Skip to main content
SpringerLink
Log in

Linking Arsenic, DNA Methylation Biomarkers, and Transgenerational Neurotoxicity: Modeling in Zebrafish

  • Living reference work entry
  • First Online:
Biomarkers in Toxicology

Abstract

Epigenetic mechanisms play a crucial role in maintaining nervous system functions, and dysregulation has been related to the development of neurological disorders. The factors that induce these alterations are diverse, but in recent years the role of environmental pollutants has been the subject of intense study. Arsenic (As) is a ubiquitous neurotoxicant in the environment that has been recognized for decades as a deregulator of epigenetic processes inducing DNA methylation modifications in animal models and humans. As can alter methylation at the promoter of neural genes and cause changes in their expression level and potentially could be transmitted to subsequent generations. However, transgenerational toxicity studies with arsenic and other contaminants remain very scarce in the literature. The zebrafish is an emerging model with qualities such as rapid and inexpensive generation and represents an opportunity to increase knowledge about the mechanisms of transgenerational transmission associated with exposure to pollutants. In this chapter, we review some relevant aspects of modeling the transgenerational effect of arsenic by using epigenetic biomarkers associated with DNA methylation. Recommendations are made for obtaining generations; also some specific gene biomarkers of interest are proposed as some cost-effective methodologies for the analysis.

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

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

Abbreviations

As:

Arsenic

As/L:

Arsenic per liter

AS3MT:

Arsenite methyltransferase

AsIII:

Trivalent arsenic/arsenite

AsV:

Pentavalent arsenic/arsenate

BDNF:

Brain-derived neurotrophic factor

CNS:

Central nervous system

CpG:

Cytosine guanine dinucleotide

Darpp-32:

Dopamine- and cAMP-regulated neuronal phosphoprotein

DML:

Differentially methylated loci

DMRs:

Differentially methylated regions

DNMTs:

DNA methyltransferases

ELISA:

Enzyme-linked immunosorbent assay

F0:

Parental generation

F1/F2/F3:

Offspring generations

H3K27ac:

Histone 3 lysine 27 acetylation

H3K4me3:

Histone 3 lysine 4 trimethylation

HPLC:

High-performance liquid chromatography

HPTMs:

Histone posttranslational modifications

LC-MS/MS:

Liquid chromatography-mass spectrometry

LTP:

Long-term potentiation

LUMA:

Luminometric methylation assay

MAsIII:

Monomethylarsenite

MBP:

Myelin basic protein

MMA:

Monomethylarsonic acid

MSP:

Methylation-specific PCR

NaAsO2:

Sodium arsenite

PP1:

Phosphatase 1

PPP1R1B:

Protein phosphatase 1 regulatory subunit 1B

qRT-PCR:

Quantitative real-time polymerase chain reaction

RELN:

Reelin

SAM:

S-Adenosylmethionine

TEI:

Transgenerational epigenetic inheritance

Tm:

Melting temperature

TrkB:

Tropomyosin-related receptor kinase B

5hmC:

5-Hydroxymethylcytosine

5mC:

5-Methylcytosine

References

  • Bailey KA, Fry RC. Arsenic-associated changes to the epigenome: what are the functional consequences? Current Environ Health Rep. 2014;1:23–34.

    Google Scholar 

  • Bardullas U, Limón-Pacheco JH, Giordano M, et al. Chronic low-level arsenic exposure causes gender-specific alterations in locomotor activity, dopaminergic systems, and thioredoxin expression in mice. Toxicol Appl Pharmacol. 2009;239(2):169–77.

    CAS  PubMed  Google Scholar 

  • Blake GE, Watson ED. Unravelling the complex mechanisms of transgenerational epigenetic inheritance. Curr Opin Chem Biol. 2016;33:101–7.

    CAS  PubMed  Google Scholar 

  • Bozack AK, Domingo-Relloso A, Haack K, et al. Locus-specific differential DNA methylation and urinary arsenic: an epigenome-wide association study in blood among adults with low-to-moderate arsenic exposure. Environ Health Perspect. 2020;128:067015.

    CAS  PubMed Central  Google Scholar 

  • Brandes JC, Carraway H, Herman JG. Optimal primer design using the novel primer design program: MSPprimer provides accurate methylation analysis of the ATM promoter. Oncogene. 2007;26(42):6229–37.

    CAS  PubMed  Google Scholar 

  • Bridges RJ, Natale NR, Patel SA. System Xc− cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol. 2012;165(1):20–34.

    Google Scholar 

  • Brinkel J, Khan M, Kraemer A. A systematic review of arsenic exposure and its social and mental health effects with special reference to Bangladesh. Int J Environ Res Public Health. 2009;6(5):1609–19.

    PubMed  PubMed Central  Google Scholar 

  • Calderón J, Navarro ME, Jimenez-Capdeville ME, et al. Exposure to arsenic and Lead and neuropsychological development in Mexican children. Environ Res. 2001;85(2):69–76.

    PubMed  Google Scholar 

  • Campagnoni AT. Molecular biology of myelin proteins from the central nervous system. J Neurochem. 1988;51(1):1–14.

    CAS  PubMed  Google Scholar 

  • Caputo V, Sinibaldi L, Fiorentino A, et al. Brain derived neurotrophic factor (BDNF) expression is regulated by MicroRNAs miR-26a and miR-26b allele-specific binding. PLoS One. 2011;6(12):e28656.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Carone BR, Fauquier L, Habib N, et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell J. 2010;143(7):1084–96.

    CAS  Google Scholar 

  • Chen K-W, Chen L. Epigenetic regulation of BDNF gene during development and diseases. Internat J Mol Sci. 2017;18(3):571.

    Google Scholar 

  • Concha G. Exposure to inorganic arsenic metabolites during early human development. Toxicol Sci. 1998;44(2):185–90.

    CAS  PubMed  Google Scholar 

  • Coral JA, Heaps S, Glaholt SP, et al. Arsenic exposure induces a bimodal toxicity response in zebrafish. Environ Pollut. 2021;287:117637.

    CAS  PubMed  Google Scholar 

  • Delcourt J, Ovidio M, Denoël M, et al. Individual identification and marking techniques for zebrafish. Rev Fish Biol Fish. 2018;28(4):839–64.

    Google Scholar 

  • Dipp VR, Valles S, Ortiz-Kerbertt H, et al. Neurobehavioral alterations in zebrafish due to long-term exposure to low doses of inorganic arsenic. Zebrafish. 2018;15(6):575–85.

    CAS  PubMed  Google Scholar 

  • Du X, Tian M, Wang X, et al. Cortex and hippocampus DNA epigenetic response to a long-term arsenic exposure via drinking water. Environ Pollut. 2018;234:590–600.

    CAS  PubMed  Google Scholar 

  • Eads CA, Danenberg KD, Kawakami K, et al. MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res. 2000;28(8):32e–0.

    Google Scholar 

  • Fan X, Hou T, Guan Y, et al. Genomic responses of DNA methylation and transcript profiles in zebrafish cells upon nutrient deprivation stress. Nucleic Acids Res. 2020;722:137980.

    CAS  Google Scholar 

  • Farzan SF, Karagas MR, Chen Y. In utero and early life arsenic exposure in relation to long-term health and disease. Toxicol Appl Pharmacol. 2013;272(2):384–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ghosh S, Yates AJ, Frühwald MC, et al. Tissue specific DNA methylation of CpG islands in normal human adult somatic tissues distinguishes neural from non-neural tissues. Epigenetics. 2010;5(6):527:538.

    PubMed Central  Google Scholar 

  • Gillette R, Miller-Crews I, Nilsson EE, et al. Sexually dimorphic effects of ancestral exposure to Vinclozolin on stress reactivity in rats. Endocrinology. 2014;155(10):3853–66.

    PubMed  PubMed Central  Google Scholar 

  • Gliga AR, Engström K, Kippler M, et al. Prenatal arsenic exposure is associated with increased plasma IGFBP3 concentrations in 9-year-old children partly via changes in DNA methylation. Arch Toxicol. 2018;92(8):2487–500.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gong Y, Xue Y, Li X, et al. Inter- and transgenerational effects of paternal exposure to inorganic arsenic. Adv Sci. 2021;8(7):2002715.

    CAS  Google Scholar 

  • Guidotti A, Grayson DR, Caruncho HJ. Epigenetic RELN dysfunction in schizophrenia and related neuropsychiatric disorders. Front Cell Neurosci. 2016;10

    Google Scholar 

  • Guo X, Chen X, Wang J, et al. Multi-generational impacts of arsenic exposure on genome-wide DNA methylation and the implications for arsenic-induced skin lesions. Environ Int. 2018;119:250–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hamdi M, Sanchez MA, Beene LC, et al. Arsenic transport by zebrafish aquaglyceroporins. BMC Mol Biol. 2009;10(1):104.

    PubMed  PubMed Central  Google Scholar 

  • Hamdi M, Yoshinaga M, Packianathan C, et al. Identification of an S-adenosylmethionine (SAM) dependent arsenic methyltransferase in Danio rerio. Toxicol Appl Pharmacol. 2012;262(2):185–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heinrich G, Pagtakhan C. Both 5′ and 3′ flanks regulate zebrafish brain-derived neurotrophic factor gene expression. BMC Neurosci. 2004;5:19.

    PubMed  PubMed Central  Google Scholar 

  • Herman JG, Graff JR, Myohanen S, et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci. 1996;93(18):9821–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ikegame T, Bundo M, Murata Y, et al. DNA methylation of the BDNF gene and its relevance to psychiatric disorders. J Human Genet. 2013;58(7):434–8.

    CAS  Google Scholar 

  • Kamstra JH, Hurem S, Martin LM, et al. Ionizing radiation induces transgenerational effects of DNA methylation in zebrafish. Sci Rep. 2018;8(1):15373.

    PubMed  PubMed Central  Google Scholar 

  • Karim Y, Siddique AE, Hossen F, et al. Dose-dependent relationships between chronic arsenic exposure and cognitive impairment and serum brain-derived neurotrophic factor. Environ Int. 2019;131:105029.

    CAS  PubMed  Google Scholar 

  • Karpova NN. Role of BDNF epigenetics in activity-dependent neuronal plasticity. Neuropharmacology. 2014;76:709–18.

    CAS  PubMed  Google Scholar 

  • Kim S, Lim IK, Park G-H, et al. Biological methylation of myelin basic protein: enzymology and biological significance. Int J Biochem Cell Biol. 1997;29(5):743–51.

    CAS  PubMed  Google Scholar 

  • Kinniburgh D, Kosmus W. Arsenic contamination in groundwater: some analytical considerations. Talanta. 2002;58(1):165–80.

    CAS  PubMed  Google Scholar 

  • Koppula P, Zhang Y, Zhuang L, et al. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun. 2018;38(1):12.

    Google Scholar 

  • Kordas K, Ardoino G, Coffman DL, et al. Patterns of exposure to multiple metals and associations with neurodevelopment of preschool children from Montevideo, Uruguay. J Environ Public Health. 2015;2015:1–9.

    Google Scholar 

  • Kurdyukov S, Bullock M. DNA methylation analysis: choosing the right method. Biology. 2016;5(1):3.

    PubMed Central  Google Scholar 

  • Ladd-Acosta C, Pevsner J, Sabunciyan S, et al. DNA methylation signatures within the human brain. Am J Hum Genet. 2007;81(6):1304–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Landgrave-Gómez J, Mercado-Gómez O, Guevara-Guzmán R. Epigenetic mechanisms in neurological and neurodegenerative diseases. Front Cell Neurosci. 2015;9:58.

    PubMed  PubMed Central  Google Scholar 

  • Li J, Guo Y, Duan X, et al. Tissue- and region-specific accumulation of arsenic species, especially in the brain of mice, after long-term Arsenite exposure in drinking water. Biol Trace Elem Res. 2020;198(1):168–76.

    CAS  PubMed  Google Scholar 

  • Lo PK, Watanabe H, Cheng PC, et al. MethySYBR, a novel quantitative PCR assay for the dual analysis of DNA methylation and CpG methylation density. J Mol Diagn. 2009;11(5):400–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  • López-Carrillo L, Hernández-Ramírez RU, Gandolfi AJ, et al. Arsenic methylation capacity is associated with breast cancer in northern Mexico. Toxicol Appl Pharmacol. 2014;280(1):53–9.

    PubMed  Google Scholar 

  • Manikkam M, Guerrero-Bosagna C, Tracey R, et al. Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS One. 2012;7(2):e31901.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martin SC, Marazzi G, Sandell JH, Heinrich G. Five Trk receptors in the zebrafish. Dev Biol. 1995;169(2):745–58.

    CAS  PubMed  Google Scholar 

  • Martínez L, Jiménez V, García-Sepúlveda C, et al. Impact of early developmental arsenic exposure on promotor CpG-island methylation of genes involved in neuronal plasticity. Neurochem Int. 2011;58(5):574–81.

    PubMed  Google Scholar 

  • Miranda TB, Jones PA. DNA methylation: the nuts and bolts of repression. J Cell Physiol. 2007;213(2):384–90.

    CAS  PubMed  Google Scholar 

  • Mitchelmore C, Gede L. Brain derived neurotrophic factor: epigenetic regulation in psychiatric disorders. Brain Res. 2014;1586:162–72.

    CAS  PubMed  Google Scholar 

  • Moonat S, Pandey SC. Stress, epigenetics, and alcoholism. Alcohol Res. 2012;34(4):495–505.

    PubMed  PubMed Central  Google Scholar 

  • Mueller T, Wullimann MF. Atlas of early zebrafish brain development. Second. Elsevier; 2016.

    Google Scholar 

  • Munton RP, Vizi S, Mansuy IM. The role of protein phosphatase-1 in the modulation of synaptic and structural plasticity. FEBS Lett. 2004;567(1):121–8.

    CAS  PubMed  Google Scholar 

  • Nava-Rivera LE, Betancourt-Martínez ND, Lozoya-Martínez R, et al. Transgenerational effects in DNA methylation, genotoxicity and reproductive phenotype by chronic arsenic exposure. Sci Rep. 2021;11(1):8276.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Niño SA, Chi-Ahumada E, Ortíz J, et al. Demyelination associated with chronic arsenic exposure in Wistar rats. Toxicol Appl Pharmacol. 2020;393:114955.

    PubMed  Google Scholar 

  • Olivares CI, Field JA, Simonich M, et al. Arsenic (III, V), indium (III), and gallium (III) toxicity to zebrafish embryos using a high-throughput multi-endpoint in vivo developmental and behavioral assay. Chemosphere. 2016;148:361–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ortega-Recalde O, Day RC, Gemmell NJ, et al. Zebrafish preserve global germline DNA methylation while sex-linked rDNA is amplified and demethylated during feminisation. Nat Commun. 2019;10(1):3053.

    PubMed  PubMed Central  Google Scholar 

  • Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10):1057–68.

    CAS  PubMed  Google Scholar 

  • Ramos-Chávez LA, Rendón-López CRR, Zepeda A, et al. Neurological effects of inorganic arsenic exposure: altered cysteine/glutamate transport, NMDA expression and spatial memory impairment. Front Cell Neurosci. 2015;9

    Google Scholar 

  • Ravenscroft P, Brammer H, Richards KS. Arsenic pollution: a global synthesis. Wiley-Blackwell; 2009. https://doi.org/10.1002/9781444308785.

    Book  Google Scholar 

  • Rodríguez V. The effects of arsenic exposure on the nervous system. Toxicol Lett. 2003;145(1):1–18.

    PubMed  Google Scholar 

  • Rosado JL, Ronquillo D, Kordas K, et al. Arsenic exposure and cognitive performance in Mexican schoolchildren. Environ Health Perspect. 2007;115(9):1371–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Santoyo MM, Flores CR, Torres AL, et al. Global DNA methylation in earthworms: a candidate biomarker of epigenetic risks related to the presence of metals/metalloids in terrestrial environments. Environ Pollut. 2011;159(10):2387–92.

    CAS  PubMed  Google Scholar 

  • Sato H, Shiiya A, Kimata M, et al. Redox imbalance in Cystine/Glutamate transporter-deficient Mice. J Biol Chem. 2005;280(45):37423–9.

    CAS  PubMed  Google Scholar 

  • Šestáková Š, Šálek C, Remešová H. DNA methylation validation methods: a coherent review with practical comparison. Biol Proc Online. 2019;21(1):19.

    Google Scholar 

  • Simner C, Novakovic B, Lillycrop KA, et al. DNA methylation of amino acid transporter genes in the human placenta. Placenta. 2017;60:64–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Srivastava P, Dhuriya YK, Gupta R, et al. Protective effect of curcumin by modulating BDNF/DARPP32/CREB in arsenic-induced alterations in dopaminergic signaling in rat corpus striatum. Mol Neurobiol. 2018;55(1):445–61.

    CAS  PubMed  Google Scholar 

  • Teng M, Chen X, Wang C, et al. Life cycle exposure to propiconazole reduces fecundity by disrupting the steroidogenic pathway and altering DNA methylation in zebrafish (Danio rerio). Environ Int. 2020;135:105384.

    CAS  PubMed  Google Scholar 

  • Tsai S-Y, Chou H-Y, The H-W, et al. The effects of chronic arsenic exposure from drinking water on the neurobehavioral development in adolescence. Neurotoxicology. 2003;24(4–5):747–53.

    CAS  PubMed  Google Scholar 

  • Tuscher JJ, Day JJ. Multigenerational epigenetic inheritance: one step forward, two generations back. Neurobiol Dis. 2019;132:104591.

    CAS  PubMed  Google Scholar 

  • Valles S, Hernández-Sánchez J, Dipp VR, et al. Exposure to low doses of inorganic arsenic induces transgenerational changes on behavioral and epigenetic markers in zebrafish (Danio rerio). Toxicol Appl Pharmacol. 2020;396:115002.

    CAS  PubMed  Google Scholar 

  • Williams TD, Mirbahai L, Chipman JK. The toxicological application of transcriptomics and epigenomics in zebrafish and other teleosts. Brief Funct Genom. 2014;13(2):157–71.

    Google Scholar 

  • Xin F, Susiarjo M, Bartolomei MS. Multigenerational and transgenerational effects of endocrine disrupting chemicals: a role for altered epigenetic regulation? Semin Cell Dev Biol. 2015;43:66–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yáñez J, Mansilla HD, Santander IP, et al. Urinary arsenic speciation profile in ethnic group of the Atacama desert (Chile) exposed to variable arsenic levels in drinking water. J Environ Sci Health Toxic/Hazard Subst Environ Eng. 2015;50(1):1–8.

    Google Scholar 

  • Yen C, Lu F, Huang C, et al. The diabetogenic effects of the combination of humic acid and arsenic: in vitro and in vivo studies. Toxicol Lett. 2007;172(3):91–105.

    CAS  PubMed  Google Scholar 

  • Zarazúa S, Ríos R, Delgado JM, et al. Decreased arginine methylation and myelin alterations in arsenic exposed rats. Neurotoxicology. 2010;31(1):94–100.

    PubMed  Google Scholar 

  • Zhang J, Mu X, Xu W, et al. Exposure to arsenic via drinking water induces 5-hydroxymethylcytosine alteration in rat. Sci Total Environ. 2014;497–498:618–25.

    PubMed  Google Scholar 

  • Zhang X, Zhong H, Chu Z, et al. Arsenic induces transgenerational behavior disorders in Caenorhabditis elegans and underlying mechanisms. Chemosphere. 2020;252:126510.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada, Ensenada, BC, Mexico

    Jorge Hernández-Sánchez

  2. División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica A. C, San Luis Potosi, SLP, Mexico

    Selma Valles

  3. Facultad de Ciencias, Universidad Autónoma de Baja California, Ensenada, BC, Mexico

    Ulises Bardullas

Authors
  1. Jorge Hernández-Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Selma Valles
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ulises Bardullas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ulises Bardullas .

Editor information

Editors and Affiliations

  1. Department of Biomedical Sciences, University of Westminster, London, UK

    Vinood B. Patel

  2. Sch Biomed & Health Sci, Wilkins Bldg, King's College London Franklin, London, UK

    Victor R. Preedy

  3. Department of Medicine, King Abdulaziz Med City, Riyadh, Saudi Arabia

    Rajkumar Rajendram

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Hernández-Sánchez, J., Valles, S., Bardullas, U. (2022). Linking Arsenic, DNA Methylation Biomarkers, and Transgenerational Neurotoxicity: Modeling in Zebrafish. In: Patel, V.B., Preedy, V.R., Rajendram, R. (eds) Biomarkers in Toxicology. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Cham. https://doi.org/10.1007/978-3-030-87225-0_59-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-87225-0_59-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-87225-0

  • Online ISBN: 978-3-030-87225-0

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation