, are identified and addressed in this newly evolving field of neurotoxicology. They represent both clear challenges and fruitful research domains not only in neurotoxicology, but also in neurophysiology and pharmacology. [Copyright &y& Elsevier]

The objective of this short paper is to call upon the scientific community to channel its attention to the duty and heedfulness of social justice issues. While recognized for decades the impact of social injustice on public health and its disproportionate effects on poorer communities, little has been done to systematically address it. Here, we provide several examples pertinent to the health outcomes associated with social injustice and call upon the scientific community to attend to the issue and antagonize those who attempt to subvert science and its role in ensuring social justice in health. • Where we live, work, play, and attend school will influence our health. • Relationships between social injustice and environmental health have been well documented. • Significant racial disparities persist even after controlling for other risk factors. • Achieving environmental justice necessitates greater awareness of the costs of environmental hazards. • We must harness the will and courage to mitigate exposures to hazardous chemicals. [ABSTRACT FROM AUTHOR]

Since the first report by Perry et al. (1955), most studies affirmed the hypertensive effects of cadmium (Cd) in humans. Nonetheless, conclusions between studies remain inconsistent. The aim of this study was to reevaluate the evidence for a potential relationship between Cd exposure and altered blood pressure and/or hypertension, focusing on studies published between January 2010 and March 2020. We reviewed all observational studies from database searches (PubMed and SCOPUS) on Cd exposure and blood pressure or hypertension. We extracted information from studies that provided sufficient data on population characteristics, smoking status, exposure, outcomes, and design. Thirty-eight studies met our inclusion criteria; of those, twenty-nine were cross sectional, three case control, five cohort and one interventional study. Blood or urinary Cd levels were the most commonly used biomarkers. A positive association between blood Cd levels and blood pressure and/or hypertension was identified in numerous studies at different settings. Limited number of representative population-based studies of never-smokers was observed, which may have confounded our conclusions. The association between urinary Cd and blood pressure and/or hypertension remains uncertain due to conflicting results, including inverse relationships with lack of strong mechanistic support. We point to the urgent need for additional longitudinal studies to confirm our findings. • We performed a systematic review on the effects of human Cd exposure and altered blood pressure and/or hypertension. • Observational studies were reviewed from database searches published between January 2010 and March 2020. • A positive association between blood Cd levels and blood pressure and/or hypertension was identified. • The association between urinary Cd and blood pressure and/or hypertension remains uncertain. • Future population-wide longitudinal studies, as well as studies in non-smoking populations are needed. [ABSTRACT FROM AUTHOR]

The need to develop new tools and increase capacity to test pharmaceuticals and other chemicals for potential adverse impacts on human health and the environment is an active area of development. Much of this activity was sparked by two reports from the US National Research Council (NRC) of the National Academies of Sciences, Toxicity Testing in the Twenty-first Century: A Vision and a Strategy (2007) and Science and Decisions: Advancing Risk Assessment (2009), both of which advocated for "science-informed decision-making" in the field of human health risk assessment. The response to these challenges for a "paradigm shift" toward using new approach methodologies (NAMS) for safety assessment has resulted in an explosion of initiatives by numerous organizations, but, for the most part, these have been carried out independently and are not coordinated in any meaningful way. To help remedy this situation, a framework that presents a consistent set of criteria, universal across initiatives, to evaluate a NAM's fit-for-purpose was developed by a multi-stakeholder group of industry, academic, and regulatory experts. The goal of this framework is to support greater consistency across existing and future initiatives by providing a structure to collect relevant information to build confidence that will accelerate, facilitate and encourage development of new NAMs that can ultimately be used within the appropriate regulatory contexts. In addition, this framework provides a systematic approach to evaluate the currently-available NAMs and determine their suitability for potential regulatory application. This 3-step evaluation framework along with the demonstrated application with case studies, will help build confidence in the scientific understanding of these methods and their value for chemical assessment and regulatory decision-making. • 3-step framework to focus a NAM's evaluation to criteria of higher importance. • Criteria will vary on a sliding scale in importance with changes in context-of-use and global regulatory considerations. • Case studies evaluate the NAMs for hazard screening from different approaches (e.g. in vitro, in silco , computational). [ABSTRACT FROM AUTHOR]

Abstract Several recent and prominent articles in Science and Nature deliberately mischaracterized the nature of genuine scientific evidence. Those articles take issue with the United States Environmental Protection Agency's recent proposal to structure its policies and rules only from studies with transparently published raw data. The articles claim it is an effort to obfuscate with transparency, by eliminating a host of studies not offering raw data. A remarkable declaration by a Science editorial is that properly trained experts can verify the scientific evidence of studies without access to raw data, We assert the Agency's proposal must be sustained. Transparency in reporting is a fundamental ethical imperative of objective scientific research justifying massive official regulations and policies. Putative hazards bereft of independent scientific evidence will continue to stoke public anxieties, calling for precautionary regulations and policies. These should rely not on spurious science but on transparent tradeoffs between the smallest exposures compatible with utility and with social perceptions of affordable precaution. [ABSTRACT FROM AUTHOR]

Fragrance compounds are chemicals belonging to one of several families, which are used frequently and globally in cosmetics, household products, foods and beverages. A complete list of such compounds is rarely found on the ingredients-list of such products, as “fragrance mixtures” are defined as “trade secrets” and thus protected by law. While some information regarding the general toxicity of some of these compounds is available, their neurotoxicity is known to a lesser extent. Here, we discuss the prevalence and neurotoxicity of fragrance compounds belonging to the three most common groups: phthalates, synthetic musks and chemical sensitizers. [ABSTRACT FROM AUTHOR]

Chronic lead (Pb) exposure causes neurodysfunction and contributes to the development of neurodegenerative disease. However, the mechanism of Pb-induced neurological dysfunction have yet to be fully elucidated. This study determined the role pyroptosis plays in Pb-induced neurodysfunction in neurons. We used both in vitro and in vivo approaches to explore whether Pb exposure induces caspase-1-mediated pyroptosis in neurons and its relationship to Pb-induced neurological disorders. Our findings showed that caspase-1-mediated pyroptosis in Pb-exposed neurons activated glycogen synthase kinase 3 protease activity by disrupting Ca2+/calmodulin-dependent protein kinase II/cAMP-response element binding protein pathway, leading to neurological disorders. Moreover, the caspase-1 inhibition VX-765 or the non-steroidal anti-inflammatory drug sodium para-aminosalicylic acid (PAS-Na) attenuated the Pb-induced neurological disorders by alleviating caspase-1 mediated neuronal pyroptosis. Our novel studies suggest that caspase-1-mediated pyroptosis in neurons represents a potential mechanism for Pb-induced neurodysfunction, identifying a putative target for attenuating the neurodegenerative effects induced by this metal. [Display omitted] • Pb induces pyroptosis in neurons. • Caspase-1 mediates neuronal pyroptosis. [ABSTRACT FROM AUTHOR]

The objective of the present study was to review the epidemiological and laboratory evidence on the role of aluminum (Al) exposure in the pathogenesis of cardiovascular diseases. Epidemiological data demonstrated an increased incidence of cardiovascular diseases (CVD), including hypertension and atherosclerosis in occupationally exposed subjects and hemodialysis patients. In addition, Al body burden was found to be elevated in patients with coronary heart disease, hypertension, and dyslipidemia. Laboratory studies demonstrated that Al exposure induced significant ultrastructural damage in the heart, resulting in electrocardiogram alterations in association with cardiomyocyte necrosis and apoptosis, inflammation, oxidative stress, inflammation, and mitochondrial dysfunction. In agreement with the epidemiological findings, laboratory data demonstrated dyslipidemia upon Al exposure, resulting from impaired hepatic lipid catabolism, as well as promotion of low-density lipoprotein oxidation. Al was also shown to inhibit paraoxonase 1 activity and to induce endothelial dysfunction and adhesion molecule expression, further promoting atherogenesis. The role of Al in hypertension was shown to be mediated by up-regulation of NADPH-oxidase, inhibition of nitric oxide bioavailability, and stimulation of renin-angiotensin-aldosterone system. It has been also demonstrated that Al exposure targets cerebral vasculature, which may be considered a link between Al exposure and cerebrovascular diseases. Findings from other tissues lend support that ferroptosis, pyroptosis, endoplasmic reticulum stress, and modulation of gut microbiome and metabolome are involved in the development of CVD upon Al exposure. A better understanding of the role of the cardiovascular system as a target for Al toxicity will be useful for risk assessment and the development of treatment and prevention strategies. [ABSTRACT FROM AUTHOR]

Highlights: [•] Methylmercury toxicity in worms is blocked by l-methionine. [•] Amino acid transporters transport methylmercury in the worm. [•] Knockdown of aat, increase worm the survival following methylmercury treatment. [•] Knockdown of aat also attenuate worm methylmercury content. [ABSTRACT FROM AUTHOR]

Abstract: Although manganese (Mn) is required for normal cellular function, overexposure to this metal may cause an extrapyramidal syndrome resembling Parkinson’s disease (PD). Notably, high whole-blood Mn levels have been reported in patients with idiopathic PD. Because Mn is both essential at low dose and toxic at higher dose; its transport and homeostasis are tightly regulated. Previously, the only protein known to be operant in cellular Mn export was the iron-regulating transporter, ferroportin (Fpn). The causal role for Mn in PD has yet to be fully understood, but evidence of a familial predisposition to PD associated with Mn toxicity is mounting. A recently discovered mutation in SLC30A10 identified its gene product as putatively involved in Mn efflux. Patients with the SLC30A10 mutation display Parkinsonian-like gate disturbances and hypermanganesemia. This review will address Mn transport proteins, the newly discovered SLC30A10 mutations and their implications to Parkinsonism and Mn regulation. [Copyright &y& Elsevier]

Abstract: Prophylactic agents acutely administered in response to anticholinesterases intoxication can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have long-term unknown pathophysiological effects, making rational prophylaxis/treatment problematic. Increasing evidence suggests that in addition to excessive cholinergic stimulation, organophosphate compounds such as diisopropylphosphorofluoridate (DFP) induce activation of glutamatergic neurons, generation of reactive oxygen (ROS) and nitrogen species (RNS), leading to neurodegeneration. The present study investigated multiple affectors of DFP exposure critical to cerebral oxidative damage and whether antioxidants and NMDA receptor antagonist memantine provide neuroprotection by preventing DFP-induced biochemical and morphometric changes in rat brain. Rats treated acutely with DFP (1.25 mg/kg, s.c.) developed onset of toxicity signs within 7–15 min that progressed to maximal severity of seizures and fasciculations within 60 min. At this time point, DFP caused significant (p <0.01) increases in biomarkers of ROS (F2-isoprostanes, F2-IsoPs; and F4-neuroprostanes, F4-NeuroPs), RNS (citrulline), and declines in high-energy phosphates (HEP) in rat cerebrum. At the same time, quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant (p <0.01) reductions in dendritic lengths and spine density. When rats were pretreated with the antioxidants N-tert-butyl-α-phenylnitrone (PBN, 200 mg/kg, i.p.), or vitamin E (100 mg/kg, i.p./day for 3 days), or memantine (18 mg/kg, i.p.), significant attenuations in DFP-induced increases in F2-IsoPs, F4-NeuroPs, citrulline, and depletion of HEP were noted. Furthermore, attenuation in oxidative damage following antioxidants or memantine pretreatment was accompanied by rescue from dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. These findings closely associated DFP-induced lipid peroxidation with dendritic degeneration of pyramidal neurons in the CA1 hippocampal area and point to possible interventions to limit oxidative injury and dendritic degeneration induced by anticholinesterase neurotoxicity. [Copyright &y& Elsevier]

Abstract: We have previously shown that tamoxifen can induce marked neuroprotection after middle cerebral artery occlusion (MCAo) in rats and have described two possible mechanisms of action: namely, inhibition of EAA release and inhibition of nNOS activity. In this study we tested other potential mechanisms. Namely, agonist action at estrogen receptors and an antioxidative action. Tamoxifen-treated rats had significantly improved neurobehavioral deficit scores after 24 h and showed ∼75% reduced infarct volumes. These were unaffected by ICI 182,780 (a high affinity and pure receptor antagonist) administered intravenously, or intracisternally to avoid possible lack of brain penetration, 15 min before intravenous administration of tamoxifen. In rats subjected to 2 h MCAo followed by 22 h reperfusion, 1.8-fold and 2.9-fold increases of F2-IsoPs and F4 neuroprostanes, respectively, as relatively stable markers of oxidative damage, were measured in the ischemic hemisphere compared with the corresponding contralateral hemisphere or sham controls. Tamoxifen given at 3 h after the start of ischemia reduced the IsoPs and NeuroPs to sham control levels, and also inhibited their production by chemically induced lipid peroxidation in brain homogenates. These data are consistent with at least part of tamoxifen''s marked neuroprotection in focal cerebral ischemic injury being due to its antioxidant activity but not by an acute action on estrogen receptors (212 words). [Copyright &y& Elsevier]

Aflatoxin B 1 (AFB 1), a dietary toxin from the mold Aspergillus species, is well acknowledged to elicit extra-hepatic toxicity in both animals and humans. The neurotoxicity of AFB 1 has become a global public health concern. Contemporary research on how AFB 1 enters the brain to elicit neuronal dysregulation leading to noxious neurological outcomes has increased greatly in recent years. The current review discusses several neurotoxic outcomes and susceptible targets of AFB 1 toxicity at cellular, molecular and genetic levels. Specifically, neurotoxicity studies involving the use of brain homogenates, neuroblastoma cell line IMR-32, human brain microvascular endothelial cells, microglial cells, and astrocytes, as well as mammalian and non-mammalian models to unravel the mechanisms associated with AFB 1 exposure are highlighted. Further, some naturally occurring bioactive compounds with compelling therapeutic effects on AFB 1 -induced neurotoxicity are reviewed. In conclusion, available data from literature highlight AFB 1 as a neurotoxin and its possible pathological contribution to neurological disorders. Further mechanistic studies aimed at discovering and developing effective therapeutics for AFB 1 neurotoxicity is warranted. [ABSTRACT FROM AUTHOR]

Abstract Cobalt nanoparticles (CoNPs) have been widely used in industry given their physical, chemical and magnetic properties; however, CoNPs may cause neurological symptoms and diseases in human, yet their mechanisms of toxicity remain unknown. Here, we used male Wistar rats to investigate differences in the toxic effects associated with CoNPs and CoCl 2. Upon exposure to CoCl 2 , and 96 nm or 123 nm CoNPs at the same concentration, the Co2+ content in CoCl 2 group was significantly higher than that in either the CoNPs groups in brain tissues and blood, but lower in liver. Significant neural damage was observed in both hippocampus and cortex of the temporal lobe. Increase malondialdehyde (MDA) content and CASPASE 9 protein level were associated both with CoCl 2 and CoNPs treatments, consistent with lipid perioxidation and apoptosis. Heme oxygenase-1 and (NF-E2) p45-related factor-2 protein levels were elevated in response to 96 nm CoNPs exposure. In PC12 cells, NRF2 downregulation led to reduced cell viability and increased apoptotic rate. In conclusion, both CoNPs and CoCl 2 cause adverse neural effects, with nanoparticles showing greater neurotoxic potency. In addition, NRF2 protects neural cells from damage induced by CoCl 2 and CoNPs by activating downstream antioxidant responses. Highlights • Both CoNPs and CoCl2 can enter central nervous system and cause toxic effects. • Both CoNPs and CoCl2 can induce apoptosis in vivo and in vitro. • Oxidative stress and apoptosis induced by CoNPs are more severethan CoCl2. • NRF2 protects neural cells from damage induced by both CoNPs and CoCl2. [ABSTRACT FROM AUTHOR]

Due to many advantages Caenorhabditis elegans ( C. elegans ) has become a preferred model of choice in many fields, including neurodevelopmental toxicity studies. This review discusses the benefits of using C. elegans as an alternative to mammalian systems and gives examples of the uses of the nematode in evaluating the effects of major known neurodevelopmental toxins, including manganese, mercury, lead, fluoride, arsenic and organophosphorus pesticides. Reviewed data indicates numerous similarities with mammals in response to these toxins. Thus, C. elegans studies have the potential to predict possible effects of developmental neurotoxicants in higher animals, and may be used to identify new molecular pathways behind neurodevelopmental disruptions, as well as new toxicants. [ABSTRACT FROM AUTHOR]

This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects. The ultimate application goals of these new approach methods for DNT testing are their usage for different regulatory purposes. [ABSTRACT FROM AUTHOR]

Malignant melanoma is the most dangerous type of skin cancer. It is becoming more common globally and is increasingly resistant to treatment options. Despite extensive research into its pathophysiology, there are still no proven cures for metastatic melanoma. Unfortunately, current treatments are frequently ineffective and costly, and have several adverse effects. Natural substances have been extensively researched for their anti-MM capabilities. Chemoprevention and adjuvant therapy with natural products is an emerging strategy to prevent, cure or treat melanoma. Numerous prospective drugs are found in aquatic species, providing a plentiful supply of lead cytotoxic chemicals for cancer treatment. Anticancer peptides are less harmful to healthy cells and cure cancer through several different methods, such as altered cell viability, apoptosis, angiogenesis/metastasis suppression, microtubule balance disturbances and targeting lipid composition of the cancer cell membrane. This review addresses marine peptides as effective and safe treatments for MM and details their molecular mechanisms of action. [ABSTRACT FROM AUTHOR]

The present study aimed to increase our understanding about the mode of toxic action of organophosphate pesticides in insects by evaluating the biochemical and neurobehavioral characteristics in Nauphoeta cinerea exposed to chlorpyrifos (CPF)-contaminated diet. The insects were exposed for 35 consecutive days to CPF at 0.078, 0.15625, 0.3125 and 0.625 μg/g feed. Locomotor behavior was assessed for a 10-min trial in a novel arena and subsequently, biochemical analyses were carried out using the cockroaches’ heads. In comparison to control, CPF-exposed cockroaches showed significant decreases in the total distance traveled, body rotation, turn angle and meandering, along with significant increase in the number of falls, time and episodes of immobility. The marked decrease in the exploratory profiles of CPF-exposed cockroaches was confirmed by track plots, whereas occupancy plot analyses showed a progressive dispersion at 0.15625 μg/g feed group. Moreover, the heads of CPF-exposed cockroaches showed marked decrease in acetylcholinesterase activity and antioxidant status with concomitant significant elevation in dichlorofluorescein oxidation and lipid peroxidation levels in CPF-treated cockroaches. Gas Chromatography–Mass Spectrometry analyses revealed bioaccumulation of CPF in cockroaches exposed to concentrations above 0.078 μg/g feed. The findings from this investigation showed N. cinerea as a value model organism for the risk assessment of environmental organophosphate contamination in insects. [ABSTRACT FROM AUTHOR]

As the structural basis of blood-cerebrospinal fluid barrier (BCB), epithelial cells in the choroid plexus (CP) are targets for lead (Pb). Pb is known to accumulate in the CP; however, the mechanism of Pb uptake in the choroidal epithelial cells remains unknown. Recently, hemichannels of Connexin 43 (Cx43), the most ubiquitously expressed gap junction proteins in the CP, were found to be important pathways for many substances. This study was designed to investigate the roles of Cx43 in Pb uptake in the epithelial cells. Autometallography was used to outline Pb's subcellular location, and the characteristics of Pb transport into CP cells, including concentration- and time-dependence were analyzed by atomic absorption spectroscopy. Knockdown/overexpression of Cx43 with transient siRNA/plasmids transfections before Pb exposure diminished/increased the Pb accumulation. In the Z310 cell-based doxycycline-inducible Cx43 expression cell line (iZCx43), doxycycline induced a significant increase (3-fold) in Pb uptake, corresponding to the increased Cx43 levels. Activation of Cx43 hemichannels by reduced serum conditions caused an increase of Pb concentrations. Cx43-induced Pb uptake was attenuated after blockage of Cx43 hemichannels with its inhibitor, carbenoxolone. Additionally, down-regulation of Cx43 protein levels by Pb exposure paralleled cellular Pb concentrations in the time study. Concomitantly, expressions of phosphor-Src and phosphor-Erk were both significantly increased by Pb. However, inactivation of Erk, not Src pathway, reversed Pb-induced downregulation of Cx43. Taken together, these data establish that Pb can accumulate in the BCB and validate the role of Cx43 hemichannel in Pb uptake and its regulations through Erk phosphorylation. [ABSTRACT FROM AUTHOR]

Intestinal injury assessment of hexavalent chromium (Cr-VI) in humans is crucial for quantifying assessment of adverse health risk posed by the intake of Cr (VI)-contaminated water. To overcome the deficiency in simulating human gastric reduction and intestinal absorption, we modified the constituents of simulated gastric fluid in in vitro digestion method by adding reductants glutathione (18 μM) and ascorbic acid (180 μM), which incorporated with human intestinal epithelial model to construct an in vitro gastrointestinal digestion (IVGD) model for intestinal injury assessment. Cr-VI bioaccessibility results from IVGD model showed that weak gastric acidity significantly increased the intestinal accessible Cr-VI dose by 22.41–38.43 folds. The time-course intestinal absorption indicated prolongation of intestinal exposure destroyed the intestinal epithelium, and 24 h after Cr-VI treatment was a good time point to perform intestinal absorption and toxicity assessment. A series of cell-based bioassays provided initial warning of adverse effect, suggesting that epithelial integrity exhibited greatest sensitivity to Cr-VI exposure and might be used as a sensitive marker for the toxicity assessment of oral exposure to Cr-VI. Notably, this study provides a feasible strategy for delineation of Cr-VI biotransformation and intestinal injury following ingestion exposure, which contributes to address the toxicity data gap of low-dose exposure in humans and puts forward a reference for intestinal toxicity assessment of other chemicals. • An IVGD model is developed for simulating human gastrointestinal digestion. • Gastrointestinal digestion is crucial for estimating intestinal accessible Cr-VI. • Weak gastric acidity is a risk factor for oral exposure of Cr-VI. • Impaired intestinal epithelial integrity is a good marker for intestinal toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Chronic, excessive exposure to manganese (Mn) may induce neurotoxicity and cause an irreversible brain disease, referred to as manganism. Efficacious therapies for the treatment of Mn are lacking, mandating the development of new interventions. The purpose of the present study was to investigate the efficacy of ebselen (Ebs) and para-aminosalicylic acid (PAS) in attenuating the neurotoxic effects of Mn in an in vivo rat model. Exposure biomarkers, inflammatory and oxidative stress biomarkers, as well as behavioral parameters were evaluated. Co-treatment with Mn plus Ebs or Mn plus PAS caused a significant decrease in blood and brain Mn concentrations (compared to rats treated with Mn alone), concomitant with reduced brain E2 prostaglandin (PGE2) and enhanced brain glutathione (GSH) levels, decreased serum prolactin (PRL) levels, and increased ambulation and rearing activities. Taken together, these results establish that both PAS and Ebs are efficacious in reducing Mn body burden, neuroinflammation, oxidative stress and locomotor activity impairments in a rat model of Mn-induced toxicity. [Copyright &y& Elsevier]

Abstract: Exposure to excessive manganese (Mn) levels leads to neurotoxicity, referred to as manganism, which resembles Parkinson''s disease (PD). Manganism is caused by neuronal injury in both cortical and subcortical regions, particularly in the basal ganglia. The basis for the selective neurotoxicity of Mn is not yet fully understood. However, several studies suggest that oxidative damage and inflammatory processes play prominent roles in the degeneration of dopamine-containing neurons. In the present study, we assessed the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates and associated neuronal dysfunctions both in vitro and in vivo. Results from our in vitro study showed a significant (p <0.01) increase in biomarkers of oxidative damage, F2-isoprostanes (F2-IsoPs), as well as the depletion of ATP in primary rat cortical neurons following exposure to Mn (500 μM) for 2h. These effects were protected when neurons were pretreated for 30min with 100 of an antioxidant, the hydrophilic vitamin E analog, trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), or an anti-inflammatory agent, indomethacin. Results from our in vivo study confirmed a significant increase in F2-IsoPs levels in conjunction with the progressive spine degeneration and dendritic damage of the striatal medium spiny neurons (MSNs) of mice exposed to Mn (100mg/kg, s.c.) 24h. Additionally, pretreatment with vitamin E (100mg/kg, i.p.) or ibuprofen (140 μg/ml in the drinking water for two weeks) attenuated the Mn-induced increase in cerebral F2-IsoPs? and protected the MSNs from dendritic atrophy and dendritic spine loss. Our findings suggest that the mediation of oxidative stress/mitochondrial dysfunction and the control of alterations in biomarkers of oxidative injury, neuroinflammation and synaptodendritic degeneration may provide an effective, multi-pronged therapeutic strategy for protecting dysfunctional dopaminergic transmission and slowing of the progression of Mn-induced neurodegenerative processes. [Copyright &y& Elsevier]

Abstract: Methylmercury (MeHg) is an ubiquitous environmental pollutant which is transported into the mammalian cells when present as the methylmercury-cysteine conjugate (MeHg–Cys). With special emphasis on hepatic cells, due to their particular propensity to accumulate an appreciable amount of Hg after exposure to MeHg, this study was performed to evaluate the effects of methionine (Met) on Hg uptake, reactive species (RS) formation, oxygen consumption and mitochondrial function/cellular viability in both liver slices and mitochondria isolated from these slices, after exposure to MeHg or the MeHg–Cys complex. The liver slices were pre-treated with Met (250μM) 15min before being exposed to MeHg (25μM) or MeHg–Cys (25μM each) for 30min at 37°C. The treatment with MeHg caused a significant increase in the Hg concentration in both liver slices and mitochondria isolated from liver slices. Moreover, the Hg uptake was higher in the group exposed to the MeHg–Cys complex. In the DCF (dichlorofluorescein) assay, the exposure to MeHg and MeHg–Cys produced a significant increase in DFC reactive species (DFC-RS) formation only in the mitochondria isolated from liver slices. As observed with Hg uptake, DFC-RS levels were significantly higher in the mitochondria treated with the MeHg–Cys complex compared to MeHg alone. MeHg exposure also caused a marked decrease in the oxygen consumption of liver slices when compared to the control group, and this effect was more pronounced in the liver slices treated with the MeHg–Cys complex. Similarly, the loss of mitochondrial activity/cell viability was greater in liver slices exposed to the MeHg–Cys complex when compared to slices treated only with MeHg. In all studied parameters, Met pre-treatment was effective in preventing the MeHg- and/or MeHg–Cys-induced toxicity in both liver slices and mitochondria. Part of the protection afforded by Met against MeHg may be related to a direct interaction with MeHg or to the competition of Met with the complex formed between MeHg and endogenous cysteine. In summary, our results show that Met pre-treatment produces pronounced protection against the toxic effects induced by MeHg and/or the MeHg–Cys complex on mitochondrial function and cell viability. Consequently, this amino acid offers considerable promise as a potential agent for treating acute MeHg exposure. [Copyright &y& Elsevier]

Abstract: Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson''s disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterations in biomarkers of oxidative damage, F2-isoprostanes (F2-IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 μM Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E2 (PGE2). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F2-IsoPs and PGE2 in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration. [Copyright &y& Elsevier]

Abstract: The rising prevalence of methylmercury (MeHg) in seafood and in the global environment provides an impetus for delineating the mechanism of the toxicity of MeHg. Deleterious effects of MeHg have been widely observed in humans and in other mammals, the most striking of which occur in the nervous system. Here we test the model organism, Caenorhabditis elegans (C. elegans), for MeHg toxicity. The simple, well-defined anatomy of the C. elegans nervous system and its ready visualization with green fluorescent protein (GFP) markers facilitated our study of the effects of methylmercuric chloride (MeHgCl) on neural development. Although MeHgCl was lethal to C. elegans, induced a developmental delay, and decreased pharyngeal pumping, other traits including lifespan, brood size, swimming rate, and nervous system morphology were not obviously perturbed in animals that survived MeHgCl exposure. Despite the limited effects of MeHgCl on C. elegans development and behavior, intracellular mercury (Hg) concentrations (≤3 ng Hg/mg protein) in MeHgCl-treated nematodes approached levels that are highly toxic to mammals. If MeHgCl reaches these concentrations throughout the animal, this finding indicates that C. elegans cells, particularly neurons, may be less sensitive to MeHgCl toxicity than mammalian cells. We propose, therefore, that C. elegans should be a useful model for discovering intrinsic mechanisms that confer resistance to MeHgCl exposure. [Copyright &y& Elsevier]

Abstract: During the perinatal period, the central nervous system (CNS) is extremely sensitive to metals, including methylmercury (MeHg). Although the mechanism(s) associated with MeHg-induced developmental neurotoxicity remains obscure, several studies point to the glutathione (GSH) antioxidant system as an important molecular target for this toxicant. To extend our recent findings of MeHg-induced GSH dyshomeostasis, the present study was designed to assess the developmental profile of the GSH antioxidant system in the mouse brain during the early postnatal period after in utero exposure to MeHg. Pregnant mice were exposed to different doses of MeHg (1, 3 and 10 mg/l, diluted in drinking water, ad libitum) during the gestational period. After delivery, pups were killed at different time points – postnatal days (PND) 1, 11 and 21 – and the whole brain was used for determining biochemical parameters related to the antioxidant GSH system, as well as mercury content and the levels of F2-isoprostane. In control animals, cerebral GSH levels significantly increased over time during the early postnatal period; gestational exposure to MeHg caused a dose-dependent inhibition of this developmental event. Cerebral glutathione peroxidase (GPx) and glutathione reductase (GR) activities significantly increased over time during the early postnatal period in control animals; gestational MeHg exposure induced a dose-dependent inhibitory effect on both developmental phenomena. These adverse effects of prenatal MeHg exposure were corroborated by marked increases in cerebral F2-isoprostanes levels at all time points. Significant negative correlations were found between F2-isoprostanes and GSH, as well as between F2-isoprostanes and GPx activity, suggesting that MeHg-induced disruption of the GSH system maturation is related to MeHg-induced increased lipid peroxidation in the pup brain. In utero MeHg exposure also caused a dose-dependent increase in the cerebral levels of mercury at birth. Even though the cerebral mercury concentration decreased to nearly basal levels at postnatal day 21, GSH levels, GPx and GR activities remained decreased in MeHg-exposed mice, indicating that prenatal exposure to MeHg affects the cerebral GSH antioxidant systems by inducing biochemical alterations that endure even when mercury tissue levels decrease and become indistinguishable from those noted in pups born to control dams. This study is the first to show that prenatal exposure to MeHg disrupts the postnatal development of the glutathione antioxidant system in the mouse brain, pointing to an additional molecular mechanism by which MeHg induces pro-oxidative damage in the developing CNS. Moreover, our experimental observation corroborates previous reports on the permanent functional deficits observed after prenatal MeHg exposure. [Copyright &y& Elsevier]

Abstract: Carbamate insecticides mediate their neurotoxicity by acetylcholinesterase (AChE) inactivation. Male Sprague–Dawley rats acutely intoxicated with the carbamate insecticide carbofuran (1.5 mg/kg, sc) developed hypercholinergic signs within 5–7 min of exposure, with maximal severity characterized by seizures within 30–60 min, lasting for about 2 h. At the time of peak severity, compared with controls, AChE was maximally inhibited (by 82–90%), radical oxygen species (ROS) markers (F2-isoprostanes, F2-IsoPs; and F4-neuroprostanes, F4-NeuroPs) were elevated 2- to 3-fold, and the radical nitrogen species (RNS) marker citrulline was elevated 4- to 8-fold in discrete brain regions (cortex, amygdala, and hippocampus). In addition, levels of high-energy phosphates (HEPs) were significantly reduced (ATP, by 43–56%; and phosphocreatine, by 37–48%). Values of total adenine nucleotides and total creatine compounds declined markedly (by 41–56% and 35–45%, respectively), while energy charge potential remained unchanged. Quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant decreases in dendritic lengths (by 64%) and spine density (by 60%). Pretreatment with the N-methyl-d-aspartate (NMDA) receptor antagonist memantine (18 mg/kg, sc), in combination with atropine sulfate (16 mg/kg, sc), significantly attenuated carbofuran-induced changes in AChE activity and levels of F2-IsoPs and F4-NeuroPs, declines in HEPs, as well as the alterations in morphology of hippocampal neurons. MEM and ATS pretreatment also protected rats from carbofuran-induced hypercholinergic behavioral activity, including seizures. These findings support the involvement of ROS and RNS in seizure-induced neuronal injury and suggest that memantine by preventing carbofuran-induced neuronal hyperactivity blocks pathways associated with oxidative damage in neurons. [Copyright &y& Elsevier]

Cadmium (Cd) is a toxic metal that is widely present in the environment due to geologic and anthropogenic sources. Exposures to high Cd levels may cause nephrotoxicity, carcinogenicity, pulmonary and cardiovascular disease, among others. The goal of this study was to investigate in an adult urban population whether an association exists between sources and levels of Cd exposure and blood Cd concentrations. Using a census-based design, a total of 959 adults, aged 40 years or older, were randomly selected. Information on socio-demographics, dietary, and lifestyle background was obtained by household interviews. Blood Cd levels were measured by inductively coupled-plasma mass spectrometry. Geometric means (GM) (95% CI) and the 50th percentile were determined, stratified by sex, age, race, education, income class, smoking status, consumption of vegetables, red meat and milk, occupation and blood pressure. To assess the association between Cd exposure and the aforementioned variables, we estimated the geometric mean ratio (GMR) (95%CI) of blood Cd concentrations. The geometric mean (95%CI) of blood Cd levels in the total population was 0.25 (0.22, 0.27) ug/dL. In a univariate analysis, significantly higher blood Cd levels were found in men (p < 0.001), current and former smokers (p < 0.001), alcohol drinkers (p < 0.001), those who never or almost never consumed milk (p < 0.001), and in subjects with higher diastolic blood pressure (p = 0.03). Significant correlations were found between the number of cigarettes consumed daily and blood Cd levels. Multivariate analysis confirmed higher blood Cd concentrations were associated with alcohol consumption (GMR 95%CI = 1.28, 1.04–1.59) and in former and current smokers (GMR 95% IC = 1.33, 1.06–1.67 and 4.23, 3.24–5.52, respectively). Our results shed novel information on variables associated with blood Cd levels in an urban Brazilian population, and should encourage additional research to prevent environmental Cd exposure, both in Brazil and globally. • The association between sources of Cd exposure, blood Cd levels, and blood pressure in an urban population was evaluated. • Smoking and drinking were associated with higher blood Cd concentrations. • Significant correlations were found between the number of cigarettes smoked daily and blood cadmium levels. [ABSTRACT FROM AUTHOR]

• We determined Reference Values (RVs) for blood As, Cd, Co, Cu, Pb, Mg, Hg, Mo, Se and Zn in an urban population. • This is a cross-sectional population-based study. • RVs were calculated as the upper limits of the 95% CIs at the 95th percentile of the measured distributions. • We detected high correlation between blood Cu and blood Zn levels (ρ=0.68). • Diet, smoking habits, place of residence, gender, and the period in which the study was performed, may contribute to RVs. [ABSTRACT FROM AUTHOR]

Climate change is one of the biggest and most urgent challenges for the 21st century. Rising average temperatures and ocean levels, altered precipitation patterns and increased occurrence of extreme weather events affect not only the global landscape and ecosystem, but also human health. Multiple environmental factors influence the onset and severity of human diseases and changing climate may have a great impact on these factors. Climate shifts disrupt the quantity and quality of water, increase environmental pollution, change the distribution of pathogens and severely impacts food production – all of which are important regarding public health. This paper focuses on brain health and provides an overview of climate change impacts on risk factors specific to brain diseases and disorders. We also discuss emerging hazards in brain health due to mitigation and adaptation strategies in response to climate changes. • Climate change is one of the biggest and most urgent challenges regarding human health. • Multiple environmental factors affecting human health can be modulated in the changing climate. • The paper provides an overview of climate change impacts on risk factors specific to brain diseases. • Hazards due to mitigation and adaptation strategies in response to climate changes are also discussed. [ABSTRACT FROM AUTHOR]