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Wu YJ, Chang SJ, Huang YS, Chai CY. Overexpression of BMAL-1 is related to progression of urothelial carcinoma in arsenic exposure area. Int Urol Nephrol 2025; 57:1175-1187. [PMID: 39643860 DOI: 10.1007/s11255-024-04320-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 11/28/2024] [Indexed: 12/09/2024]
Abstract
BACKGROUND Environmental exposure to arsenic has long been associated with various clinical and pathophysiological aspects of urothelial carcinoma (UC), although the role of arsenic in UC and its impact on circadian proteins, particularly BMAL-1, remains unestablished. Previous research suggests that arsenic upregulates Aurora kinase A (AURKA), subsequently inhibiting GSK-3β, which might lead to overexpression of BMAL-1; nevertheless, the underlying pathway and its clinical significance in UC with arsenic exposure have yet to be validated. This study focuses on two potential upstream regulators of BMAL-1, AURKA and GSK-3β. METHODS Ninety-nine tumor tissue samples were retrospectively collected along with their respective clinical data. Immunohistochemistry was employed to assess the expression of each protein. RESULTS A positive relationship was observed between the expression levels of AURKA and BMAL-1 (p < 0.001), while negative correlations were noted between the expression levels of GSK-3β and AURKA (p < 0.001), and between GSK-3β and BMAL-1 (p = 0.003). Tissue samples exposed to arsenic exhibited significantly higher levels of AURKA (p < 0.001) and BMAL-1 (p < 0.001), a markedly lower expression of GSK-3β (p = 0.001), alongside a decreased survival status (p = 0.025) compared to non-exposed samples. Furthermore, patients with UC of higher tumor grade tended to show increased levels of AURKA (p < 0.001), BMAL-1 (p < 0.001), and decreased levels of GSK-3β (p < 0.001). Elevated expression of AURKA (p < 0.001) and BMAL-1 (p = 0.002), as well as reduced expression of GSK-3β (p = 0.003), were also associated with a decreased survival status. CONCLUSIONS This study highlights the differential expression of BMAL-1, AURKA, and GSK-3β in association with arsenic exposure and their significant impact on clinical and pathological features of UC. Moreover, BMAL-1, AURKA, and GSK-3β emerge as potential prognostic markers for UC in regions with arsenic exposure.
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Affiliation(s)
- Yu-Jui Wu
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Jyuan Chang
- Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pathology, Kaohsiung Medical University Hospital, No.100, Tzyou 1St Road, Kaohsiung, 807, Taiwan
| | - Yen-Shuo Huang
- Department of Pathology, Kaohsiung Medical University Hospital, No.100, Tzyou 1St Road, Kaohsiung, 807, Taiwan
| | - Chee-Yin Chai
- Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Pathology, Kaohsiung Medical University Hospital, No.100, Tzyou 1St Road, Kaohsiung, 807, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
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2
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Banaeeyeh S, Razavi BM, Hosseinzadeh H. Neuroprotective Effects of Morin Against Cadmium- and Arsenic-Induced Cell Damage in PC12 Neurons. Biol Trace Elem Res 2024:10.1007/s12011-024-04407-x. [PMID: 39436547 DOI: 10.1007/s12011-024-04407-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 10/01/2024] [Indexed: 10/23/2024]
Abstract
Arsenic and cadmium, both toxic metals and widespread environmental pollutants, can trigger apoptosis and oxidative stress in various tissues and cells. Morin, a natural flavonoid with diverse biological properties, has been found to protect neurons from oxidative stress and apoptosis-induced damage. This research aimed to examine the protective properties of morin against neurotoxicity caused by arsenic and cadmium, utilizing PC12 cells as a model for nerve cells. The cells were pre-treated with different concentrations of morin and then exposed to arsenic and cadmium, after which cell viability and reactive oxygen species (ROS) production were assessed. Additionally, western blotting was performed to evaluate the protein levels of the Bax/Bcl-2 ratio and cleaved-caspase-3. Following exposure to arsenic and cadmium, there were significant increases in ROS, Bax/Bcl-2 ratio, and cleaved-caspase-3. However, the results of the study demonstrated the beneficial effects of morin at various concentrations, as it increased cell viability and decreased ROS production. Furthermore, morin at a concentration of 10 µM was found to reduce the elevated levels of cleaved-caspase-3 induced by arsenic and diminish the increased Bax/Bcl-2 ratio after exposure to arsenic and cadmium. The findings of this study suggest that morin can effectively protect cells from arsenic and cadmium-induced neurotoxicity through its antioxidant and anti-apoptotic effects. Thus, morin should be considered a promising agent for treating arsenic and cadmium toxicity.
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Affiliation(s)
- Sara Banaeeyeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Marjan Razavi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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3
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Zsarnovszky A, Alymbaeva D, Jocsak G, Szabo C, Mária Schilling-Tóth B, Sandor Kiss D. Endocrine disrupting effects on morphological synaptic plasticity. Front Neuroendocrinol 2024; 75:101157. [PMID: 39393417 DOI: 10.1016/j.yfrne.2024.101157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 10/03/2024] [Accepted: 10/05/2024] [Indexed: 10/13/2024]
Abstract
Neural regulation of the homeostasis depends on healthy synaptic function. Adaptation of synaptic functions to physiological needs manifests in various forms of synaptic plasticity (SP), regulated by the normal hormonal regulatory circuits. During the past several decades, the hormonal regulation of animal and human organisms have become targets of thousands of chemicals that have the potential to act as agonists or antagonists of the endogenous hormones. As the action mechanism of these endocrine disrupting chemicals (EDCs) came into the focus of research, a growing number of studies suggest that one of the regulatory avenues of hormones, the morphological form of SP, may well be a neural mechanism affected by EDCs. The present review discusses known and potential effects of some of the best known EDCs on morphological synaptic plasticity (MSP). We highlight molecular mechanisms altered by EDCs and indicate the growing need for more research in this area of neuroendocrinology.
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Affiliation(s)
- Attila Zsarnovszky
- Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary; Department of Physiology and Animal Health, Agrobiotechnology and Precision Breeding for Food Security National Laboratory, Institute of Physiology and Nutrition, Hungarian University of Agriculture and Life Sciences, H-7400 Kaposvár, Hungary.
| | - Daiana Alymbaeva
- Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary.
| | - Gergely Jocsak
- Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary.
| | - Csaba Szabo
- Department of Physiology and Animal Health, Agrobiotechnology and Precision Breeding for Food Security National Laboratory, Institute of Physiology and Nutrition, Hungarian University of Agriculture and Life Sciences, H-7400 Kaposvár, Hungary
| | | | - David Sandor Kiss
- Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary.
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4
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Brooks AW, Sandri BJ, Nixon JP, Nurkiewicz TR, Barach P, Trembley JH, Butterick TA. Neuroinflammation and Brain Health Risks in Veterans Exposed to Burn Pit Toxins. Int J Mol Sci 2024; 25:9759. [PMID: 39337247 PMCID: PMC11432193 DOI: 10.3390/ijms25189759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/04/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
Military burn pits, used for waste disposal in combat zones, involve the open-air burning of waste materials, including plastics, metals, chemicals, and medical waste. The pits release a complex mixture of occupational toxic substances, including particulate matter (PM), volatile organic compounds (VOCs), heavy metals, dioxins, and polycyclic aromatic hydrocarbons (PAHs). Air pollution significantly impacts brain health through mechanisms involving neuroinflammation. Pollutants penetrate the respiratory system, enter the bloodstream, and cross the blood-brain barrier (BBB), triggering inflammatory responses in the central nervous system (CNS). Chronic environmental exposures result in sustained inflammation, oxidative stress, and neuronal damage, contributing to neurodegenerative diseases and cognitive impairment. Veterans exposed to burn pit toxins are particularly at risk, reporting higher rates of respiratory issues, neurological conditions, cognitive impairments, and mental health disorders. Studies demonstrate that Veterans exposed to these toxins have higher rates of neuroinflammatory markers, accelerated cognitive decline, and increased risks of neurodegenerative diseases. This narrative review synthesizes the research linking airborne pollutants such as PM, VOCs, and heavy metals to neuroinflammatory processes and cognitive effects. There is a need for targeted interventions to mitigate the harmful and escalating effects of environmental air pollution exposures on the CNS, improving public health outcomes for vulnerable populations, especially for Veterans exposed to military burn pit toxins.
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Affiliation(s)
- Athena W Brooks
- Minneapolis Veterans Affairs Health Care System, Minneapolis, MN 55417, USA
- Medical School, University of Minnesota, Minneapolis, MN 55455, USA
| | - Brian J Sandri
- Minneapolis Veterans Affairs Health Care System, Minneapolis, MN 55417, USA
| | - Joshua P Nixon
- Minneapolis Veterans Affairs Health Care System, Minneapolis, MN 55417, USA
- Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108, USA
| | - Timothy R Nurkiewicz
- Department of Physiology, Pharmacology, and Toxicology, West Virginia University, Morgantown, WV 26506, USA
- Center for Inhalation Toxicology, West Virginia University, Morgantown, WV 26506, USA
| | - Paul Barach
- The Department of Safety and Quality Science in the College of Population Health, Thomas Jefferson University, Philadelphia, PA 19144, USA
| | - Janeen H Trembley
- Minneapolis Veterans Affairs Health Care System, Minneapolis, MN 55417, USA
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Tammy A Butterick
- Minneapolis Veterans Affairs Health Care System, Minneapolis, MN 55417, USA
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108, USA
- Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA
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5
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Kiper K, Mild B, Chen J, Yuan C, Wells EM, Zheng W, Freeman JL. Cerebral Vascular Toxicity after Developmental Exposure to Arsenic (As) and Lead (Pb) Mixtures. TOXICS 2024; 12:624. [PMID: 39330552 PMCID: PMC11435665 DOI: 10.3390/toxics12090624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/08/2024] [Accepted: 08/19/2024] [Indexed: 09/28/2024]
Abstract
Arsenic (As) and lead (Pb) are environmental pollutants found in common sites linked to similar adverse health effects. This study determined driving factors of neurotoxicity on the developing cerebral vasculature with As and Pb mixture exposures. Cerebral vascular toxicity was evaluated at mixture concentrations of As and Pb representing human exposures levels (10 or 100 parts per billion; ppb; µg/L) in developing zebrafish by assessing behavior, morphology, and gene expression. In the visual motor response assay, hyperactivity was observed in all three outcomes in dark phases in larvae with exposure (1-120 h post fertilization, hpf) to 10 ppb As, 10 ppb Pb, or 10 ppb mix treatment. Time spent moving exhibited hyperactivity in dark phases for 100 ppb As and 100 ppb mix treatment groups only. A decreased brain length and ratio of brain length to total length in the 10 ppb mix group was measured with no alterations in other treatment groups or other endpoints (i.e., total larval length, head length, or head width). Alternatively, measurements of cerebral vasculature in the midbrain and cerebellum uncovered decreased total vascularization at 72 hpf in all treatment groups in the mesencephalon and in all treatment groups, except the 100 ppb Pb and 10 ppb As groups, in the cerebellum. In addition, decreased sprouting and branching occurred in the mesencephalon, while only decreased branching was measured in the cerebellum. The 10 ppb Pb group showed several cerebral vasculature modifications that were aligned with a specific gene expression alteration pattern different from other treatment groups. Additionally, the 100 ppb As group drove gene alterations, along with several other endpoints, for changes observed in the 100 ppb mix treatment group. Perturbations assessed in this study displayed non-linear concentration-responses, which are important to consider in environmental health outcomes for As and Pb neurotoxicity.
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Affiliation(s)
- Keturah Kiper
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Breeann Mild
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Jenny Chen
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Chongli Yuan
- Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Ellen M. Wells
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Wei Zheng
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
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6
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Dhapola R, Sharma P, Kumari S, Bhatti JS, HariKrishnaReddy D. Environmental Toxins and Alzheimer's Disease: a Comprehensive Analysis of Pathogenic Mechanisms and Therapeutic Modulation. Mol Neurobiol 2024; 61:3657-3677. [PMID: 38006469 DOI: 10.1007/s12035-023-03805-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 11/13/2023] [Indexed: 11/27/2023]
Abstract
Alzheimer's disease is a leading cause of mortality worldwide. Inorganic and organic hazards, susceptibility to harmful metals, pesticides, agrochemicals, and air pollution are major environmental concerns. As merely 5% of AD cases are directly inherited indicating that these environmental factors play a major role in disease development. Long-term exposure to environmental toxins is believed to progress neuropathology, which leads to the development of AD. Numerous in-vitro and in-vivo studies have suggested the harmful impact of environmental toxins at cellular and molecular level. Common mechanisms involved in the toxicity of these environmental pollutants include oxidative stress, neuroinflammation, mitochondrial dysfunction, abnormal tau, and APP processing. Increased expression of GSK-3β, BACE-1, TNF-α, and pro-apoptotic molecules like caspases is observed upon exposure to these environmental toxins. In addition, the expression of neurotrophins like BDNF and GAP-43 have been found to be reduced as a result of toxicity. Further, modulation of signaling pathways involving PARP-1, PGC-1α, and MAPK/ERK induced by toxins have been reported to contribute in AD pathogenesis. These pathways are a promising target for developing novel AD therapeutics. Drugs like epigallocatechin-gallate, neflamapimod, salsalate, dexmedetomidine, and atabecestat are in different phases of clinical trials targeting the pathways for possible treatment of AD. This review aims to culminate the correlation between environmental toxicants and AD development. We emphasized upon the signaling pathways involved in the progression of the disease and the therapeutics under clinical trial targeting the altered pathways for possible treatment of AD.
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Affiliation(s)
- Rishika Dhapola
- Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, Central University of Punjab, Bathinda, 151 401, India
| | - Prajjwal Sharma
- Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, Central University of Punjab, Bathinda, 151 401, India
| | - Sneha Kumari
- Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, Central University of Punjab, Bathinda, 151 401, India
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151 401, India
| | - Dibbanti HariKrishnaReddy
- Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, Central University of Punjab, Bathinda, 151 401, India.
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7
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Venkatesan D, Muthukumar S, Iyer M, Babu HWS, Gopalakrishnan AV, Yadav MK, Vellingiri B. Heavy metals toxicity on epigenetic modifications in the pathogenesis of Alzheimer's disease (AD). J Biochem Mol Toxicol 2024; 38:e23741. [PMID: 38816991 DOI: 10.1002/jbt.23741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 03/09/2024] [Accepted: 05/09/2024] [Indexed: 06/01/2024]
Abstract
Alzheimer's disease (AD) is a progressive decline in cognitive ability and behavior which eventually disrupts daily activities. AD has no cure and the progression rate varies unlikely. Among various causative factors, heavy metals are reported to be a significant hazard in AD pathogenesis. Metal-induced neurodegeneration has been focused globally with thorough research to unravel the mechanistic insights in AD. Recently, heavy metals suggested to play an important role in epigenetic alterations which might provide evidential results on AD pathology. Epigenetic modifications are known to play towards novel therapeutic approaches in treating AD. Though many studies focus on epigenetics and heavy metal implications in AD, there is a lack of research on heavy metal influence on epigenetic toxicity in neurological disorders. The current review aims to elucidate the plausible role of cadmium (Cd), iron (Fe), arsenic (As), copper (Cu), and lithium (Li) metals on epigenetic factors and the increase in amyloid beta and tau phosphorylation in AD. Also, the review discusses the common methods of heavy metal detection to implicate in AD pathogenesis. Hence, from this review, we can extend the need for future research on identifying the mechanistic behavior of heavy metals on epigenetic toxicity and to develop diagnostic and therapeutic markers in AD.
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Affiliation(s)
- Dhivya Venkatesan
- Centre for Neuroscience, Department of Biotechnology, Karpagam Academy of Higher Education (Deemed to be University), Coimbatore, India
| | - Sindduja Muthukumar
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Mahalaxmi Iyer
- Centre for Neuroscience, Department of Biotechnology, Karpagam Academy of Higher Education (Deemed to be University), Coimbatore, India
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Harysh Winster Suresh Babu
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Mukesh Kumar Yadav
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Balachandar Vellingiri
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India
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8
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Hua W, Han X, Li F, Lu L, Sun Y, Hassanian-Moghaddam H, Tian M, Lu Y, Huang Q. Transgenerational Effects of Arsenic Exposure on Learning and Memory in Rats: Crosstalk between Arsenic Methylation, Hippocampal Metabolism, and Histone Modifications. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:6475-6486. [PMID: 38578163 DOI: 10.1021/acs.est.3c07989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/06/2024]
Abstract
Arsenic (As) is widely present in the natural environment, and exposure to it can lead to learning and memory impairment. However, the underlying epigenetic mechanisms are still largely unclear. This study aimed to reveal the role of histone modifications in environmental levels of arsenic (sodium arsenite) exposure-induced learning and memory dysfunction in male rats, and the inter/transgenerational effects of paternal arsenic exposure were also investigated. It was found that arsenic exposure impaired the learning and memory ability of F0 rats and down-regulated the expression of cognition-related genes Bdnf, c-Fos, mGlur1, Nmdar1, and Gria2 in the hippocampus. We also observed that inorganic arsenite was methylated to DMA and histone modification-related metabolites were altered, contributing to the dysregulation of H3K4me1/2/3, H3K9me1/2/3, and H3K4ac in rat hippocampus after exposure. Therefore, it is suggested that arsenic methylation and hippocampal metabolism changes attenuated H3K4me1/2/3 and H3K4ac while enhancing H3K9me1/2/3, which repressed the key gene expressions, leading to cognitive impairment in rats exposed to arsenic. In addition, paternal arsenic exposure induced transgenerational effects of learning and memory disorder in F2 male rats through the regulation of H3K4me2 and H3K9me1/2/3, which inhibited c-Fos, mGlur1, and Nmdar1 expression. These results provide novel insights into the molecular mechanism of arsenic-induced neurotoxicity and highlight the risk of neurological deficits in offspring with paternal exposure to arsenic.
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Affiliation(s)
- Weizhen Hua
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou 350122, China
| | - Xuejingping Han
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Fuping Li
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Lu Lu
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Yiqiong Sun
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Hossein Hassanian-Moghaddam
- Department of Clinical Toxicology, Shohada-e Tajrish Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Meiping Tian
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Yanyang Lu
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Qingyu Huang
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
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Mohd Nor Ihsan NS, Abdul Sani SF, Looi LM, Pathmanathan D, Cheah PL, Chiew SF, Bradley DA. EDXRF and the relative presence of K, Ca, Fe and as in amyloidogenic tissues. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2024; 308:123743. [PMID: 38113556 DOI: 10.1016/j.saa.2023.123743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 11/09/2023] [Accepted: 12/07/2023] [Indexed: 12/21/2023]
Abstract
Trace and minor elements play crucial roles in a variety of biological processes, including amyloid fibrils formation. Mechanisms include activation or inhibition of enzymatic reactions, competition between elements and metal proteins for binding positions, also changes to the permeability of cellular membranes. These may influence carcinogenic processes, with trace and minor element concentrations in normal and amyloid tissues potentially aiding in cancer diagnosis and etiology. With the analytical capability of the spectroscopic technique X-ray fluorescence (XRF), this can be used to detect and quantify the presence of elements in amyloid characterization, two of the trace elements known to be associated with amyloid fibrils. In present work, involving samples from a total of 22 subjects, samples of normal and amyloid-containing tissues of heart, kidney, thyroid, and other tissue organs were obtained, analyzed via energy-dispersive X-ray fluorescence (EDXRF). The elemental distribution of potassium (K), calcium (Ca), arsenic (As), and iron (Fe) was examined in both normal and amyloidogenic tissues using perpetual thin slices. In amyloidogenic tissues the levels of K, Ca, and Fe were found to be less than in corresponding normal tissues. Moreover, the presence of As was only observed in amyloidogenic samples; in a few cases in which there was an absence of As, amyloid samples were found to contain Fe. Analysis of arsenic in amyloid plaques has previously been difficult, often producing contradictory results. Using the present EDXRF facility we could distinguish between amyloidogenic and normal samples, with potential correlations in respect of the presence or concentration of specific elements.
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Affiliation(s)
- N S Mohd Nor Ihsan
- Department of Physics, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - S F Abdul Sani
- Department of Physics, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - L M Looi
- Department of Pathology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Dharini Pathmanathan
- Institute of Mathematical Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - P L Cheah
- Department of Pathology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - S F Chiew
- Department of Pathology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - D A Bradley
- Sunway University, Centre for Applied Physics and Radiation Technologies, Jalan Universiti, 46150 PJ, Malaysia; School of Mathematics and Physics, University of Surrey, Guildford GU2 7XH, UK
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Ariafar S, Makhdoomi S, Mohammadi M. Arsenic and Tau Phosphorylation: a Mechanistic Review. Biol Trace Elem Res 2023; 201:5708-5720. [PMID: 37211576 DOI: 10.1007/s12011-023-03634-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/14/2023] [Indexed: 05/23/2023]
Abstract
Arsenic poisoning can affect the peripheral nervous system and cause peripheral neuropathy. Despite different studies on the mechanism of intoxication, the complete process is not explained yet, which can prevent further intoxication and produce effective treatment. In the following paper, we would like to consider the idea that arsenic might cause some diseases via inflammation induction, and tauopathy in neurons. Tau protein, one of the microtubule-associated proteins expressed in neurons, contributes to neuronal microtubules structure. Arsenic may be involved in cellular cascades involved in modulating tau function or hyperphosphorylation of tau protein, which ultimately leads to nerve destruction. For proof of this assumption, some investigations have been planned to measure the association between arsenic and quantities of phosphorylation of tau protein. Additionally, some researchers have investigated the association between microtubule trafficking in neurons and the levels of tau protein phosphorylation. It should be noticed that changing tau phosphorylation in arsenic toxicity may add a new feature to understanding the mechanism of poisonousness and aid in discovering novel therapeutic candidates such as tau phosphorylation inhibitors for drug development.
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Affiliation(s)
- Saba Ariafar
- Department of Pharmacology & Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sajjad Makhdoomi
- Department of Pharmacology & Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mojdeh Mohammadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.
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11
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Wysocki R, Rodrigues JI, Litwin I, Tamás MJ. Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony. Cell Mol Life Sci 2023; 80:342. [PMID: 37904059 PMCID: PMC10616229 DOI: 10.1007/s00018-023-04992-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/12/2023] [Accepted: 09/29/2023] [Indexed: 11/01/2023]
Abstract
Arsenic and antimony are metalloids with profound effects on biological systems and human health. Both elements are toxic to cells and organisms, and exposure is associated with several pathological conditions including cancer and neurodegenerative disorders. At the same time, arsenic- and antimony-containing compounds are used in the treatment of multiple diseases. Although these metalloids can both cause and cure disease, their modes of molecular action are incompletely understood. The past decades have seen major advances in our understanding of arsenic and antimony toxicity, emphasizing genotoxicity and proteotoxicity as key contributors to pathogenesis. In this review, we highlight mechanisms by which arsenic and antimony cause toxicity, focusing on their genotoxic and proteotoxic effects. The mechanisms used by cells to maintain proteostasis during metalloid exposure are also described. Furthermore, we address how metalloid-induced proteotoxicity may promote neurodegenerative disease and how genotoxicity and proteotoxicity may be interrelated and together contribute to proteinopathies. A deeper understanding of cellular toxicity and response mechanisms and their links to pathogenesis may promote the development of strategies for both disease prevention and treatment.
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Affiliation(s)
- Robert Wysocki
- Department of Genetics and Cell Physiology, Faculty of Biological Sciences, University of Wroclaw, 50-328, Wroclaw, Poland.
| | - Joana I Rodrigues
- Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, 405 30, Göteborg, Sweden
| | - Ireneusz Litwin
- Academic Excellence Hub - Research Centre for DNA Repair and Replication, Faculty of Biological Sciences, University of Wroclaw, 50-328, Wroclaw, Poland
| | - Markus J Tamás
- Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, 405 30, Göteborg, Sweden.
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12
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Hu X, Yuan X, Yang M, Han M, Ommati MM, Ma Y. Arsenic exposure induced anxiety-like behaviors in male mice via influencing the GABAergic Signaling in the prefrontal cortex. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:86352-86364. [PMID: 37402917 DOI: 10.1007/s11356-023-28426-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 06/21/2023] [Indexed: 07/06/2023]
Abstract
Arsenic contamination in drinking water causes a global public health problem. Emerging evidence suggests that arsenic may act as an environmental risk factor for anxiety disorders. However, the exact mechanism underlying the adverse effects has not been fully elucidated. This study aimed to evaluate the anxiety-like behaviors of mice exposed to arsenic trioxide (As2O3), to observe the neuropathological changes, and to explore the link between the GABAergic system and behavioral manifestations. For this purpose, male C57BL/6 mice were exposed to various doses of As2O3 (0, 0.15, 1.5, and 15 mg/L) through drinking water for 12 weeks. Anxiety-like behaviors were assessed using the open field test (OFT), light/dark choice test, and elevated zero maze (EZM). Neuronal injuries in the cerebral cortex and hippocampus were assessed by light microscopy with H&E and Nissl staining. Ultrastructural alteration in the cerebral cortex was assessed by transmission electron microscope (TEM). The expression levels of GABAergic system-related molecules (i.e., glutamate decarboxylase, GABA transporter, and GABAB receptor subunits) in the prefrontal cortex (PFC) were determined by qRT-PCR and western blotting. Arsenic exposure showed a striking anxiogenic effect on mice, especially in the group exposed to 15 mg/L As2O3. Light microscopy showed neuron necrosis and reduced cell counts. TEM revealed marked ultrastructural changes, including the vacuolated mitochondria, disrupted Nissl bodies, an indentation in the nucleus membrane, and delamination of myelin sheath in the cortex. In addition, As2O3 influenced the GABAergic system in the PFC by decreasing the expression of the glutamate decarboxylase 1 (GAD1) and the GABAB2 receptor subunit, but not the GABAB1 receptor subunit. To sum up, sub-chronic exposure to As2O3 is associated with increased anxiety-like behaviors, which may be mediated by altered GABAergic signaling in the PFC. These findings shed light on the mechanisms responsible for the neurotoxic effects of arsenic and therefore more cautions should be taken.
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Affiliation(s)
- Xin Hu
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Xiaohong Yuan
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Mingyu Yang
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Mingsheng Han
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Yanqin Ma
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China.
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13
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Ding B, Ma X, Liu Y, Ni B, Lu S, Chen Y, Liu X, Zhang W. Arsenic-Induced, Mitochondria-Mediated Apoptosis Is Associated with Decreased Peroxisome Proliferator-Activated Receptor γ Coactivator α in Rat Brains. TOXICS 2023; 11:576. [PMID: 37505542 PMCID: PMC10384476 DOI: 10.3390/toxics11070576] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/18/2023] [Accepted: 06/23/2023] [Indexed: 07/29/2023]
Abstract
Chronic exposure to arsenic in drinking water damages cognitive function, and nerve cell apoptosis is one of the primary characteristics. The damage to mitochondrial structure and/or function is one of the main characteristics of apoptosis. Peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) is involved in the regulation of mitochondrial biogenesis, energy metabolism, and apoptosis. In this study, we aimed to study the role of PGC-1α in sodium arsenite (NaAsO2)-induced mitochondrial apoptosis in rat hippocampal cells. We discovered that increased arsenic-induced apoptosis in rat hippocampus increased with NaAsO2 (0, 2, 10, and 50 mg/L, orally via drinking water for 12 weeks) exposure by TUNEL assay, and the structure of mitochondria was incomplete and swollen and had increased lysosomes, lipofuscins, and nuclear membrane shrinkage observed via transmission electron microscopy. Furthermore, NaAsO2 reduced the levels of Bcl-2 and PGC-1α and increased the levels of Bax and cytochrome C expression. Moreover, correlation analysis showed that brain arsenic content was negatively correlated with PGC-1α levels and brain ATP content; PGC-1α levels were negatively correlated with apoptosis rate; and brain ATP content was positively correlated with PGC-1α levels, but no significant correlation between ATP content and apoptosis has been observed in this study. Taken together, the results of this study indicate that NaAsO2-induced mitochondrial pathway apoptosis is related to the reduction of PGC-1α, accompanied by ATP depletion.
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Affiliation(s)
- Bo Ding
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin 150081, China
| | - Xinbo Ma
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin 150081, China
| | - Yang Liu
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin 150081, China
| | - Bangyao Ni
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin 150081, China
| | - Siqi Lu
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin 150081, China
| | - Yuting Chen
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin 150081, China
| | - Xiaona Liu
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin 150081, China
| | - Wei Zhang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin 150081, China
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14
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Aguilera-Velázquez JR, Calleja A, Moreno I, Bautista J, Alonso E. Metallic profiles and health risk assessment of the most consumed rice varieties in Spain. J Food Compost Anal 2022. [DOI: 10.1016/j.jfca.2022.105101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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15
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Wisessaowapak C, Worasuttayangkurn L, Maliphol K, Nakareangrit W, Cholpraipimolrat W, Nookabkaew S, Watcharasit P, Satayavivad J. The 28-day repeated arsenic exposure increases tau phosphorylation in the rat brain. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 95:103974. [PMID: 36089238 DOI: 10.1016/j.etap.2022.103974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 08/30/2022] [Accepted: 09/06/2022] [Indexed: 05/10/2023]
Abstract
Herein, we examined whether prolonged arsenic exposure altered tau phosphorylation in the brain of Sprague Dawley rats expressing endogenous wild-type tau. The results showed that daily intraperitoneal injections of 2.5 mg/kg BW sodium arsenite over 28 days caused arsenic accumulation in the rat brain. Interestingly, we found an increase in tau phosphorylation at the Tau 1 region (189-207) and S202 in the hippocampus, S404 in the cerebral cortex, and S396 and S404 in the cerebellum of arsenic-treated rats. Additionally, arsenic increased active ERK1/2 phosphorylation at T202/Y204 in the hippocampus, cerebral cortex, and cerebellum. Meanwhile, we detected increasing active JNK phosphorylation at T183/Y185 in the hippocampus and cerebellum. Moreover, p35, a neuron-specific activator of CDK5, was also elevated in the cerebellum of arsenic-treated rats, suggesting that CDK5 activity may be increased by arsenic. These results suggested that arsenic may induce tau phosphorylation through the activation of tau kinases, ERK1/2, JNK, and CDK5. Together, the findings from this study demonstrated that prolonged arsenic exposure is implicated in neurodegeneration by promoting tau phosphorylation in the rat brain and points toward a possible prevention strategy against neurodegeneration induced by environmental arsenic exposure.
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Affiliation(s)
| | | | | | - Watanyoo Nakareangrit
- Translational Research Unit, Chulabhorn Research Institute, 54 KamphaengPhet6 Rd, Bangkok 10210 Thailand
| | | | - Sumontha Nookabkaew
- Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand
| | - Piyajit Watcharasit
- Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand; Chulabhorn Graduate Institute, 906 KamphaengPhet6 Rd, Bangkok, 10210 Thailand.
| | - Jutamaad Satayavivad
- Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand; Chulabhorn Graduate Institute, 906 KamphaengPhet6 Rd, Bangkok, 10210 Thailand
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16
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Tripathi R, Gupta R, Sahu M, Srivastava D, Das A, Ambasta RK, Kumar P. Free radical biology in neurological manifestations: mechanisms to therapeutics interventions. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:62160-62207. [PMID: 34617231 DOI: 10.1007/s11356-021-16693-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 09/20/2021] [Indexed: 06/13/2023]
Abstract
Recent advancements and growing attention about free radicals (ROS) and redox signaling enable the scientific fraternity to consider their involvement in the pathophysiology of inflammatory diseases, metabolic disorders, and neurological defects. Free radicals increase the concentration of reactive oxygen and nitrogen species in the biological system through different endogenous sources and thus increased the overall oxidative stress. An increase in oxidative stress causes cell death through different signaling mechanisms such as mitochondrial impairment, cell-cycle arrest, DNA damage response, inflammation, negative regulation of protein, and lipid peroxidation. Thus, an appropriate balance between free radicals and antioxidants becomes crucial to maintain physiological function. Since the 1brain requires high oxygen for its functioning, it is highly vulnerable to free radical generation and enhanced ROS in the brain adversely affects axonal regeneration and synaptic plasticity, which results in neuronal cell death. In addition, increased ROS in the brain alters various signaling pathways such as apoptosis, autophagy, inflammation and microglial activation, DNA damage response, and cell-cycle arrest, leading to memory and learning defects. Mounting evidence suggests the potential involvement of micro-RNAs, circular-RNAs, natural and dietary compounds, synthetic inhibitors, and heat-shock proteins as therapeutic agents to combat neurological diseases. Herein, we explain the mechanism of free radical generation and its role in mitochondrial, protein, and lipid peroxidation biology. Further, we discuss the negative role of free radicals in synaptic plasticity and axonal regeneration through the modulation of various signaling molecules and also in the involvement of free radicals in various neurological diseases and their potential therapeutic approaches. The primary cause of free radical generation is drug overdosing, industrial air pollution, toxic heavy metals, ionizing radiation, smoking, alcohol, pesticides, and ultraviolet radiation. Excessive generation of free radicals inside the cell R1Q1 increases reactive oxygen and nitrogen species, which causes oxidative damage. An increase in oxidative damage alters different cellular pathways and processes such as mitochondrial impairment, DNA damage response, cell cycle arrest, and inflammatory response, leading to pathogenesis and progression of neurodegenerative disease other neurological defects.
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Affiliation(s)
- Rahul Tripathi
- Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), Delhi, India
| | - Rohan Gupta
- Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), Delhi, India
| | - Mehar Sahu
- Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), Delhi, India
| | - Devesh Srivastava
- Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), Delhi, India
| | - Ankita Das
- Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), Delhi, India
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), Delhi, India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), Delhi, India.
- , Delhi, India.
- Molecular Neuroscience and Functional Genomics Laboratory, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India.
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17
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Gupta K, Vishwakarma J, Garg A, Pandey R, Jain V, Gupta R, Das U, Roy S, Bandyopadhyay S. Arsenic Induces GSK3β-dependent p-tau, neuronal apoptosis and cognitive impairment via an interdependent hippocampal ERα and IL-1/IL-1R1 mechanism in female rats. Toxicol Sci 2022; 190:79-98. [PMID: 35993674 DOI: 10.1093/toxsci/kfac087] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Arsenic is an environmental contaminant with potential neurotoxicity. We previously reported that arsenic promoted hippocampal neuronal apoptosis, inducing cognitive loss. Here, we correlated it with tau pathology. We observed that environmentally relevant arsenic exposure increased tau phosphorylation and the principal tau kinase, glycogen synthase kinase-3 beta (GSK3β), in the female rat hippocampal neurons. We detected the same in primary hippocampal neurons. Since a regulated estrogen receptor (ER) level and inflammation contributed to normal hippocampal functions, we examined their levels following arsenic exposure. Our ER screening data revealed that arsenic down-regulated hippocampal neuronal ERα. We also detected an up-regulated hippocampal interleukin-1 (IL-1) and its receptor, IL-1R1. Further, co-treating arsenic with the ERα agonist, 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), or IL-1R antagonist (IL-1Ra) resulted in reduced GSK3β and p-tau, indicating involvement of decreased ERα and increased IL-1/IL-1R1 in tau hyperphosphorylation. We then checked whether ERα and IL-1/IL-1R1 had linkage, and detected that while PPT reduced IL-1 and IL-1R1, the IL-1Ra restored ERα, suggesting their arsenic-induced interdependence. We finally correlated this pathway with apoptosis and cognition. We observed that PPT, IL-1Ra and the GSK3β inhibitor, LiCl, reduced hippocampal neuronal cleaved caspase-3 and TUNEL+ve apoptotic count, and decreased the number of errors during learning and increased the saving-memory for Y-Maze Test and retention performance for Passive avoidance test in arsenic-treated rats. Thus, our study reveals a novel mechanism of arsenic-induced GSK3β-dependent tau pathology via interdependent ERα and IL-1/IL-1R1 signaling. It also envisages the protective role of ERα agonist and IL-1 inhibitor against arsenic-induced neurotoxicity.
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Affiliation(s)
- Keerti Gupta
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jitendra Vishwakarma
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Asmita Garg
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Rukmani Pandey
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Veena Jain
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.,Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India
| | - Raksha Gupta
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.,DAV PG College, Nasirabad, Buxipur, Gorakhpur, Uttar Pradesh, 273001, India
| | - Uttara Das
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Somendu Roy
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.,Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India
| | - Sanghamitra Bandyopadhyay
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
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18
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Fei HX, Qian CF, Wu XM, Wei YH, Huang JY, Wei LH. Role of micronutrients in Alzheimer's disease: Review of available evidence. World J Clin Cases 2022; 10:7631-7641. [PMID: 36158513 PMCID: PMC9372870 DOI: 10.12998/wjcc.v10.i22.7631] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/29/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
Alzheimer's disease (AD) is one of the most common age-related neurodegenerative disorders that have been studied for more than 100 years. Although an increased level of amyloid precursor protein is considered a key contributor to the development of AD, the exact pathogenic mechanism remains known. Multiple factors are related to AD, such as genetic factors, aging, lifestyle, and nutrients. Both epidemiological and clinical evidence has shown that the levels of micronutrients, such as copper, zinc, and iron, are closely related to the development of AD. In this review, we summarize the roles of eight micronutrients, including copper, zinc, iron, selenium, silicon, manganese, arsenic, and vitamin D in AD based on recently published studies.
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Affiliation(s)
- Hong-Xin Fei
- Department of Pathology, Guangxi University of Science and Technology, Liuzhou 545000, Guangxi Zhuang Autonomous Region, China
| | - Chao-Fan Qian
- Department of Pathology, Guangxi University of Science and Technology, Liuzhou 545000, Guangxi Zhuang Autonomous Region, China
| | - Xiang-Mei Wu
- Department of Pathology, Guangxi University of Science and Technology, Liuzhou 545000, Guangxi Zhuang Autonomous Region, China
| | - Yu-Hua Wei
- Department of Pathology, Guangxi University of Science and Technology, Liuzhou 545000, Guangxi Zhuang Autonomous Region, China
| | - Jin-Yu Huang
- Department of Neurology, The First Affiliated Hospital of Guangxi University of Science and Technology, Liuzhou 545000, Guangxi Zhuang Autonomous Region, China
| | - Li-Hua Wei
- Department of Pathology, Guangxi University of Science and Technology, Liuzhou 545000, Guangxi Zhuang Autonomous Region, China
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19
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Nabi M, Tabassum N. Role of Environmental Toxicants on Neurodegenerative Disorders. FRONTIERS IN TOXICOLOGY 2022; 4:837579. [PMID: 35647576 PMCID: PMC9131020 DOI: 10.3389/ftox.2022.837579] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 04/22/2022] [Indexed: 12/22/2022] Open
Abstract
Neurodegeneration leads to the loss of structural and functioning components of neurons over time. Various studies have related neurodegeneration to a number of degenerative disorders. Neurological repercussions of neurodegeneration can have severe impacts on the physical and mental health of patients. In the recent past, various neurodegenerative ailments such as Alzheimer’s and Parkinson’s illnesses have received global consideration owing to their global occurrence. Environmental attributes have been regarded as the main contributors to neural dysfunction-related disorders. The majority of neurological diseases are mainly related to prenatal and postnatal exposure to industrially produced environmental toxins. Some neurotoxic metals, like lead (Pb), aluminium (Al), Mercury (Hg), manganese (Mn), cadmium (Cd), and arsenic (As), and also pesticides and metal-based nanoparticles, have been implicated in Parkinson’s and Alzheimer’s disease. The contaminants are known for their ability to produce senile or amyloid plaques and neurofibrillary tangles (NFTs), which are the key features of these neurological dysfunctions. Besides, solvent exposure is also a significant contributor to neurological diseases. This study recapitulates the role of environmental neurotoxins on neurodegeneration with special emphasis on major neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.
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Affiliation(s)
- Masarat Nabi
- Department of Environmental Science, University of Kashmir, Srinagar, India
- *Correspondence: Masarat Nabi, , orcid.org/0000-0003-1677-6498; Nahida Tabassum,
| | - Nahida Tabassum
- Department of Pharmaceutical Sciences, University of Kashmir, Srinagar, India
- *Correspondence: Masarat Nabi, , orcid.org/0000-0003-1677-6498; Nahida Tabassum,
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20
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Kwon YR, Kim JH, Lee S, Kim HY, Cho EJ. Protective effects of Populus tomentiglandulosa against cognitive impairment by regulating oxidative stress in an amyloid beta 25-35-induced Alzheimer's disease mouse model. Nutr Res Pract 2022; 16:173-193. [PMID: 35392529 PMCID: PMC8971824 DOI: 10.4162/nrp.2022.16.2.173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/12/2021] [Accepted: 06/29/2021] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND/OBJECTIVES Alzheimer's disease (AD) is one of the most representative neurodegenerative disease mainly caused by the excessive production of amyloid beta (Aβ). Several studies on the antioxidant activity and protective effects of Populus tomentiglandulosa (PT) against cerebral ischemia-induced neuronal damage have been reported. Based on this background, the present study investigated the protective effects of PT against cognitive impairment in AD. MATERIALS/METHODS We orally administered PT (50 and 100 mg/kg/day) for 14 days in an Aβ25-35-induced mouse model and conducted behavioral experiments to test cognitive ability. In addition, we evaluated the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum and measured the production of lipid peroxide, nitric oxide (NO), and reactive oxygen species (ROS) in tissues. RESULTS PT treatment improved the space perceptive ability in the T-maze test, object cognitive ability in the novel object recognition test, and spatial learning/long-term memory in the Morris water-maze test. Moreover, the levels of AST and ALT were not significantly different among the groups, indicating that PT did not show liver toxicity. Furthermore, administration of PT significantly inhibited the production of lipid peroxide, NO, and ROS in the brain, liver, and kidney, suggesting that PT protected against oxidative stress. CONCLUSIONS Our study demonstrated that administration of PT improved Aβ25-35-induced cognitive impairment by regulating oxidative stress. Therefore, we propose that PT could be used as a natural agent for AD improvement.
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Affiliation(s)
- Yu Ri Kwon
- Department of Food Science and Nutrition, Pusan National University, Busan 46241, Korea
| | - Ji-Hyun Kim
- Department of Food Science and Nutrition, Pusan National University, Busan 46241, Korea
| | - Sanghyun Lee
- Department of Plant Science and Technology, Chung-Ang University, Anseong 17546, Korea
- Natural Product Institute of Science and Technology, Anseong 17546, Korea
| | - Hyun Young Kim
- Department of Food Science, Gyeongsang National University, Jinju 52725, Korea
| | - Eun Ju Cho
- Department of Food Science and Nutrition, Pusan National University, Busan 46241, Korea
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21
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Kushwaha AS, Thakur RS, Patel DK, Kumar M. Impact of arsenic on phosphate solubilization, acquisition and poly-phosphate accumulation in endophytic fungus Serendipita indica. Microbiol Res 2022; 259:127014. [PMID: 35349854 DOI: 10.1016/j.micres.2022.127014] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 03/10/2022] [Accepted: 03/16/2022] [Indexed: 12/12/2022]
Abstract
Symbiotic interactions play a crucial role in the phosphate (Pi) nutrient status of the host plant and offer resilience during biotic and abiotic stresses. Despite a competitive behavior of arsenic (AsV) with Pi, Serendipita indica association promotes plant growth by reducing arsenic bioavailability in the rhizosphere. Reduced arsenic availability is due to the adsorption, accumulation, and precipitation of arsenic in the fungus. The present investigation focused on the fitness and performance of Pi acquisition and utilization in S. indica for growth and metabolism under arsenic stress. The fungus accumulates a massive amount of arsenic up to 2459.3 ppm at a tolerable limit of arsenic supply (1 mM) with a bioaccumulation factor (BAF) 32. Arsenic induces Pi transporter expression to stimulate the arsenic acquisition in the fungus. At the same time, Pi accumulation was also enhanced by 112.2 times higher than the control with an increase in poly-P (polyphosphate) content (6.69 times) of the cell. This result suggests arsenic does not hamper poly-P storage in the cell but shows a marked delocalization of stored poly-P from the vacuoles. Furthermore, an enhanced exopolyphosphatase activity and poly-P storage during arsenic stress suggest induction of cellular machinery for the utilization of Pi is required to deal with arsenic toxicity and competition. However, at high arsenic supply (2.5 and 5 mM), 14.55 and 22.07 times reduced Pi utilization, respectively, was observed during the Pi uptake by the fungus. The reduction of Pi uptake reduces the cell growth and biomass due to competition between arsenic and phosphate. The study suggests no negative impact of arsenic on the Pi acquisition, storage, and metabolism in symbiotic fungus, S. indica, under environmental arsenic contamination.
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Affiliation(s)
- Aparna Singh Kushwaha
- Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Ravindra Singh Thakur
- Analytical Chemistry Division and Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Devendra K Patel
- Analytical Chemistry Division and Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Manoj Kumar
- Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India.
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22
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Niño SA, Chi-Ahumada E, Carrizales L, Estrada-Sánchez AM, Gonzalez-Billault C, Zarazúa S, Concha L, Jiménez-Capdeville ME. Life-long arsenic exposure damages the microstructure of the rat hippocampus. Brain Res 2022; 1775:147742. [PMID: 34848172 DOI: 10.1016/j.brainres.2021.147742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/19/2022]
Abstract
Epidemiological studies demonstrate that arsenic exposure is associated with cognitive dysfunction. Experimental arsenic exposure models showed learning and memory deficits and molecular changes resembling the functional and pathologic neurodegeneration features. The present work focuses on hippocampal pathological changes in Wistar rats induced by continuous arsenic exposure from in utero up to 12 months of age, evaluated by magnetic resonance imaging along with immunohistochemistry. Diffusion-weighted images revealed age-related lower fractional anisotropy and higher radial-axial and mean diffusivity at 6 and 12 months, indicating that arsenic exposure leads to hippocampal demyelination. These structural alterations were paralleled by immunohistochemical changes that showed a significant loss of myelin basic protein in CA1 and CA3 regions accompanied by increased glial fibrillary acidic protein expression at all time-points studied. Concomitantly, arsenic exposure induced an altered morphology of astrocytes at all studied ages, whereas increased synaptogenesis was only observed at two months of age. These results suggest that environmental arsenic exposure is linked to impaired hippocampal connectivity and perhaps early glial senescence, which together might resemble a premature aging phenomenon leading to cognitive deficits.
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Affiliation(s)
- Sandra A Niño
- Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí, Mexico; Geroscience Center for Brain Health and Metabolism (GERO), Santiago de Chile, Chile
| | - Erika Chi-Ahumada
- Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí, Mexico
| | - Leticia Carrizales
- Coordination for Innovation and Application of Science and Technology (CIACYT), Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí, Mexico
| | - Ana María Estrada-Sánchez
- División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica (IPICYT), San Luis Potosí, San Luis Potosi, Mexico
| | - Christian Gonzalez-Billault
- Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago de Chile, Chile; Geroscience Center for Brain Health and Metabolism (GERO), Santiago de Chile, Chile
| | - Sergio Zarazúa
- Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí, Mexico
| | - Luis Concha
- Instituto de Neurobiología, UNAM Campus Juriquilla, Querétaro, Querétaro, Mexico
| | - María E Jiménez-Capdeville
- Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí, Mexico.
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23
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El-Sewify IM, Radwan A, Elghazawy NH, Fritzsche W, Azzazy HME. Optical chemosensors for environmental monitoring of toxic metals related to Alzheimer's disease. RSC Adv 2022; 12:32744-32755. [PMID: 36425686 PMCID: PMC9664454 DOI: 10.1039/d2ra05384e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 11/07/2022] [Indexed: 11/16/2022] Open
Abstract
Alzheimer's disease (AD) is the most common type of dementia and progresses from mild memory loss to severe decline in thinking, behavioral and social skills, which dramatically impairs a person's ability to function independently. Genetics, some health disorders and lifestyle have all been connected to AD. Also, environmental factors are reported as contributors to this illness. The presence of heavy metals in air, water, food, soil and commercial products has increased tremendously. Accumulation of heavy metals in the body leads to serious malfunctioning of bodily organs, specifically the brain. For AD, a wide range of heavy metals have been reported to contribute to its onset and progression and the manifestation of its hallmarks. In this review, we focus on detection of highly toxic heavy metals such as mercury, cadmium, lead and arsenic in water. The presence of heavy metals in water is very troubling and regular monitoring is warranted. Optical chemosensors were designed and fabricated for determination of ultra-trace quantities of heavy metals in water. They have shown advantages when compared to other sensors, such as selectivity, low-detection limit, fast response time, and wide-range determination under optimal sensing conditions. Therefore, implementing optical chemosensors for monitoring levels of toxic metals in water represents an important contribution in fighting AD. This review briefly summarizes evidence that links toxic metals to onset and progression of Alzheimer's disease. It discusses the structure and fabrication of optical chemosensors, and their use for monitoring toxic metals in water.![]()
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Affiliation(s)
- Islam M. El-Sewify
- Department of Chemistry, Faculty of Science, Ain Shams University, 11566, Abbassia, Cairo, Egypt
- Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, SSE, Rm #1194, P.O. Box 74, New Cairo 11835, Egypt
| | - Ahmed Radwan
- Department of Chemistry, Faculty of Science, Ain Shams University, 11566, Abbassia, Cairo, Egypt
- Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, SSE, Rm #1194, P.O. Box 74, New Cairo 11835, Egypt
| | - Nehal H. Elghazawy
- Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, SSE, Rm #1194, P.O. Box 74, New Cairo 11835, Egypt
| | - Wolfgang Fritzsche
- Department of Nanobiophotonics, Leibniz Institute for Photonic Technology, Jena 07745, Germany
| | - Hassan M. E. Azzazy
- Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, SSE, Rm #1194, P.O. Box 74, New Cairo 11835, Egypt
- Department of Nanobiophotonics, Leibniz Institute for Photonic Technology, Jena 07745, Germany
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24
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Nutritional Quality of the Most Consumed Varieties of Raw and Cooked Rice in Spain Submitted to an In Vitro Digestion Model. Foods 2021; 10:foods10112584. [PMID: 34828863 PMCID: PMC8618410 DOI: 10.3390/foods10112584] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 12/25/2022] Open
Abstract
Rice is one of the most consumed staple foods around the world and its trade is highly globalized. Increased environmental pollution generates a large amount of waste that, in many cases, is discarded close to culture fields. Some species are able to bioaccumulate toxic substances, such as metals, that could be transferred to the food chain. The main goal of this study was to evaluate the content of metallic (Al, Cd, Pb, and Cr) and metalloid elements (As) in 14 of the most consumed varieties of rice in Spain and their effects on human health. The samples were cooked, and human digestion was simulated by using a standard in vitro digestion method. Metallic and metalloid element levels were analysed by Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES), previous called microwave digestion. Both the human health risk index, Hazard Quotient, and Lifetime Cancer Risk did not show toxic values in any case. Rice with a higher non-digestible fraction showed a higher liberation of proteins and a lower glycemic index. There were no significant differences in the concentrations of metallic and metalloid elements in cooked rice or in the digestible fraction in all varieties analysed. However, Al concentrations were higher than other metals in all varieties studied due to its global distribution. No relationship has been observed between the digestibility of rice and the bioaccessibility of each metallic and metalloid element. All of the studied rice varieties are healthy food products and its daily consumption is safe. The regular monitoring of metals and As in rice consumed in Spain may contribute to improvements in the human health risk evaluation.
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25
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Martínez-Castillo M, García-Montalvo EA, Arellano-Mendoza MG, Sánchez-Peña LDC, Soria Jasso LE, Izquierdo-Vega JA, Valenzuela OL, Hernández-Zavala A. Arsenic exposure and non-carcinogenic health effects. Hum Exp Toxicol 2021; 40:S826-S850. [PMID: 34610256 DOI: 10.1177/09603271211045955] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inorganic arsenic (iAs) exposure is a serious health problem that affects more than 140 million individuals worldwide, mainly, through contaminated drinking water. Acute iAs poisoning produces several symptoms such as nausea, vomiting, abdominal pain, and severe diarrhea, whereas prolonged iAs exposure increased the risk of several malignant disorders such as lung, urinary tract, and skin tumors. Another sensitive endpoint less described of chronic iAs exposure are the non-malignant health effects in hepatic, endocrine, renal, neurological, hematological, immune, and cardiovascular systems. The present review outlines epidemiology evidence and possible molecular mechanisms associated with iAs-toxicity in several non-carcinogenic disorders.
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Affiliation(s)
- Macario Martínez-Castillo
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, 27740Instituto Politécnico Nacional, Ciudad de México, México
| | | | - Mónica G Arellano-Mendoza
- Laboratorio de Investigación en Enfermedades Crónico-Degenerativas, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, 27740Instituto Politécnico Nacional, Ciudad de México, México
| | - Luz Del C Sánchez-Peña
- Departamento de Toxicología, 540716Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de Mexico, México
| | - Luis E Soria Jasso
- Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina del Instituto de Ciencias de la Salud, 103794Universidad Autónoma del Estado de Hidalgo, Pachuca, México
| | - Jeannett A Izquierdo-Vega
- Área Académica de Medicina, Instituto de Ciencias de la Salud, 103794Universidad Autónoma del Estado de Hidalgo, Pachuca, México
| | - Olga L Valenzuela
- Facultad de Ciencias Químicas, 428055Universidad Veracruzana, Orizaba, México
| | - Araceli Hernández-Zavala
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, 27740Instituto Politécnico Nacional, Ciudad de México, México
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26
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Niño SA, Vázquez-Hernández N, Arevalo-Villalobos J, Chi-Ahumada E, Martín-Amaya-Barajas FL, Díaz-Cintra S, Martel-Gallegos G, González-Burgos I, Jiménez-Capdeville ME. Cortical Synaptic Reorganization Under Chronic Arsenic Exposure. Neurotox Res 2021; 39:1970-1980. [PMID: 34533753 DOI: 10.1007/s12640-021-00409-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/02/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022]
Abstract
There is solid epidemiological evidence that arsenic exposure leads to cognitive impairment, while experimental work supports the hypothesis that it also contributes to neurodegeneration. Energy deficit, oxidative stress, demyelination, and defective neurotransmission are demonstrated arsenic effects, but it remains unclear whether synaptic structure is also affected. Employing both a triple-transgenic Alzheimer's disease model and Wistar rats, the cortical microstructure and synapses were analyzed under chronic arsenic exposure. Male animals were studied at 2 and 4 months of age, after exposure to 3 ppm sodium arsenite in drinking water during gestation, lactation, and postnatal development. Through nuclear magnetic resonance, diffusion-weighted images were acquired and anisotropy (integrity; FA) and apparent diffusion coefficient (dispersion degree; ADC) metrics were derived. Postsynaptic density protein and synaptophysin were analyzed by means of immunoblot and immunohistochemistry, while dendritic spine density and morphology of cortical pyramidal neurons were quantified after Golgi staining. A structural reorganization of the cortex was evidenced through high-ADC and low-FA values in the exposed group. Similar changes in synaptic protein levels in the 2 models suggest a decreased synaptic connectivity at 4 months of age. An abnormal dendritic arborization was observed at 4 months of age, after increased spine density at 2 months. These findings demonstrate alterations of cortical synaptic connectivity and microstructure associated to arsenic exposure appearing in young rodents and adults, and these subtle and non-adaptive plastic changes in dendritic spines and in synaptic markers may further progress to the degeneration observed at older ages.
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Affiliation(s)
- Sandra A Niño
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Nallely Vázquez-Hernández
- División de Neurociencias, Centro de Investigación Biomédica de Occidente, IMSS. Guadalajara, Jalisco, Mexico
| | - Jaime Arevalo-Villalobos
- Facultad de Agronomía y Veterinaria, Universidad Autónoma de San Luis Potosí, Soledad de Graciano Sánchez, San Luis Potosí, Mexico
| | - Erika Chi-Ahumada
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | | | - Sofía Díaz-Cintra
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico
| | - Guadalupe Martel-Gallegos
- Laboratorio de Biomedicina, Unidad Académica Multidisciplinaria Zona Media, Universidad Autónoma de San Luis Potosí, Rio Verde, San Luis Potosí, Mexico
| | - Ignacio González-Burgos
- División de Neurociencias, Centro de Investigación Biomédica de Occidente, IMSS. Guadalajara, Jalisco, Mexico
| | - María E Jiménez-Capdeville
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico.
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27
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Thakur M, Rachamalla M, Niyogi S, Datusalia AK, Flora SJS. Molecular Mechanism of Arsenic-Induced Neurotoxicity including Neuronal Dysfunctions. Int J Mol Sci 2021; 22:ijms221810077. [PMID: 34576240 PMCID: PMC8471829 DOI: 10.3390/ijms221810077] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 12/15/2022] Open
Abstract
Arsenic is a key environmental toxicant having significant impacts on human health. Millions of people in developing countries such as Bangladesh, Mexico, Taiwan, and India are affected by arsenic contamination through groundwater. Environmental contamination of arsenic leads to leads to various types of cancers, coronary and neurological ailments in human. There are several sources of arsenic exposure such as drinking water, diet, wood preservatives, smoking, air and cosmetics, while, drinking water is the most explored route. Inorganic arsenic exhibits higher levels of toxicity compared its organic forms. Exposure to inorganic arsenic is known to cause major neurological effects such as cytotoxicity, chromosomal aberration, damage to cellular DNA and genotoxicity. On the other hand, long-term exposure to arsenic may cause neurobehavioral effects in the juvenile stage, which may have detrimental effects in the later stages of life. Thus, it is important to understand the toxicology and underlying molecular mechanism of arsenic which will help to mitigate its detrimental effects. The present review focuses on the epidemiology, and the toxic mechanisms responsible for arsenic induced neurobehavioral diseases, including strategies for its management from water, community and household premises. The review also provides a critical analysis of epigenetic and transgenerational modifications, mitochondrial oxidative stress, molecular mechanisms of arsenic-induced oxidative stress, and neuronal dysfunction.
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Affiliation(s)
- Manisha Thakur
- Department of Pharmacology and Toxicology, Transit Campus, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India; (M.T.); (A.K.D.)
| | - Mahesh Rachamalla
- Department of Biology, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada; (M.R.); (S.N.)
| | - Som Niyogi
- Department of Biology, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada; (M.R.); (S.N.)
- Toxicology Centre, Department of Biology, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada
| | - Ashok Kumar Datusalia
- Department of Pharmacology and Toxicology, Transit Campus, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India; (M.T.); (A.K.D.)
| | - Swaran Jeet Singh Flora
- Department of Pharmacology and Toxicology, Transit Campus, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India; (M.T.); (A.K.D.)
- Correspondence:
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28
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Liu X, Chen Y, Wang H, Wei Y, Yuan Y, Zhou Q, Fang F, Shi S, Jiang X, Dong Y, Li X. Microglia-derived IL-1β promoted neuronal apoptosis through ER stress-mediated signaling pathway PERK/eIF2α/ATF4/CHOP upon arsenic exposure. JOURNAL OF HAZARDOUS MATERIALS 2021; 417:125997. [PMID: 34229406 DOI: 10.1016/j.jhazmat.2021.125997] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/23/2021] [Accepted: 04/29/2021] [Indexed: 06/13/2023]
Abstract
Arsenic is the leading toxicant of hazardous environmental chemicals, which is linked with neurotoxicity including cognitive dysfunction, neurodevelopmental alterations and neurodegenerative disorders. It has been suggested that sustained pro-inflammatory response is one of the triggering factors of arsenic-induced neurotoxicity. Microglia, the immune cells in the central nervous system, response to physiological and pathological stress, and release a large array of pro-inflammatory cytokines if activated excessively. Several studies indicated that arsenic was capable of inducing microglia activation, however, the role of the subsequently released pro-inflammatory cytokines in arsenic-induced neurotoxicity remains to be elucidated. Our findings demonstrated that arsenic-induced cognitive dysfunction, microglia activation, up-regulation and release of IL-1β and ER stress-mediated apoptosis could be attenuated by minocycline, a recognized inhibitor of microglia activation. In addition, the IL-1 receptor antagonist IL-1ra diminished arsenic-induced activation of ER stress-mediated apoptotic pathway PERK/eIF2α/ATF4/CHOP and neuronal apoptosis. Our findings provided evidences that arsenic-induced microglia activation also contributed to neuronal apoptosis through pro-inflammatory cytokine. Microglia-derived IL-1β promoted hippocampal neuronal apoptosis through ER stress-mediated PERK/eIF2α/ATF4/CHOP apoptotic pathway. Neuronal apoptosis induced by prolonged activation of microglia was partially involved in the arsenic-induced cognitive dysfunction.
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Affiliation(s)
- Xudan Liu
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China
| | - Yao Chen
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China
| | - Huanhuan Wang
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China
| | - Yuting Wei
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China
| | - Ye Yuan
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China
| | - Qianqian Zhou
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China
| | - Fang Fang
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China
| | - Sainan Shi
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China
| | - Xiaojing Jiang
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China
| | - Yinqiao Dong
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China
| | - Xin Li
- Department of Occupational and Environmental Health, Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, Shenyang 110122, China.
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Exposure to Environmental Arsenic and Emerging Risk of Alzheimer's Disease: Perspective Mechanisms, Management Strategy, and Future Directions. TOXICS 2021; 9:toxics9080188. [PMID: 34437506 PMCID: PMC8402411 DOI: 10.3390/toxics9080188] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/11/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022]
Abstract
Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases, characterized by memory dysfunction and the presence of hyperphosphorylated tau and amyloid β (Aβ) aggregates in multiple brain regions, including the hippocampus and cortex. The exact etiology of AD has not yet been confirmed. However, epidemiological reports suggest that populations who were exposed to environmental hazards are more likely to develop AD than those who were not. Arsenic (As) is a naturally occurring environmental risk factor abundant in the Earth’s crust, and human exposure to As predominantly occurs through drinking water. Convincing evidence suggests that As causes neurotoxicity and impairs memory and cognition, although the hypothesis and molecular mechanism of As-associated pathobiology in AD are not yet clear. However, exposure to As and its metabolites leads to various pathogenic events such as oxidative stress, inflammation, mitochondrial dysfunctions, ER stress, apoptosis, impaired protein homeostasis, and abnormal calcium signaling. Evidence has indicated that As exposure induces alterations that coincide with most of the biochemical, pathological, and clinical developments of AD. Here, we overview existing literature to gain insights into the plausible mechanisms that underlie As-induced neurotoxicity and the subsequent neurological deficits in AD. Prospective strategies for the prevention and management of arsenic exposure and neurotoxicity have also been discussed.
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30
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Cheng H, Yang B, Ke T, Li S, Yang X, Aschner M, Chen P. Mechanisms of Metal-Induced Mitochondrial Dysfunction in Neurological Disorders. TOXICS 2021; 9:142. [PMID: 34204190 PMCID: PMC8235163 DOI: 10.3390/toxics9060142] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/12/2021] [Accepted: 06/14/2021] [Indexed: 01/31/2023]
Abstract
Metals are actively involved in multiple catalytic physiological activities. However, metal overload may result in neurotoxicity as it increases formation of reactive oxygen species (ROS) and elevates oxidative stress in the nervous system. Mitochondria are a key target of metal-induced toxicity, given their role in energy production. As the brain consumes a large amount of energy, mitochondrial dysfunction and the subsequent decrease in levels of ATP may significantly disrupt brain function, resulting in neuronal cell death and ensuing neurological disorders. Here, we address contemporary studies on metal-induced mitochondrial dysfunction and its impact on the nervous system.
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Affiliation(s)
- Hong Cheng
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning 530021, China; (H.C.); (X.Y.)
| | - Bobo Yang
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (B.Y.); (T.K.)
| | - Tao Ke
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (B.Y.); (T.K.)
| | - Shaojun Li
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China;
| | - Xiaobo Yang
- Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning 530021, China; (H.C.); (X.Y.)
- Department of Public Health, School of Medicine, Guangxi University of Science and Technology, Liuzhou 545006, China
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (B.Y.); (T.K.)
| | - Pan Chen
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (B.Y.); (T.K.)
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31
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Wisessaowapak C, Watcharasit P, Satayavivad J. Arsenic disrupts neuronal insulin signaling through increasing free PI3K-p85 and decreasing PI3K activity. Toxicol Lett 2021; 349:40-50. [PMID: 34118311 DOI: 10.1016/j.toxlet.2021.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 05/18/2021] [Accepted: 06/07/2021] [Indexed: 11/28/2022]
Abstract
Previously, we reported that prolonged arsenic exposure impaired neuronal insulin signaling. Here we have further identified novel molecular mechanisms underlying neuronal insulin signaling impairment by arsenic. Arsenic treatment altered insulin dose-response curve and reduced maximum insulin response in differentiated human neuroblastoma SH-SY5Y cells, suggesting that arsenic hindered neuronal insulin signaling in a non-competitive like manner. Mechanistically, arsenic suppressed insulin receptor (IR) kinase activity, as witnessed by a decreased insulin-activated autophosphorylation of IR at Y1150/1151. Arsenic decreased the level of insulin receptor substrate 1 (IRS1) but increased the protein ratio between PI3K regulatory subunit, p85, and PI3K catalytic subunit, p110. Interestingly, co-immunoprecipitation demonstrated that arsenic did not alter a level of PI3K-p110/PI3K-p85 complex while increased PI3K-p85 levels in a PI3K-p110 depletion supernatant resulted from PI3K-p110 immunoprecipitation. These results indicated that arsenic increased PI3K-p85 which was free from PI3K-p110 binding. In addition, arsenic significantly increased interaction between IRS1 and PI3K-p85 but not PI3K-p110, suggesting that there may be a fraction of free PI3K-p85 interacting with IRS1. In vitro PI3K activity demonstrated that arsenic lowered PI3K activity in both basal and insulin-stimulated conditions. These results suggested that the increase in free PI3K-p85 by arsenic might compete with PI3K heterodimer for the same IRS1 binding site, in turn blocking the activation of its catalytic subunit, PI3K-p110. Taken together, our results provide additional insights into mechanisms underlying the impairment of neuronal insulin signaling by arsenic through the reduction of IR autophosphorylation, the increase in free PI3K-p85, and the impeding of PI3K activity.
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Affiliation(s)
- Churaibhon Wisessaowapak
- Laboratory of Pharmacology, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Rd, Bangkok, 10210, Thailand; Environmental Toxicology Program, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok, 10210, Thailand
| | - Piyajit Watcharasit
- Laboratory of Pharmacology, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Rd, Bangkok, 10210, Thailand; Environmental Toxicology Program, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok, 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Higher Education, Science, Research and Innovation, Thailand.
| | - Jutamaad Satayavivad
- Laboratory of Pharmacology, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Rd, Bangkok, 10210, Thailand; Environmental Toxicology Program, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok, 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Higher Education, Science, Research and Innovation, Thailand
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Wisessaowapak C, Visitnonthachai D, Watcharasit P, Satayavivad J. Prolonged arsenic exposure increases tau phosphorylation in differentiated SH-SY5Y cells: The contribution of GSK3 and ERK1/2. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2021; 84:103626. [PMID: 33621689 DOI: 10.1016/j.etap.2021.103626] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 01/19/2021] [Accepted: 02/17/2021] [Indexed: 06/12/2023]
Abstract
Arsenic is a metalloid that has been hypothesized to be an environmental risk factor for Alzheimer's disease (AD), a disease having hyperphosphorylated tau aggregate as a marker. The present study demonstrated that prolonged exposure to sodium arsenite at low micromolar range (1-10 μM) reduced Tau 1 (recognizing dephosphorylated tau at residues 189-207) and elevated pS202 tau in differentiated human neuroblastoma SH-SY5Y cells indicating that arsenic increases tau phosphorylation in neurons. Sodium arsenite elevated GSK3β kinase activity, while GSK3 inhibitors, BIO, SB216763, and lithium, reversed the Tau 1 reduction by sodium arsenite. Additionally, sodium arsenite increased levels of active phosphorylation of ERK1/2, and inhibition of ERK1/2 by U0126 partially improved the Tau1 reduction. These results suggest that arsenic may cause tau hyperphosphorylation in neurons through the activation of GSK3 and ERK1/2. Furthermore, sodium arsenite augmented tau phosphorylation in the membrane and cytosolic fractions. Inductions of GSK3 activity by sodium arsenite treatment were observed in the membrane fraction, as evidenced by a reduction of β-catenin, a protein signaled for degradation following phosphorylation by GSK3. An enhancement of ERK1/2 phosphorylation by sodium arsenite was also witnessed in the cytosol. Additionally, sodium arsenite increased insoluble tau aggregation. These results suggest that arsenic induces tau hyperphosphorylation in the membrane fraction which may lead to its redistribution from the membrane fraction to the cytosol, where it promotes neurofibrillary formation. Collectively, we demonstrate that prolonged arsenic exposure increases tau phosphorylation, partly through GSK3 and ERK1/2 activation, and insoluble tau aggregates, hence possibly contributing to the development of sporadic AD.
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Affiliation(s)
- Churaibhon Wisessaowapak
- Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Environmental Toxicology Program, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok, 10210, Thailand
| | | | - Piyajit Watcharasit
- Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Environmental Toxicology Program, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok, 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Higher Education Science Research and Innovation, Thailand.
| | - Jutamaad Satayavivad
- Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Environmental Toxicology Program, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok, 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Higher Education Science Research and Innovation, Thailand
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Mir RH, Sawhney G, Pottoo FH, Mohi-Ud-Din R, Madishetti S, Jachak SM, Ahmed Z, Masoodi MH. Role of environmental pollutants in Alzheimer's disease: a review. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:44724-44742. [PMID: 32715424 DOI: 10.1007/s11356-020-09964-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 06/30/2020] [Indexed: 06/11/2023]
Abstract
Neurodegenerative disorders are commonly erratic influenced by various factors including lifestyle, environmental, and genetic factors. In recent observations, it has been hypothesized that exposure to various environmental factors enhances the risk of Alzheimer's disease (AD). The exact etiology of Alzheimer's disease is still unclear; however, the contribution of environmental factors in the pathology of AD is widely acknowledged. Based on the available literature, the review aims to culminate in the prospective correlation between the various environmental factors and AD. The prolonged exposure to the various well-known environmental factors including heavy metals, air pollutants (particulate matter), pesticides, nanoparticles containing metals, industrial chemicals results in accelerating the progression of AD. Common mechanisms have been documented in the field of environmental contaminants for enhancing amyloid-β (Aβ) peptide along with tau phosphorylation, resulting in the initiation of senile plaques and neurofibrillary tangles, which results in the death of neurons. This review offers a compilation of available data to support the long-suspected correlation between environmental risk factors and AD pathology. Graphical abstract .
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Affiliation(s)
- Reyaz Hassan Mir
- Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, Kashmir, 190006, India.
| | - Gifty Sawhney
- Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, Jammu, 180001, India
| | - Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O.BOX 1982, Dammam, 31441, Saudi Arabia
| | - Roohi Mohi-Ud-Din
- Pharmacognosy Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, Kashmir, 190006, India
| | - Sreedhar Madishetti
- Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, Jammu, 180001, India
| | - Sanjay M Jachak
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab, 160062, India
| | - Zabeer Ahmed
- Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, Jammu, 180001, India
| | - Mubashir Hussain Masoodi
- Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, Kashmir, 190006, India.
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Liu Y, Tang J, Yuan J, Yao C, Hosoi K, Han Y, Yu S, Wei H, Chen G. Arsenite-induced downregulation of occludin in mouse lungs and BEAS-2B cells via the ROS/ERK/ELK1/MLCK and ROS/p38 MAPK signaling pathways. Toxicol Lett 2020; 332:146-154. [PMID: 32683294 DOI: 10.1016/j.toxlet.2020.07.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 06/08/2020] [Accepted: 07/09/2020] [Indexed: 02/06/2023]
Abstract
Occludin is an important tight junction (TJ) protein in pulmonary epithelial cells. In this study, we identified changes in occludin in arsenic-induced lung injury in vivo and in vitro. Upon intratracheal instillation with arsenic trioxide (As2O3) at a daily dose of 30 μg/kg for 1 week, levels of occludin mRNA and protein expression decreased significantly in mouse lung tissue. Levels of occludin mRNA and protein expression in BEAS-2B cells were reduced upon exposure to As2O3 in a concentration- and time-dependent manner. In addition, exposure to As2O3 significantly increased expression of p-p38, p-ERK1/2, p-ELK1, and MLCK in mouse lung tissue and BEAS-2B cells. Treatment with As2O3 induced oxidative stress in mouse lung tissue and BEAS-2B cells. In BEAS-2B cells, exposure to As2O3 reduced transepithelial resistance, which was partially restored with N-acetyl-cysteine (NAC) treatment. Reduced expression of occludin mRNA and protein induced by As2O3 was entirely restored with NAC and resveratrol. However, SB203580, PD98059, and ML-7 partially blocked As2O3-induced occludin reduction in BEAS-2B cells. These results indicate that As2O3 inhibits occludin expression in vivo and in vitro at least partially via the ROS/ERK/ELK1/MLCK and ROS/p38 MAPK signaling pathways.
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Affiliation(s)
- Yingqi Liu
- Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China
| | - Jing Tang
- Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China
| | - Jiaming Yuan
- Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China
| | - Chenjuan Yao
- Department of Molecular Oral Physiology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima-Shi, Tokushima, 770-8504, Japan
| | - Kazuo Hosoi
- Department of Molecular Oral Physiology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima-Shi, Tokushima, 770-8504, Japan; Kosei Pharmaceutical Co. Ltd., Osaka-shi, Osaka, 540-0039, Japan
| | - Yu Han
- Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China
| | - Shali Yu
- Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China
| | - Haiyan Wei
- Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China.
| | - Gang Chen
- Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu, 226019, China.
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Abstract
Exposure to arsenic in contaminated drinking water is a worldwide public health problem that affects more than 200 million people. Protein quality control constitutes an evolutionarily conserved mechanism for promoting proper folding of proteins, refolding of misfolded proteins, and removal of aggregated proteins, thereby maintaining homeostasis of the proteome (i.e., proteostasis). Accumulating lines of evidence from epidemiological and laboratory studies revealed that chronic exposure to inorganic arsenic species can elicit proteinopathies that contribute to neurodegenerative disorders, cancer, and type II diabetes. Here, we review the effects of arsenic exposure on perturbing various elements of the proteostasis network, including mitochondrial homeostasis, molecular chaperones, inflammatory response, ubiquitin-proteasome system, autophagy, as well as asymmetric segregation and axonal transport of misfolded proteins. We also discuss arsenic-induced disruptions of post-translational modifications of proteins, for example, ubiquitination, and their implications in proteostasis. Together, studies in the past few decades support that disruption of protein quality control may constitute an important mechanism underlying the arsenic-induced toxicity.
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Hirano S. Biotransformation of arsenic and toxicological implication of arsenic metabolites. Arch Toxicol 2020; 94:2587-2601. [PMID: 32435915 DOI: 10.1007/s00204-020-02772-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 05/04/2020] [Indexed: 12/13/2022]
Abstract
Arsenic is a well-known environmental carcinogen and chronic exposure to arsenic through drinking water has been reported to cause skin, bladder and lung cancers, with arsenic metabolites being implicated in the pathogenesis. In contrast, arsenic trioxide (As2O3) is an effective therapeutic agent for the treatment of acute promyelocytic leukemia, in which the binding of arsenite (iAsIII) to promyelocytic leukemia (PML) protein is the proposed initial step. These findings on the two-edged sword characteristics of arsenic suggest that after entry into cells, arsenic reaches the nucleus and triggers various nuclear events. Arsenic is reduced, conjugated with glutathione, and methylated in the cytosol. These biotransformations, including the production of reactive metabolic intermediates, appear to determine the intracellular dynamics, target organs, and biological functions of arsenic.
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Affiliation(s)
- Seishiro Hirano
- Center for Health and Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki, 305-8506, Japan.
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Zhang W, Huo T, Li A, Wu X, Feng C, Liu J, Jiang H. Identification of neurotoxicity markers induced by realgar exposure in the mouse cerebral cortex using lipidomics. JOURNAL OF HAZARDOUS MATERIALS 2020; 389:121567. [PMID: 32061421 DOI: 10.1016/j.jhazmat.2019.121567] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 10/12/2019] [Accepted: 10/29/2019] [Indexed: 06/10/2023]
Abstract
Realgar is a traditional Chinese medicine containing arsenic and has neurotoxicity. This study used realgar exposure mice model, neurobehavioral tests, analytical chemistry, molecular biology and nontargeted lipidomics to explore the mechanism of realgar damages the nervous system. The arsenic contained in realgar passed through the BBB and accumulated in the brain. Neurons, synapses and myelin showed abnormal changes in the cerebral cortex. The number of autophagosomes were incresed as well as levels of MDA, Lp-PLA2, and cPLA2 but the CAT level was significant reduced. Finally, the cognition and memory of mice were decreased. Nontargeted lipidomics detected 34 lipid subclasses including 1603 lipid molecules. The levels of the LPC and LPE were significantly increased. Under the condition of variable importance for the projection (VIP)>1 and P < 0.05, only 28 lipid molecules satisfied the criteria. The lipid molecular markers SM (d36:2), PE (18:2/22:6) and PE (36:3) which were filtered by receiver operating characteristic (ROC) curve (AUC>0.8 or AUC<0.2) were used to identify the neurotoxicity induced by realgar. Therefore, realgar induces neurotoxicity through exacerbating oxidative damage and lipid dysfunction. Providing research basis for the clinical diagnosis and treatment of realgar-induced neurotoxicity.
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Affiliation(s)
- Weiwei Zhang
- Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Taoguang Huo
- Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Aihong Li
- Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Xinyu Wu
- Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Cong Feng
- Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Jieyu Liu
- Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Hong Jiang
- Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China.
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Niño SA, Chi-Ahumada E, Ortíz J, Zarazua S, Concha L, Jiménez-Capdeville ME. Demyelination associated with chronic arsenic exposure in Wistar rats. Toxicol Appl Pharmacol 2020; 393:114955. [PMID: 32171569 DOI: 10.1016/j.taap.2020.114955] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 02/18/2020] [Accepted: 03/10/2020] [Indexed: 02/01/2023]
Abstract
Inorganic arsenic is among the major contaminants of groundwater in the world. Worldwide population-based studies demonstrate that chronic arsenic exposure is associated with poor cognitive performance among children and adults, while research in animal models confirms learning and memory deficits after arsenic exposure. The aim of this study was to investigate the long-term effects of environmentally relevant arsenic exposure in the myelination process of the prefrontal cortex (PFC) and corpus callosum (CC). A longitudinal study with repeated follow-up assessments was performed in male Wistar rats exposed to 3 ppm sodium arsenite in drinking water. Animals received the treatment from gestation until 2, 4, 6, or 12 months of postnatal age. The levels of myelin basic protein (MBP) were evaluated by immunohistochemistry/histology and immunoblotting from the PFC and CC. As plausible alterations associated with demyelination, we considered mitochondrial mass (VDAC) and two axonal damage markers: amyloid precursor protein (APP) level and phosphorylated neurofilaments. To analyze the microstructure of the CC in vivo, we acquired diffusion-weighted images at the same ages, from which we derived metrics using the tensor model. Significantly decreased levels of MBP were found in both regions together with significant increases of mitochondrial mass and slight axonal damage at 12 months in the PFC. Ultrastructural imaging demonstrated arsenic-associated decreases of white matter volume, water diffusion anisotropy, and increases in radial diffusivity. This study indicates that arsenic exposure is associated with a significant and persistent negative impact on microstructural features of white matter tracts.
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Affiliation(s)
- Sandra A Niño
- Laboratorio de Neurotoxicología, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, Av. Manuel Nava 6, C.P 78210 San Luis Potosí, Mexico
| | - Erika Chi-Ahumada
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Av. Venustiano Carranza 2405, C.P 78210 San Luis Potosí, Mexico
| | - Juan Ortíz
- Instituto de Neurobiología, Universidad Nacional Autónoma de México, Boulevard Juriquilla 3001, Querétaro, Querétaro C.P 76230, Mexico
| | - Sergio Zarazua
- Laboratorio de Neurotoxicología, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, Av. Manuel Nava 6, C.P 78210 San Luis Potosí, Mexico
| | - Luis Concha
- Instituto de Neurobiología, Universidad Nacional Autónoma de México, Boulevard Juriquilla 3001, Querétaro, Querétaro C.P 76230, Mexico
| | - Maria E Jiménez-Capdeville
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Av. Venustiano Carranza 2405, C.P 78210 San Luis Potosí, Mexico.
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Garza-Lombó C, Pappa A, Panayiotidis MI, Gonsebatt ME, Franco R. Arsenic-induced neurotoxicity: a mechanistic appraisal. J Biol Inorg Chem 2019; 24:1305-1316. [PMID: 31748979 DOI: 10.1007/s00775-019-01740-8] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 10/24/2019] [Indexed: 12/19/2022]
Abstract
Arsenic is a metalloid found in groundwater as a byproduct of soil/rock erosion and industrial and agricultural processes. This xenobiotic elicits its toxicity through different mechanisms, and it has been identified as a toxicant that affects virtually every organ or tissue in the body. In the central nervous system, exposure to arsenic can induce cognitive dysfunction. Furthermore, iAs has been linked to several neurological disorders, including neurodevelopmental alterations, and is considered a risk factor for neurodegenerative disorders. However, the exact mechanisms involved are still unclear. In this review, we aim to appraise the neurotoxic effects of arsenic and the molecular mechanisms involved. First, we discuss the epidemiological studies reporting on the effects of arsenic in intellectual and cognitive function during development as well as studies showing the correlation between arsenic exposure and altered cognition and mental health in adults. The neurotoxic effects of arsenic and the potential mechanisms associated with neurodegeneration are also reviewed including data from experimental models supporting epidemiological evidence of arsenic as a neurotoxicant. Next, we focused on recent literature regarding arsenic metabolism and the molecular mechanisms that begin to explain how arsenic damages the central nervous system including, oxidative stress, energy failure and mitochondrial dysfunction, epigenetics, alterations in neurotransmitter homeostasis and synaptic transmission, cell death pathways, and inflammation. Outlining the specific mechanisms by which arsenic alters the cell function is key to understand the neurotoxic effects that convey cognitive dysfunction, neurodevelopmental alterations, and neurodegenerative disorders.
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Affiliation(s)
- Carla Garza-Lombó
- Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.,School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA.,Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Aglaia Pappa
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | | | - María E Gonsebatt
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Rodrigo Franco
- Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA. .,School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA.
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Zuo Z, Liu Z, Gao T, Yin Y, Wang Z, Hou Y, Fu J, Liu S, Wang H, Xu Y, Pi J. Prolonged inorganic arsenic exposure via drinking water impairs brown adipose tissue function in mice. THE SCIENCE OF THE TOTAL ENVIRONMENT 2019; 668:310-317. [PMID: 30852208 DOI: 10.1016/j.scitotenv.2019.03.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 05/02/2023]
Abstract
Although epidemiologic studies show an association between long-term environmental inorganic arsenic (iAs) exposure and various disorders of glucose and lipid metabolism, the mechanisms of these ailments remain unclear. While white adipose tissue (WAT) essentially acts as a storage tissue for energy and is key to energy homeostasis, brown adipose tissue (BAT) consumes excess energy via uncoupling protein 1-mediated non-shivering thermogenesis in mitochondria and helps maintain the steady state of glucose and lipid metabolism. Our previous in vitro work found that iAs may inhibit adipogenesis and glucose uptake in adipocytes, leading us to hypothesize that chronic exposure to iAs in vivo may also affect the development and function of BAT, which plays a part in iAs-induced metabolic disorders. Thus, adult C57BL/6J female mice were provided drinking water containing 5 or 20 ppm of inorganic arsenicals (iAs3+ and iAs5+) for 17 weeks and control mice were given unaltered water. In these mice, iAs exposure induced cold intolerance and lipid accretion in BAT. In addition, iAs exposure impaired expression of various genes related to thermogenesis, mitochondrial function, adipocyte differentiation, as well as lipolysis in BAT of the exposed mice. These findings suggest a novel toxicity of iAs in BAT occurring via induction of BAT malfunction and impairment of thermogenesis. This novel toxicological linkage helps explain the mechanisms linking iAs exposure to increased risk of disorders of glucose and lipid metabolism.
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Affiliation(s)
- Zhuo Zuo
- Program of Environmental Toxicology, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China
| | - Zhiyuan Liu
- Program of Environmental Toxicology, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China
| | - Tianchang Gao
- Program of Environmental Toxicology, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China
| | - Yuanyuan Yin
- Program of Environmental Toxicology, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China
| | - Zhendi Wang
- Program of Environmental Toxicology, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China
| | - Yongyong Hou
- Program of Environmental Toxicology, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China.
| | - Jingqi Fu
- Program of Environmental Toxicology, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China
| | - Shengnan Liu
- Program of Environmental Toxicology, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China
| | - Huihui Wang
- Group of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China
| | - Yuanyuan Xu
- Group of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China
| | - Jingbo Pi
- Program of Environmental Toxicology, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China.
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