Skip to main content

Advertisement

SpringerLink
Log in

Heavy Metal Mediated Progressive Degeneration and Its Noxious Effects on Brain Microenvironment

  • Review
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Heavy metals, including lead (Pb), cadmium (Cd), arsenic (As), cobalt (Co), copper (Cu), manganese (Mn), zinc (Zn), and others, have a significant impact on the development and progression of neurodegenerative diseases in the human brain. This comprehensive review aims to consolidate the recent research on the harmful effects of different metals on specific brain cells such as neurons, microglia, astrocytes, and oligodendrocytes. Understanding the potential influence of these metals in neurodegeneration is crucial for effectively combating the ongoing advancement of these diseases. Metal-induced neurodegeneration involves molecular mechanisms such as apoptosis induction, dysregulation of metabolic and signaling pathways, metal imbalance, oxidative stress, loss of synaptic transmission, pathogenic peptide aggregation, and neuroinflammation. This review provides valuable insights by compiling the supportive evidence from recent research findings. Additionally, we briefly discuss the modes of action of natural neuroprotective compounds. While this comprehensive review aims to consolidate the recent research on the harmful effects of various metals on specific brain cells, it may not cover all studies and findings related to metal-induced neurodegeneration. Studies that are done using bioinformatics tools, microRNAs, long non-coding RNAs, emerging disease models, and studies based on the modes of exposure to toxic metals are a future prospect to be explored.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

Not applicable.

References

  1. Wareham LK, Liddelow SA, Temple S et al (2022) Solving neurodegeneration: common mechanisms and strategies for new treatments. Mol Neurodegener 17:1–29. https://doi.org/10.1186/s13024-022-00524-0

    Article  CAS  Google Scholar 

  2. Dugger BN, Dickson DW (2016) cshperspect-PRI-a028035.pdf. Cold Spring Harb Persepect Biol 9:1–22

    Google Scholar 

  3. Huang J, Li C, Shang H (2022) Astrocytes in neurodegeneration: inspiration from genetics. Front Neurosci 16:1–17. https://doi.org/10.3389/fnins.2022.882316

    Article  Google Scholar 

  4. Xu Y, Jin MZ, Yang ZY, Jin WL (2021) Microglia in neurodegenerative diseases. Neural Regen Res 16:270–280. https://doi.org/10.4103/1673-5374.290881

    Article  PubMed  CAS  Google Scholar 

  5. Andreone BJ, Larhammar M, Lewcock JW (2020) Cell death and neurodegeneration. Cold Spring Harb Perspect Biol 12(2):a036434. https://doi.org/10.1101/cshperspect.a036434

  6. Muddapu VR, Dharshini SAP, Chakravarthy VS, Gromiha MM (2020) Neurodegenerative diseases—is metabolic deficiency the root cause? Front Neurosci 14:1–19. https://doi.org/10.3389/fnins.2020.00213

    Article  Google Scholar 

  7. Kwon HS, Koh SH (2020) Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener 9:1–12. https://doi.org/10.1186/s40035-020-00221-2

    Article  Google Scholar 

  8. Bandaru LJM, Ayyalasomayajula N, Murumulla L et al (2022) Mechanisms associated with the dysregulation of mitochondrial function due to lead exposure and possible implications on the development of Alzheimer's disease. Biometals 35(1):1–25. https://doi.org/10.1007/s10534-021-00360-7

  9. Bellenguez C, Küçükali F, Jansen IE et al (2022) New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet 54:412–436. https://doi.org/10.1038/s41588-022-01024-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Stage E, Risacher SL, Lane KA et al (2022) Association of the top 20 Alzheimer’s disease risk genes with [18 F]flortaucipir PET. Alzheimer’s Dement Diagn, Assess Dis Monit 14:1–11. https://doi.org/10.1002/dad2.12308

    Article  Google Scholar 

  11. Gialluisi A, Reccia MG, Modugno N et al (2021) Identification of sixteen novel candidate genes for late onset Parkinson’s disease. Mol Neurodegener 16:1–18. https://doi.org/10.1186/s13024-021-00455-2

    Article  CAS  Google Scholar 

  12. Fang T, Je G, Pacut P et al (2022) Gene therapy in amyotrophic lateral sclerosis. Cells 11(13):2066. https://doi.org/10.3390/cells11132066

  13. Ayyalasomayajula N, Suresh C (2018) Mechanistic comparison of current pharmacological treatments and novel phytochemicals to target amyloid peptides in Alzheimer’s and neurodegenerative diseases. Nutr Neurosci 21:682–694. https://doi.org/10.1080/1028415X.2017.1345425

    Article  PubMed  CAS  Google Scholar 

  14. Tripathi PN, Srivastava P, Sharma P et al (2019) Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory. Bioorg Chem 85:82–96. https://doi.org/10.1016/j.bioorg.2018.12.017

    Article  PubMed  CAS  Google Scholar 

  15. Srivastava P, Tripathi PN, Sharma P et al (2019) Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory. Eur J Med Chem 163:116–135. https://doi.org/10.1016/j.ejmech.2018.11.049

    Article  PubMed  CAS  Google Scholar 

  16. Rai SN, Singh C, Singh A et al (2020) Mitochondrial dysfunction: a potential therapeutic target to treat Alzheimer’s disease. Mol Neurobiol 57:3075–3088. https://doi.org/10.1007/s12035-020-01945-y

    Article  PubMed  CAS  Google Scholar 

  17. Rai SN, Chaturvedi VK, Singh BK et al (2020) Commentary: trem2 deletion reduces late-stage amyloid plaque accumulation, elevates the aβ42:aβ40 ratio, and exacerbates axonal dystrophy and dendritic spine loss in the ps2app alzheimer's mouse model. Front Aging Neurosci 12:219. https://doi.org/10.3389/fnagi.2020.00219

  18. Maiti P, Manna J, Dunbar GL et al (2017) Current understanding of the molecular mechanisms in Parkinson’s disease: targets for potential treatments. Transl Neurodegener 6:1–35. https://doi.org/10.1186/s40035-017-0099-z

    Article  CAS  Google Scholar 

  19. Rai SN, Singh P (2020) Advancement in the modelling and therapeutics of Parkinson's disease. J Chem Neuroanat 104:101752. https://doi.org/10.1016/j.jchemneu.2020.101752

  20. Yadav SK, Rai SN, Singh SP (2017) Mucuna pruriens reduces inducible nitric oxide synthase expression in Parkinsonian mice model. J Chem Neuroanat 80:1–10. https://doi.org/10.1016/j.jchemneu.2016.11.009

    Article  PubMed  CAS  Google Scholar 

  21. Rai SN, Yadav SK, Singh D, Singh SP (2016) Ursolic acid attenuates oxidative stress in nigrostriatal tissue and improves neurobehavioral activity in MPTP-induced Parkinsonian mouse model. J Chem Neuroanat 71:41–49. https://doi.org/10.1016/j.jchemneu.2015.12.002

    Article  PubMed  CAS  Google Scholar 

  22. Prakash J, Chouhan S, Yadav SK et al (2014) Withania somnifera alleviates parkinsonian phenotypes by inhibiting apoptotic pathways in dopaminergic neurons. Neurochem Res 39:2527–2536. https://doi.org/10.1007/s11064-014-1443-7

    Article  PubMed  CAS  Google Scholar 

  23. Rojas P, Ramírez AI, Fernández-Albarral JA et al (2020) Amyotrophic lateral sclerosis: a neurodegenerative motor neuron disease with ocular involvement. Front Neurosci 14:566858. https://doi.org/10.3389/fnins.2020.566858

  24. Brown RC, Lockwood AH, Sonawane BR (2005) Neurodegenerative diseases: an overview of environmental risk factors. Environ Health Perspect 113:1250–1256. https://doi.org/10.1289/ehp.7567

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Nabi M, Tabassum N (2022) Role of Environmental Toxicants on Neurodegenerative Disorders. Front Toxicol 4:1–20. https://doi.org/10.3389/ftox.2022.837579

    Article  Google Scholar 

  26. He ZL, Yang XE, Stoffella PJ (2005) Trace elements in agroecosystems and impacts on the environment. J Trace Elem Med Biol 19:125–140. https://doi.org/10.1016/j.jtemb.2005.02.010

    Article  PubMed  CAS  Google Scholar 

  27. Zoroddu MA, Aaseth J, Crisponi G et al (2019) The essential metals for humans: a brief overview. J Inorg Biochem 195:120–129. https://doi.org/10.1016/j.jinorgbio.2019.03.013

    Article  PubMed  CAS  Google Scholar 

  28. Jomova K, Makova M, Alomar SY et al (2022) Essential metals in health and disease. Chem Biol Interact 367:110173. https://doi.org/10.1016/j.cbi.2022.110173

    Article  PubMed  CAS  Google Scholar 

  29. Martínez-Hernández MI, Acosta-Saavedra LC, Hernández-Kelly LC et al (2023) Microglial activation in metal neurotoxicity: impact in neurodegenerative diseases. Biomed Res Int 2023:7389508. https://doi.org/10.1155/2023/7389508

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Raj K, Kaur P, Gupta GD, Singh S (2021) Metals associated neurodegeneration in Parkinson’s disease: insight to physiological, pathological mechanisms and management. Neurosci Lett 753:135873. https://doi.org/10.1016/j.neulet.2021.135873

    Article  PubMed  CAS  Google Scholar 

  31. Oteiza PI, Mackenzie GG, Verstraeten SV (2004) Metals in neurodegeneration: involvement of oxidants and oxidant-sensitive transcription factors. Mol Aspects Med 25:103–115. https://doi.org/10.1016/j.mam.2004.02.012

    Article  PubMed  CAS  Google Scholar 

  32. Gerhardsson L, Blennow K, Lundh T et al (2009) Concentrations of metals, β-amyloid and tau-markers in cerebrospinal fluid in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 28:88–94. https://doi.org/10.1159/000233353

    Article  PubMed  CAS  Google Scholar 

  33. Fathabadi B, Dehghanifiroozabadi M, Aaseth J et al (2018) Comparison of blood lead levels in patients with Alzheimer’s disease and healthy people. Am J Alzheimers Dis Other Demen 33:541–547. https://doi.org/10.1177/1533317518794032

    Article  PubMed  Google Scholar 

  34. Szabo ST, Jean Harry G, Hayden KM et al (2016) Comparison of metal levels between postmortem brain and ventricular fluid in Alzheimer’s disease and nondemented elderly controls. Toxicol Sci 150:292–300. https://doi.org/10.1093/toxsci/kfv325

    Article  PubMed  CAS  Google Scholar 

  35. Calabrese G, Molzahn C, Mayor T (2022) Protein interaction networks in neurodegenerative diseases: from physiological function to aggregation. J Biol Chem 298:102062. https://doi.org/10.1016/j.jbc.2022.102062

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Zapadka KL, Becher FJ, Gomes Dos Santos AL et al (2017) Factors affecting the physical stability (aggregation) of peptide therapeutics. Interface Focus 7(6):20170030. https://doi.org/10.1098/rsfs.2017.0030

  37. Durst F, Tropea C (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608

    Article  Google Scholar 

  38. Poewe W, Seppi K, Tanner CM et al (2017) Parkinson disease. Nat Rev Dis Prim 3:1–21. https://doi.org/10.1038/nrdp.2017.13

    Article  Google Scholar 

  39. Foerster BR, Welsh RC, Feldman EL (2013) 25 years of neuroimaging in amyotrophic lateral sclerosis. Nat Rev Neurol 9:513–524. https://doi.org/10.1038/nrneurol.2013.153

    Article  PubMed  PubMed Central  Google Scholar 

  40. Uversky VN, Li J, Fink AL (2001) Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein: a possible molecular link between parkinson’s disease and heavy metal exposure. J Biol Chem 276:44284–44296. https://doi.org/10.1074/jbc.M105343200

    Article  PubMed  CAS  Google Scholar 

  41. Rana M, Sharma AK (2019) Cu and Zn interactions with Aβ peptides: consequence of coordination on aggregation and formation of neurotoxic soluble Aβ oligomers. Metallomics 11:64–84. https://doi.org/10.1039/c8mt00203g

    Article  PubMed  CAS  Google Scholar 

  42. Lee M, Kim JI, Na S, Eom K (2018) Metal ions affect the formation and stability of amyloid β aggregates at multiple length scales. Phys Chem Chem Phys 20:8951–8961. https://doi.org/10.1039/c7cp05072k

    Article  PubMed  CAS  Google Scholar 

  43. Boopathi S, Kolandaivel P (2016) Fe2+ binding on amyloid β-peptide promotes aggregation. Proteins Struct Funct Bioinforma 84:1257–1274. https://doi.org/10.1002/prot.25075

    Article  CAS  Google Scholar 

  44. Duroux C, Hagège A (2022) CE-ICP-MS to probe Aβ1–42/copper (II) interactions, a complementary tool to study amyloid aggregation in Alzheimer’s disease. Metallomics 14(1):mfab075. https://doi.org/10.1093/mtomcs/mfab075

  45. Basha MR, Murali M, Siddiqi HK et al (2005) Lead (Pb) exposure and its effect on APP proteolysis and Aβ aggregation. FASEB J 19:2083–2084. https://doi.org/10.1096/fj.05-4375fje

    Article  PubMed  CAS  Google Scholar 

  46. Wallin C, Sholts SB, Österlund N et al (2017) Alzheimer’s disease and cigarette smoke components: effects of nicotine, PAHs, and Cd(II), Cr(III), Pb(II), Pb(IV) ions on amyloid-β peptide aggregation. Sci Rep 7:1–14. https://doi.org/10.1038/s41598-017-13759-5

    Article  CAS  Google Scholar 

  47. Xie Y, Yu L, Fu Y et al (2021) Evaluating effect of metallic ions on aggregation behavior of β-amyloid peptides by atomic force microscope and surface-enhanced Raman Scattering. Biomed Eng Online 20:1–17. https://doi.org/10.1186/s12938-021-00972-7

    Article  Google Scholar 

  48. Moons R, Konijnenberg A, Mensch C et al (2020) Metal ions shape α-synuclein Sci Rep 10:1–13. https://doi.org/10.1038/s41598-020-73207-9

    Article  CAS  Google Scholar 

  49. Li Y, Yang C, Wang S et al (2020) Copper and iron ions accelerate the prion-like propagation of α-synuclein: a vicious cycle in Parkinson’s disease. Int J Biol Macromol 163:562–573. https://doi.org/10.1016/j.ijbiomac.2020.06.274

    Article  PubMed  CAS  Google Scholar 

  50. Lorentzon E, Horvath I, Kumar R et al (2021) Effects of the toxic metals arsenite and cadmium on α-synuclein aggregation in vitro and in cells. Int J Mol Sci 22(21):11455. https://doi.org/10.3390/ijms222111455

  51. Han JY, Choi TS, Kim HI (2018) Molecular role of Ca2+ and hard divalent metal cations on accelerated fibrillation and interfibrillar aggregation of α-synuclein. Sci Rep 8:1–11. https://doi.org/10.1038/s41598-018-20320-5

    Article  CAS  Google Scholar 

  52. Farace C, Fenu G, Lintas S et al (2020) Amyotrophic lateral sclerosis and lead: a systematic update. Neurotoxicology 81:80–88. https://doi.org/10.1016/j.neuro.2020.09.003

    Article  PubMed  CAS  Google Scholar 

  53. Ash PEA, Dhawan U, Boudeau S et al (2019) Heavy metal neurotoxicants induce ALS-Linked TDP-43 pathology. Toxicol Sci 167:3–4. https://doi.org/10.1093/toxsci/kfy267

    Article  CAS  Google Scholar 

  54. Golovin AV, Devred F, Yatoui D et al (2020) Zinc binds to RRM2 peptide of TDP-43. Int J Mol Sci 21:1–12. https://doi.org/10.3390/ijms21239080

    Article  CAS  Google Scholar 

  55. Leal SS, Cristóvão JS, Biesemeier A et al (2015) Aberrant zinc binding to immature conformers of metal-free copper-zinc superoxide dismutase triggers amorphous aggregation. Metallomics 7:333–346. https://doi.org/10.1039/c4mt00278d

    Article  PubMed  CAS  Google Scholar 

  56. Leal SS, Cardoso I, Valentine JS, Gomes CM (2013) Calcium ions promote superoxide dismutase 1 (SOD1) aggregation into non-fibrillar amyloid: a link to toxic effects of calcium overload in amyotrophic lateral sclerosis (ALS)? J Biol Chem 288:25219–25228. https://doi.org/10.1074/jbc.M113.470740

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Gu H, Wei X, Monnot AD et al (2011) Lead exposure increases levels of β-amyloid in the brain and CSF and inhibits LRP1 expression in APP transgenic mice. Neurosci Lett 490:16–20. https://doi.org/10.1016/j.neulet.2010.12.017

    Article  PubMed  CAS  Google Scholar 

  58. Gu H, Robison G, Hong L et al (2012) Increased β-amyloid deposition in Tg-SWDI transgenic mouse brain following in vivo lead exposure. Toxicol Lett 213:211–219. https://doi.org/10.1016/j.toxlet.2012.07.002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Zhou CC, Gao ZY, Wang J et al (2018) Lead exposure induces Alzheimers’s disease (AD)-like pathology and disturbes cholesterol metabolism in the young rat brain. Toxicol Lett 296:173–183. https://doi.org/10.1016/j.toxlet.2018.06.1065

    Article  PubMed  CAS  Google Scholar 

  60. Gassowska M, Baranowska-Bosiacka I, Moczydłowska J et al (2016) Perinatal exposure to lead (Pb) promotes Tau phosphorylation in the rat brain in a GSK-3β and CDK5 dependent manner: relevance to neurological disorders. Toxicology 347–349:17–28. https://doi.org/10.1016/j.tox.2016.03.002

    Article  PubMed  CAS  Google Scholar 

  61. Ayyalasomayajula N, Bandaru M, Dixit PK et al (2020) Inactivation of GAP-43 due to the depletion of cellular calcium by the Pb and amyloid peptide induced toxicity: an in vitro approach. Chem Biol Interact 316:108927. https://doi.org/10.1016/j.cbi.2019.108927

    Article  PubMed  CAS  Google Scholar 

  62. Neelima A, Rajanna A, Bhanuprakash RG et al (2017) Deleterious effects of combination of lead and β-Amyloid peptides in inducing apoptosis and altering cell cycle in human neuroblastoma cells. Interdiscip Toxicol 10:93–98. https://doi.org/10.1515/intox-2017-0015

    Article  PubMed  CAS  Google Scholar 

  63. Bandaru LJM, Ayyalasomayajula N, Murumulla L et al (2022) Defective mitophagy and induction of apoptosis by the depleted levels of PINK1 and Parkin in Pb and β-amyloid peptide induced toxicity. Toxicol Mech Methods 32:559–568. https://doi.org/10.1080/15376516.2022.2054749

    Article  PubMed  CAS  Google Scholar 

  64. Bandaru LJM, Murumulla L, C BL, et al (2023) Exposure of combination of environmental pollutant, lead (Pb) and β-amyloid peptides causes mitochondrial dysfunction and oxidative stress in human neuronal cells. J Bioenerg Biomembr. https://doi.org/10.1007/s10863-023-09956-9

    Article  PubMed  Google Scholar 

  65. Huang H, Jin Y, Chen C et al (2021) A toxicity pathway-based approach for modeling the mode of action framework of lead-induced neurotoxicity. Environ Res 199:111328. https://doi.org/10.1016/j.envres.2021.111328

    Article  PubMed  CAS  Google Scholar 

  66. Villa-Cedillo SA, Nava-Hernández MP, Soto-Domínguez A et al (2019) Neurodegeneration, demyelination, and astrogliosis in rat spinal cord by chronic lead treatment. Cell Biol Int 43:706–714. https://doi.org/10.1002/cbin.11147

    Article  PubMed  CAS  Google Scholar 

  67. Leão LKR, Bittencourt LO, Oliveira ACA et al (2021) Lead-induced motor dysfunction is associated with oxidative stress, proteome modulation, and neurodegeneration in motor cortex of rats. Oxid Med Cell Longev 2021:5595047. https://doi.org/10.1155/2021/5595047

  68. Bai L, Wu Y, Wang R et al (2022) Prepubertal exposure to Pb alters autophagy in the brain of aging mice: a time-series based model. Brain Res Bull 189:22–33. https://doi.org/10.1016/j.brainresbull.2022.08.013

    Article  PubMed  CAS  Google Scholar 

  69. Forcella M, Lau P, Oldani M et al (2020) Neuronal specific and non-specific responses to cadmium possibly involved in neurodegeneration: a toxicogenomics study in a human neuronal cell model. Neurotoxicology 76:162–173. https://doi.org/10.1016/j.neuro.2019.11.002

    Article  PubMed  CAS  Google Scholar 

  70. Pulido G, Treviño S, Brambila E et al (2019) The administration of cadmium for 2, 3 and 4 months causes a loss of recognition memory, promotes neuronal hypotrophy and apoptosis in the hippocampus of rats. Neurochem Res 44:485–497. https://doi.org/10.1007/s11064-018-02703-2

    Article  PubMed  CAS  Google Scholar 

  71. Zhang H, Dong X, Zhao R et al (2019) Cadmium results in accumulation of autophagosomes-dependent apoptosis through activating Akt-impaired autophagic flux in neuronal cells. Cell Signal 55:26–39. https://doi.org/10.1016/j.cellsig.2018.12.008

    Article  PubMed  CAS  Google Scholar 

  72. Xu C, Chen S, Xu M et al (2021) Cadmium impairs autophagy leading to apoptosis by Ca2+-dependent activation of JNK signaling pathway in neuronal cells. Neurochem Res 46:2033–2045. https://doi.org/10.1007/s11064-021-03341-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Khan A, Ikram M, Muhammad T et al (2019) Caffeine modulates cadmium-induced oxidative stress, neuroinflammation, and cognitive impairments by regulating Nrf-2/HO-1 in vivo and in vitro. J Clin Med 8:1–19. https://doi.org/10.3390/jcm8050680

    Article  CAS  Google Scholar 

  74. Wang T, Yuan Y, Zou H et al (2016) The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence. Sci Rep 6:1–14. https://doi.org/10.1038/srep38091

    Article  CAS  Google Scholar 

  75. Zheng F, Li Y, Zhang F et al (2021) Cobalt induces neurodegenerative damages through Pin1 inactivation in mice and human neuroglioma cells. J Hazard Mater 419:126378. https://doi.org/10.1016/j.jhazmat.2021.126378

    Article  PubMed  CAS  Google Scholar 

  76. Kumar V, Singh D, Singh BK et al (2018) Alpha-synuclein aggregation, Ubiquitin proteasome system impairment, and l-Dopa response in zinc-induced Parkinsonism: resemblance to sporadic Parkinson’s disease. Mol Cell Biochem 444:149–160. https://doi.org/10.1007/s11010-017-3239-y

    Article  PubMed  CAS  Google Scholar 

  77. Cong L, Lei MY, Liu ZQ et al (2021) Resveratrol attenuates manganese-induced oxidative stress and neuroinflammation through SIRT1 signaling in mice. Food Chem Toxicol 153:112283. https://doi.org/10.1016/j.fct.2021.112283

    Article  PubMed  CAS  Google Scholar 

  78. Morcillo P, Cordero H, Ijomone OM et al (2021) Defective mitochondrial dynamics underlie manganese-induced neurotoxicity. Mol Neurobiol 58:3270–3289. https://doi.org/10.1007/s12035-021-02341-w

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Lu Q, Zhang Y, Zhao C et al (2022) Copper induces oxidative stress and apoptosis of hippocampal neuron via pCREB/BDNF/ and Nrf2/HO-1/NQO1 pathway. J Appl Toxicol 42:694–705. https://doi.org/10.1002/JAT.4252

    Article  PubMed  CAS  Google Scholar 

  80. Sarawi WS, Alhusaini AM, Fadda LM et al (2021) Curcumin and nano-curcumin mitigate copper neurotoxicity by modulating oxidative stress, inflammation, and akt/gsk-3β signaling. Molecules 26(18):5591. https://doi.org/10.3390/molecules26185591

  81. Chakraborty J, Pakrashi S, Sarbajna A et al (2022) (2022) Quercetin attenuates copper-induced apoptotic cell death and endoplasmic reticulum stress in SH-SY5Y cells by autophagic modulation. Biol Trace Elem Res 20012(200):5022–5041. https://doi.org/10.1007/S12011-022-03093-X

    Article  Google Scholar 

  82. Tanaka KI, Kasai M, Shimoda M et al (2019) Nickel enhances zinc-induced neuronal cell death by priming the endoplasmic reticulum stress response. Oxid Med Cell Longev 2019:9693726. https://doi.org/10.1155/2019/9693726

  83. Tanaka KI, Shimoda M, Kasai M et al (2019) Involvement of SAPK/JNK signaling pathway in copper enhanced zinc-induced neuronal cell death. Toxicol Sci 169:293–302. https://doi.org/10.1093/toxsci/kfz043

    Article  PubMed  CAS  Google Scholar 

  84. Colonna M, Butovsky O (2017) Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 35:441–468. https://doi.org/10.1146/annurev-immunol-051116-052358

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Gilman S (2007) Neurobiology of disease. Neurobiol Dis 151:105260. https://doi.org/10.1016/B978-0-12-088592-3.X5000-2

    Article  Google Scholar 

  86. Baufeld C, O’Loughlin E, Calcagno N et al (2018) Differential contribution of microglia and monocytes in neurodegenerative diseases. J Neural Transm 125:809–826. https://doi.org/10.1007/s00702-017-1795-7

    Article  PubMed  CAS  Google Scholar 

  87. Xu Y, Zhao H, Wang Z et al (2022) Developmental exposure to environmental levels of cadmium induces neurotoxicity and activates microglia in zebrafish larvae: from the perspectives of neurobehavior and neuroimaging. Chemosphere 291:132802. https://doi.org/10.1016/J.CHEMOSPHERE.2021.132802

    Article  PubMed  CAS  Google Scholar 

  88. Xu Y, Liu J, Tian Y et al (2022) Wnt/β-catenin signaling pathway is strongly implicated in cadmium-induced developmental neurotoxicity and neuroinflammation: clues from zebrafish neurobehavior and in vivo neuroimaging. Int J Mol Sci 23:11434. https://doi.org/10.3390/ijms231911434

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Chauhan AK, Mittra N, Patel DK, Singh C (2018) Cyclooxygenase-2 directs microglial activation-mediated inflammation and oxidative stress leading to intrinsic apoptosis in Zn-induced Parkinsonism. Mol Neurobiol 55:2162–2173. https://doi.org/10.1007/s12035-017-0455-0

    Article  PubMed  CAS  Google Scholar 

  90. Langley MR, Shivani Ghaisas MA, Luo J et al (2019) Manganese exposure exacerbates progressive motor deficits and neurodegeneration in the MitoPark mouse model of Parkinson’s disease: relevance to gene and environment interactions in metal neurotoxicity. Neurotoxicology 64:240–255. https://doi.org/10.1016/j.neuro.2017.06.002.Manganese

    Article  Google Scholar 

  91. Yin L, Dai Q, Jiang P et al (2018) Manganese exposure facilitates microglial JAK2-STAT3 signaling and consequent secretion of TNF-a and IL-1β to promote neuronal death. Neurotoxicology 64:195–203. https://doi.org/10.1016/j.neuro.2017.04.001

    Article  PubMed  CAS  Google Scholar 

  92. Yan D, Gao L, Lang J et al (2021) Effects of manganese on microglia M1/M2 polarization and SIRT1-mediated transcription of STAT3-dependent genes in mouse. Environ Toxicol 36:1729–1741. https://doi.org/10.1002/tox.23294

    Article  PubMed  CAS  Google Scholar 

  93. Guo T, Liu C, Yang C et al (2022) Immunoproteasome subunit PSMB8 regulates microglia-mediated neuroinflammation upon manganese exposure by PERK signaling. Food Chem Toxicol 163:112951.  https://doi.org/10.1016/j.fct.2022.112951

  94. Li J, Deng Y, Peng D et al (2021) Sodium P-aminosalicylic acid attenuates manganese-induced neuroinflammation in BV2 microglia by modulating NF-κB pathway. Biol Trace Elem Res 199:4688–4699. https://doi.org/10.1007/s12011-021-02581-w

    Article  PubMed  CAS  Google Scholar 

  95. Liu X, Yao C, Tang Y et al (2022) Role of p53 methylation in manganese-induced cyclooxygenase-2 expression in BV2 microglial cells. Ecotoxicol Environ Saf 241:113824. https://doi.org/10.1016/j.ecoenv.2022.113824

    Article  PubMed  CAS  Google Scholar 

  96. Guan R, Wang T, Dong X et al (2022) Effects of co-exposure to lead and manganese on learning and memory deficits. J Environ Sci (China) 121:65–76. https://doi.org/10.1016/J.JES.2021.09.012

    Article  PubMed  CAS  Google Scholar 

  97. Kirkley KS, Popichak KA, Afzali MF et al (2017) Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity. J Neuroinflammation 14:0–17. https://doi.org/10.1186/s12974-017-0871-0

    Article  CAS  Google Scholar 

  98. Lang J, Gao L, Wu J et al (2022) Resveratrol attenuated manganese-induced learning and memory impairments in mice through PGC-1alpha-mediated autophagy and microglial M1/M2 polarization. Neurochem Res 47:3414–3427. https://doi.org/10.1007/s11064-022-03695-w

    Article  PubMed  CAS  Google Scholar 

  99. Yan D, Yang Y, Lang J et al (2023) SIRT1/FOXO3-mediated autophagy signaling involved in manganese-induced neuroinflammation in microglia. Ecotoxicol Environ Saf 256:114872. https://doi.org/10.1016/j.ecoenv.2023.114872

    Article  PubMed  CAS  Google Scholar 

  100. Hao W, Hao C, Wu C et al (2021) Aluminum impairs cognitive function by activating DDX3X-NLRP3-mediated pyroptosis signaling pathway. Food Chem Toxicol 157:112591. https://doi.org/10.1016/J.FCT.2021.112591

    Article  PubMed  CAS  Google Scholar 

  101. Peng J, Zhou F, Wang Y et al (2019) Differential response to lead toxicity in rat primary microglia and astrocytes. Toxicol Appl Pharmacol 363:64–71. https://doi.org/10.1016/j.taap.2018.11.010

    Article  PubMed  CAS  Google Scholar 

  102. Wu L, Li S, Pang S et al (2021) Effects of lead exposure on the activation of microglia in mice fed with high-fat diets. Environ Toxicol 36:1923–1931. https://doi.org/10.1002/tox.23312

    Article  PubMed  CAS  Google Scholar 

  103. Su P, Wang D, Cao Z et al (2021) The role of NLRP3 in lead-induced neuroinflammation and possible underlying mechanism. Environ Pollut 287:117520. https://doi.org/10.1016/j.envpol.2021.117520

  104. Zhu J, Zhou F, Zhou Q et al (2023) NLRP3 activation in microglia contributes to learning and memory impairment induced by chronic lead exposure in mice. Toxicol Sci 191:179–191. https://doi.org/10.1093/toxsci/kfac115

    Article  PubMed  CAS  Google Scholar 

  105. Lim SL, Rodriguez-Ortiz CJ, Hsu HW et al (2020) Chronic copper exposure directs microglia towards degenerative expression signatures in wild-type and J20 mouse model of Alzheimer’s disease. J Trace Elem Med Biol 62:126578. https://doi.org/10.1016/j.jtemb.2020.126578

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Zhou Q, Zhang Y, Lu L et al (2022) Copper induces microglia-mediated neuroinflammation through ROS/NF-κB pathway and mitophagy disorder. Food Chem Toxicol an Int J Publ Br Ind Biol Res Assoc 168:113369. https://doi.org/10.1016/j.fct.2022.113369

    Article  CAS  Google Scholar 

  107. Kenkhuis B, van Eekeren M, Parfitt DA et al (2022) Iron accumulation induces oxidative stress, while depressing inflammatory polarization in human iPSC-derived microglia. Stem Cell Reports 17:1351–1365. https://doi.org/10.1016/j.stemcr.2022.04.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Yauger YJ, Bermudez S, Moritz KE et al (2019) Iron accentuated reactive oxygen species release by NADPH oxidase in activated microglia contributes to oxidative stress in vitro. J Neuroinflammation 16:1–15. https://doi.org/10.1186/s12974-019-1430-7

    Article  Google Scholar 

  109. Nnah IC, Lee CH, Wessling-Resnick M (2020) Iron potentiates microglial interleukin-1β secretion induced by amyloid-β. J Neurochem 154:177–189. https://doi.org/10.1111/jnc.14906

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Siracusa R, Fusco R, Cuzzocrea S (2019) Astrocytes: role and functions in brain pathologies. Front Pharmacol 10:1–10. https://doi.org/10.3389/fphar.2019.01114

    Article  CAS  Google Scholar 

  111. Strohm L, Behrends C (2020) Glia-specific autophagy dysfunction in ALS. Semin Cell Dev Biol 99:172–182. https://doi.org/10.1016/J.SEMCDB.2019.05.024

    Article  PubMed  CAS  Google Scholar 

  112. Zhang Z, Yan J, Bowman AB et al (2020) Dysregulation of TFEB contributes to manganese-induced autophagic failure and mitochondrial dysfunction in astrocytes. Autophagy 16:1506–1523. https://doi.org/10.1080/15548627.2019.1688488

    Article  PubMed  CAS  Google Scholar 

  113. Hammond SL, Bantle CM, Popichak KA et al (2020) Nf-κb signaling in astrocytes modulates brain inflammation and neuronal injury following sequential exposure to manganese and mptp during development and aging. Toxicol Sci 177:506–520. https://doi.org/10.1093/toxsci/kfaa115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Ke T, Sidoryk-Wegrzynowicz M, Pajarillo E et al (2019) Role of astrocytes in manganese neurotoxicity revisited. Neurochem Res 44:2449–2459. https://doi.org/10.1007/s11064-019-02881-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Sarkar S, Malovic E, Harischandra DS et al (2018) Manganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes. Neurotoxicology 64:204–218. https://doi.org/10.1016/j.neuro.2017.05.009

    Article  PubMed  CAS  Google Scholar 

  116. Rizor A, Pajarillo E, Nyarko-Danquah I et al (2021) Manganese-induced reactive oxygen species activate IκB kinase to upregulate YY1 and impair glutamate transporter EAAT2 function in human astrocytes in vitro. Neurotoxicology 86:94–103. https://doi.org/10.1016/j.neuro.2021.07.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Rizor A, Pajarillo E, Son D-S et al (2022) Manganese phosphorylates Yin Yang 1 at serine residues to repress EAAT2 in human H4 astrocytes. Toxicol Lett 355:41–46. https://doi.org/10.1016/j.toxlet.2021.11.007

    Article  PubMed  CAS  Google Scholar 

  118. Pajarillo E, Demayo M, Digman A et al (2022) Deletion of RE1-silencing transcription factor in striatal astrocytes exacerbates manganese-induced neurotoxicity in mice. Glia 70:1886–1901. https://doi.org/10.1002/GLIA.24226

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Phuagkhaopong S, Ospondpant D, Kasemsuk T et al (2017) Cadmium-induced IL-6 and IL-8 expression and release from astrocytes are mediated by MAPK and NF-κB pathways. Neurotoxicology 60:82–91. https://doi.org/10.1016/j.neuro.2017.03.001

    Article  PubMed  CAS  Google Scholar 

  120. Ospondpant D, Phuagkhaopong S, Suknuntha K et al (2019) Cadmium induces apoptotic program imbalance and cell cycle inhibitor expression in cultured human astrocytes. Environ Toxicol Pharmacol 65:53–59. https://doi.org/10.1016/J.ETAP.2018.12.001

    Article  PubMed  CAS  Google Scholar 

  121. Kasemsuk T, Phuagkhaopong S, Yubolphan R et al (2020) Cadmium induces CCL2 production in glioblastoma cells via activation of MAPK, PI3K, and PKC pathways. J Immunotoxicol 17:186–193. https://doi.org/10.1080/1547691X.2020.1829211

    Article  PubMed  CAS  Google Scholar 

  122. Lim HJ, Park JH, Jo C et al (2019) Cigarette smoke extracts and cadmium induce COX-2 expression through γ-secretase-mediated p38 MAPK activation in C6 astroglia cells. Plos One 14:1–14. https://doi.org/10.1371/journal.pone.0212749

    Article  CAS  Google Scholar 

  123. Kushwaha R, Mishra J, Tripathi S et al (2018) Arsenic, cadmium, and lead like troglitazone trigger PPARγ-dependent poly (ADP-ribose) polymerase expression and subsequent apoptosis in rat brain astrocytes. Mol Neurobiol 55:2125–2149. https://doi.org/10.1007/s12035-017-0469-7

    Article  PubMed  CAS  Google Scholar 

  124. Fan S, Weixuan W, Han H et al (2023) Role of NF-κB in lead exposure-induced activation of astrocytes based on bioinformatics analysis of hippocampal proteomics. Chem Biol Interact 370:110310. https://doi.org/10.1016/j.cbi.2022.110310

    Article  PubMed  CAS  Google Scholar 

  125. Kalita J, Kumar V, Misra UK, Bora HK (2018) Memory and learning dysfunction following copper toxicity: biochemical and immunohistochemical basis. Mol Neurobiol 55:3800–3811. https://doi.org/10.1007/S12035-017-0619-Y

    Article  PubMed  CAS  Google Scholar 

  126. Laabbar W, Abbaoui A, Elgot A et al (2021) Aluminum induced oxidative stress, astrogliosis and cell death in rat astrocytes, is prevented by curcumin. J Chem Neuroanat 112:101915. https://doi.org/10.1016/j.jchemneu.2020.101915

  127. Yubolphan R, Phuagkhaopong S, Sangpairoj K et al (2021) Intracellular nickel accumulation induces apoptosis and cell cycle arrest in human astrocytic cells. Metallomics 13(1):mfaa006. https://doi.org/10.1093/mtomcs/mfaa006

  128. Yu F, Luo HR, Cui XF et al (2022) Changes in aggression and locomotor behaviors in response to zinc is accompanied by brain cell heterogeneity and metabolic and circadian dysregulation of the brain-liver axis. Ecotoxicol Environ Saf 248:114303. https://doi.org/10.1016/j.ecoenv.2022.114303

    Article  PubMed  CAS  Google Scholar 

  129. Maiuolo J, Macrì R, Bava I et al (2019) Myelin disturbances produced by sub-toxic concentration of heavy metals: the role of oligodendrocyte dysfunction. Int J Mol Sci 20(18):4554. https://doi.org/10.3390/ijms20184554

  130. Nam SM, Seo JS, Nahm SS et al (2019) Effects of ascorbic acid on osteopontin expression and axonal myelination in the developing cerebellum of lead-exposed rat pups. Int J Environ Res Public Health 16(6):983. https://doi.org/10.3390/ijerph16060983

  131. Latronico T, Fasano A, Fanelli M et al (2022) Lead exposure of rats during and after pregnancy induces anti-myelin proteolytic activity: a potential mechanism for lead-induced neurotoxicity. Toxicology 472:153179. https://doi.org/10.1016/J.TOX.2022.153179

    Article  PubMed  CAS  Google Scholar 

  132. Saedi S, Namavar MR, Shirazi MRJ et al (2022) Exposure to cadmium alters the population of glial cell types and disrupts the regulatory mechanisms of the HPG Axis in prepubertal female rats. Neurotox Res 40:1029–1042. https://doi.org/10.1007/s12640-022-00516-4

    Article  PubMed  CAS  Google Scholar 

  133. Pandey S, Sharma V, Chaudhary AK (2016) Chelation therapy and chelating agents of Ayurveda. Int J Green Pharm 10:143–150. https://doi.org/10.22377/IJGP.V10I03.672

    Article  CAS  Google Scholar 

  134. Kim JJ, Kim YS, Kumar V (2019) Heavy metal toxicity: an update of chelating therapeutic strategies. J Trace Elem Med Biol 54:226–231. https://doi.org/10.1016/j.jtemb.2019.05.003

    Article  PubMed  CAS  Google Scholar 

  135. Lobo V, Patil A, Phatak A, Chandra N (2010) Free radicals, antioxidants and functional foods: impact on human health. Pharmacogn Rev 4:118–126. https://doi.org/10.4103/0973-7847.70902

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Lakey-Beitia J, Burillo AM, La Penna G et al (2021) Polyphenols as potential metal chelation compounds against Alzheimer’s disease. J Alzheimers Dis 82:S335–S357. https://doi.org/10.3233/JAD-200185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Chen B, Zhao J, Zhang R et al (2022) Neuroprotective effects of natural compounds on neurotoxin-induced oxidative stress and cell apoptosis. Nutr Neurosci 25:1078–1099. https://doi.org/10.1080/1028415X.2020.1840035

    Article  PubMed  CAS  Google Scholar 

  138. Ayyalasomayajula N, Bandaru LJM, Chetty CS et al (2022) Mitochondria-mediated moderation of apoptosis by EGCG in cytotoxic neuronal cells induced by lead (Pb) and amyloid peptides. Biol Trace Elem Res 200:3582–3593. https://doi.org/10.1007/s12011-021-02959-w

    Article  PubMed  CAS  Google Scholar 

  139. Ayyalasomayajula N, Ajumeera R, Chellu CS, Challa S (2019) Mitigative effects of epigallocatechin gallate in terms of diminishing apoptosis and oxidative stress generated by the combination of lead and amyloid peptides in human neuronal cells. J Biochem Mol Toxicol 33:1–9. https://doi.org/10.1002/jbt.22393

    Article  CAS  Google Scholar 

  140. Abubakar K, Mailafiya MM, Danmaigoro A et al (2019) Curcumin attenuates lead-induced cerebellar toxicity in rats via chelating activity and inhibition of oxidative stress. Biomolecules 9(9):453. https://doi.org/10.3390/biom9090453

  141. Tamegart L, Abbaoui A, El Khiat A et al (2019) Altered nigrostriatal dopaminergic and noradrenergic system prompted by systemic lead toxicity versus a treatment by curcumin-III in the desert rodent Meriones shawi. Comptes Rendus - Biol 342:192–198. https://doi.org/10.1016/j.crvi.2019.07.004

    Article  Google Scholar 

  142. Changlek S, Rana MN, Phyu MP et al (2022) Curcumin suppresses lead-induced inflammation and memory loss in mouse model and in silico molecular docking. Foods 11:1–15. https://doi.org/10.3390/foods11060856

    Article  CAS  Google Scholar 

  143. Yang Y, Liu Y, Zhang AL et al (2022) Curcumin protects against manganese-induced neurotoxicity in rat by regulating oxidative stress-related gene expression via H3K27 acetylation. Ecotoxicol Environ Saf 236:113469. https://doi.org/10.1016/j.ecoenv.2022.113469

    Article  PubMed  CAS  Google Scholar 

  144. Oria RS, Anyanwu GE, Esom EA et al (2023) Modulatory role of curcumin on cobalt-induced memory deficit, hippocampal oxidative damage, astrocytosis, and Nrf2 expression. Neurotox Res 41:201–211. https://doi.org/10.1007/s12640-023-00635-6

    Article  PubMed  CAS  Google Scholar 

  145. Paduraru E, Flocea EI, Lazado CC et al (2021) Vitamin c mitigates oxidative stress and behavioral impairments induced by deltamethrin and lead toxicity in zebrafish. Int J Mol Sci 22(23):12714. https://doi.org/10.3390/ijms222312714

  146. Ji X, Wang B, Paudel YN et al (2021) Protective effect of chlorogenic acid and its analogues on lead-induced developmental neurotoxicity through modulating oxidative stress and autophagy. Front Mol Biosci 8:1–14. https://doi.org/10.3389/fmolb.2021.655549

    Article  CAS  Google Scholar 

  147. Yang L, Shen K, Ji D (2020) Natural compounds attenuate heavy metal-induced PC12 cell damage. J Int Med Res 48(6):300060520930847. https://doi.org/10.1177/0300060520930847

  148. Qu L, Xu H, Jia W et al (2019) Rosmarinic acid protects against MPTP-induced toxicity and inhibits iron-induced α-synuclein aggregation. Neuropharmacology 144:291–300. https://doi.org/10.1016/j.neuropharm.2018.09.042

    Article  PubMed  CAS  Google Scholar 

  149. AI Olayan EM, Aloufi AS, AlAmri OD et al (2020) Protocatechuic acid mitigates cadmium-induced neurotoxicity in rats: role of oxidative stress, inflammation and apoptosis. Sci Total Environ 723:137969. https://doi.org/10.1016/J.SCITOTENV.2020.137969

    Article  Google Scholar 

  150. Samad N, Jabeen S, Imran I et al (2019) (2019) Protective effect of gallic acid against arsenic-induced anxiety−/depression-like behaviors and memory impairment in male rats. Metab Brain Dis 344(34):1091–1102. https://doi.org/10.1007/S11011-019-00432-1

    Article  Google Scholar 

  151. Zubčić K, Radovanović V, Vlainić J et al (2020) PI3K/Akt and ERK1/2 signalling are involved in quercetin-mediated neuroprotection against copper-induced injury. Oxid Med Cell Longev 2020:9834742. https://doi.org/10.1155/2020/9834742

  152. Suryavanshi J, Prakash C, Sharma D (2022) Asiatic acid attenuates aluminium chloride-induced behavioral changes, neuronal loss and astrocyte activation in rats. Metab Brain Dis 37:1773–1785. https://doi.org/10.1007/S11011-022-00998-3

    Article  PubMed  CAS  Google Scholar 

  153. Wang H, Shao B, Yu H et al (2019) Neuroprotective role of hyperforin on aluminum maltolate-induced oxidative damage and apoptosis in PC12 cells and SH-SY5Y cells. Chem Biol Interact 299:15–26. https://doi.org/10.1016/j.cbi.2018.11.016

    Article  PubMed  CAS  Google Scholar 

  154. Caputo L, Piccialli I, Ciccone R et al (2021) Lavender and coriander essential oils and their main component linalool exert a protective effect against amyloid-β neurotoxicity. Phyther Res 35:486–493. https://doi.org/10.1002/ptr.6827

    Article  CAS  Google Scholar 

  155. Li L, Li WJ, Zheng XR et al (2022) Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation. Mol Med 28(1):11. https://doi.org/10.1186/s10020-022-00442-3

  156. Ferrucci M, Busceti CL, Lazzeri G et al (2022) Bacopa protects against neurotoxicity induced by MPP+ and methamphetamine. Molecules 27(16):5204. https://doi.org/10.3390/molecules27165204

  157. Dawson TM, Golde TE, Lagier-Tourenne C (2018) Animal models of neurodegenerative diseases. Nat Neurosci 21:1370–1379. https://doi.org/10.1038/s41593-018-0236-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Paduraru E, Iacob D, Rarinca V et al (2023) Zebrafish as a potential model for neurodegenerative diseases: a focus on toxic metals implications. Int J Mol Sci 24(4):3428. https://doi.org/10.3390/ijms24043428

  159. Ferreira GS, Veening-Griffioen DH, Boon WPC et al (2020) Levelling the translational gap for animal to human efficacy data. Animals (Basel) 10(7):1199. https://doi.org/10.3390/ani10071199

  160. Gonzalez-Alvarez MA, Hernandez-Bonilla D, Plascencia-Alvarez NI et al (2022) Environmental and occupational exposure to metals (manganese, mercury, iron) and Parkinson’s disease in low and middle-income countries: a narrative review. Rev Environ Health 37:1–11. https://doi.org/10.1515/reveh-2020-0140

    Article  PubMed  CAS  Google Scholar 

  161. Newell ME, Adhikari S, Halden RU (2022) Systematic and state-of the science review of the role of environmental factors in Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig’s Disease. Sci Total Environ 817:152504. https://doi.org/10.1016/j.scitotenv.2021.152504

    Article  PubMed  CAS  Google Scholar 

  162. Motataianu A, Serban G, Barcutean L et al (2022) Oxidative stress in amyotrophic lateral sclerosis: synergy of genetic and environmental factors. Int J Mol Sci 23(16):9339. https://doi.org/10.3390/ijms23169339

  163. Hester K, Kirrane E, Anderson T et al (2022) Environmental exposure to metals and the development of tauopathies, synucleinopathies, and TDP-43 proteinopathies: a systematic evidence map protocol. Environ Int 169:107528. https://doi.org/10.1016/j.envint.2022.107528

    Article  PubMed  CAS  Google Scholar 

  164. Vellingiri B, Suriyanarayanan A, Selvaraj P et al (2022) Role of heavy metals (copper (Cu), arsenic (As), cadmium (Cd), iron (Fe) and lithium (Li)) induced neurotoxicity. Chemosphere 301:134625. https://doi.org/10.1016/j.chemosphere.2022.134625

    Article  PubMed  CAS  Google Scholar 

  165. Wu L, Cui F, Zhang S et al (2023) Associations between multiple heavy metals exposure and neural damage biomarkers in welders: a cross-sectional study. Sci Total Environ 869:161812. https://doi.org/10.1016/j.scitotenv.2023.161812

    Article  PubMed  CAS  Google Scholar 

  166. Babić Leko M, Mihelčić M, Jurasović J, et al (2022) Heavy metals and essential metals are associated with cerebrospinal fluid biomarkers of Alzheimer’s disease. Int J Mol Sci 24:. https://doi.org/10.3390/ijms24010467

Download references

Acknowledgements

We thank the Indian Council of Medical Research (ICMR) for providing funds to carry out research and the University grants commission (UGC), Government of India for the award of fellowship.

Funding

This work was supported by the Grant 58/57/2012-BMS funded by the Indian Council of Medical Research (ICMR).

Author information

Authors and Affiliations

  1. Cell Biology Division, National Institute of Nutrition, Indian Council of Medical Research (ICMR), Hyderabad-500007, Hyderabad, Telangana, India

    Lokesh Murumulla, Lakshmi Jaya Madhuri Bandaru & Suresh Challa

Authors
  1. Lokesh Murumulla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lakshmi Jaya Madhuri Bandaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suresh Challa
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ML performed the literature search, analysis and drafted the work. SC proposed the idea and critically revised the work. LJMB helped in editing and revision of the final draft.

Corresponding author

Correspondence to Suresh Challa.

Ethics declarations

Ethics Approval

Not applicable

Consent to Participate

Not applicable

Consent for Publication

Not applicable

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Authors 1 and 2 do not have institutional mail ID

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Murumulla, L., Bandaru, L.J.M. & Challa, S. Heavy Metal Mediated Progressive Degeneration and Its Noxious Effects on Brain Microenvironment. Biol Trace Elem Res 202, 1411–1427 (2024). https://doi.org/10.1007/s12011-023-03778-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-023-03778-x

Search

Navigation