The effects of manganese (Mn) toxicity in different organs and tissues in humans and other vertebrates have been studied since the beginning of the past century, but most of its cellular effects remain largely unknown. In this study, we studied the effects of Mn in zebrafish, at the cellular level, due to the transparent nature of zebrafish larvae that enables a powerful analysis under the light microscope. The collection of our results shows that environmental concentrations of 0.5 mg/L affect swim bladder inflation; at concentration of 50 and 100 mg/L Mn (1) induces alterations in viability, swim bladder, heart, and size of zebrafish larvae, (2) induces an increase in melanocyte area and the formation of cellular aggregates in the skin, and (3) induces an accumulation of β-Catenin in mesenchymal cells in the caudal fin of zebrafish larvae. Our data suggest that increased levels of Mn induce cell aggregate formation in the skin and the presence of more melanocytes in the zebrafish caudal fin. Interestingly, the adhesion protein β-Catenin was activated in mesenchymal cells near the cell aggregates. These results open important new questions on the role of Mn toxicity on cellular organization and β-Catenin responses in fishes.
EriksonKM, AschnerM. Manganese: Its role in disease and health. Met Ions Life Sci, 2019; 19:253–266; doi: 10.1515/9783110527872-010
3.
AltenhofenS, WiprichMT, NeryLR, et al.Manganese(II) chloride alters behavioral and neurochemical parameters in larvae and adult zebrafish. Aquat Toxicol, 2017; 182:172–183; doi: 10.1016/j.aquatox.2016.11.013
4.
HuangP, ChenC, WangH, et al.Manganese effects in the liver following subacute or subchronic manganese chloride exposure in rats. Ecotoxicol Environ Saf, 2011; 74(4):615–622; doi: 10.1016/j.ecoenv.2010.08.011
5.
O'NealSL, LeeJW, ZhengW, et al.Subacute manganese exposure in rats is a neurochemical model of early manganese toxicity. Neurotoxicology, 2014; 44:303–313; doi: 10.1016/j.neuro.2014.08.001.
6.
YoonH, KimD-S, LeeG-H, et al.Apoptosis induced by manganese on neuronal SK-N-MC cell line: Endoplasmic reticulum (ER) stress and mitochondria dysfunction. Environ Health Toxicol, 2011; 26:e2011017; doi: 10.5620/eht.2011.26.e2011017
BakthavatsalamS, Das SharmaS, SonawaneM, et al.A zebrafish model of manganism reveals reversible and treatable symptoms that are independent of neurotoxicity. DMM Dis Model Mech, 2014; 7(11):1239–1251; doi: 10.1242/dmm.016683
9.
HermanP, FehérM, Molnár Á, et al. Iron and manganese retention of juvenile zebrafish (Danio rerio) exposed to contaminated dietary zooplankton (Daphnia pulex)—A model experiment. Biol Trace Elem Res, 2021; 199(2):732–743; doi: 10.1007/s12011-020-02190-z
10.
HernándezRB, NishitaMI, EspósitoBP, et al.The role of chemical speciation, chemical fractionation and calcium disruption in manganese-induced developmental toxicity in zebrafish (Danio rerio) embryos. J Trace Elem Med Biol, 2015; 32:209–217; doi: 10.1016/j.jtemb.2015.07.004
11.
MarinsK, LazzarottoLMV, BoschettiG, et al.Iron and manganese present in underground water promote biochemical, genotoxic, and behavioral alterations in zebrafish (Danio rerio). Environ Sci Pollut Res, 2019; 26(23):23555–23570; doi: 10.1007/s11356-019-05621-0
12.
TuH, FanC, ChenX, et al.Effects of cadmium, manganese, and lead on locomotor activity and neurexin 2a expression in zebrafish. Environ Toxicol Chem, 2017; 36(8):2147–2154; doi: 10.1002/etc.3748
13.
Zimmermann Prado RodriguesG, StaudtLBM, MoreiraMG, et al.Histopathological, genotoxic, and behavioral damages induced by manganese (II) in adult zebrafish. Chemosphere, 2020; 244:125550; doi: 10.1016/j.chemosphere.2019.125550
14.
ThomasonRT, PettiglioMA, HerreraC, et al.Characterization of trace metal content in the developing zebrafish embryo. PLoS One, 2017; 12(6):e0179318; doi: 10.1371/journal.pone.0179318
15.
Conama. Resolução n 357, 18 de março de 2005. Diário of, 2005; doi: no 053, de March 18, 2005.
16.
GillispieEC, AustinRE, RiveraNA, et al.Soil weathering as an engine for manganese contamination of well water. Environ Sci Technol, 2016; 50(18):9963–9971; doi: 10.1021/acs.est.6b01686
17.
FranciscoLFV, do Amaral CrispimB, SpósitoJCV, et al.Metals and emerging contaminants in groundwater and human health risk assessment. Environ Sci Pollut Res, 2019; 26(24):24581–24594; doi: 10.1007/s11356-019-05662-5
18.
QueirozHM, YingSC, AbernathyM, et al.Manganese: The overlooked contaminant in the world largest mine tailings dam collapse. Environ Int, 2021; 146:106284; doi: 10.1016/j.envint.2020.106284
19.
WesterfieldM.The Zebrafish Book. A Guide for the Laboratory Use of Zebrafish (Danio rerio), 5th Edition. Univ Oregon Press: Eugene, OR; 2007.
20.
Le GuyaderD, ReddMJ, Colucci-GuyonE, et al.Origins and unconventional behavior of neutrophils in developing zebrafish. Blood, 2008; 111(1):132–141; doi: 10.1182/blood-2007-06-095398
21.
SheehanHL, StoreyGW. An improved method of staining leucocyte granules with Sudan black B. J Pathol Bacteriol, 1947; 59(1–2):336; doi: 10.1002/path.1700590142
22.
WaltersKB, DoddME, MathiasJR, et al.Muscle degeneration and leukocyte infiltration caused by mutation of zebrafish fad24. Dev Dyn, 2009; 238(1):86–99; doi: 10.1002/dvdy.21821
23.
SchindelinJ, Arganda-CarrerasI, FriseE, et al.Fiji: An open-source platform for biological-image analysis. Nat Methods, 2012; 9(7):676–682; doi: 10.1038/nmeth.2019.
24.
LindseyBW, SmithFM, CrollRP. From inflation to flotation: Contribution of the swimbladder to whole-body density and swimming depth during development of the zebrafish (Danio rerio). Zebrafish, 2010; 7(1):85–96; doi: 10.1089/zeb.2009.0616
25.
WinataCL, KorzhS, KondrychynI, et al.Development of zebrafish swimbladder: The requirement of Hedgehog signaling in specification and organization of the three tissue layers. Dev Biol, 2009; 331(2):222–236; doi: 10.1016/j.ydbio.2009.04.035
26.
CrétonR, SpeksnijderJE, JaffeLF. Patterns of free calcium in zebrafish embryos. J Cell Sci, 1998; 111(12):1613; doi: 10.1242/jcs.111.12.1613.
O'NealSL, ZhengW. Manganese toxicity upon overexposure: A decade in review. Curr Environ Heal Rep, 2015; 2(3):315–328; doi: 10.1007/s40572-015-0056-x
31.
KimHJ, NaGY, LeeS, et al.Manganese (Mn 2+) caused significant decrease in viability of normal human melanocytes in a dose-dependent manner, while calcium (Ca2+) did not. J Am Acad Dermatol, 2005; 52(3):P39; doi: 10.1016/j.jaad.2004.10.170
32.
PajarilloE, Nyarko-DanquahI, AdinewG, et al.Neurotoxicity mechanisms of manganese in the central nervous system. 2021; 5:215–238; doi: 10.1016/bs.ant.2020.11.003
33.
FriedmanBJ, Freeland-GravesJH, BalesCW, et al.Manganese balance and clinical observations in young men fed a manganese-deficient diet. J Nutr, 1987; 117(1):133–143; doi: 10.1093/jn/117.1.133
34.
ShallcrossL, RitchieS, HarbertsE, et al.Manganese oxidation state as a cause of irritant patch test reactions. Dermatitis, 2014; 25(2):66–71; doi: 10.1097/DER.0000000000000032
35.
HatzoldJ, BeleggiaF, HerzigH, et al.Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit. Elife, 2016; 5:e14277; doi: 10.7554/eLife.14277
36.
GavinCE, GunterKK, GunterTE. Manganese and calcium efflux kinetics in brain mitochondria. Relevance to manganese toxicity. Biochem J, 1990; 266(2):329–334; doi: 10.1042/bj2660329
37.
TanJ, ZhangT, JiangL, et al.Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein. J Biol Chem, 2011; 286(34):233874; doi: 10.1074/jbc.M111.233874
38.
XiaZ, WeiJ, LiY, et al.Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis. PLoS Genet, 2017; 13(7):e1006892; doi: 10.1371/journal.pgen.1006892
39.
ChebassierN, El HousseinO, ViegasI, et al.In vitro induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in keratinocytes by boron and manganese. Exp Dermatol, 2004; 13(8):484–490; doi: 10.1111/j.0906-6705.2004.00197.x
40.
LatronicoT, BranàMT, MerraE, et al.Impact of manganese neurotoxicity on MMP-9 production and superoxide dismutase activity in rat primary astrocytes. Effect of resveratrol and therapeutical implications for the treatment of CNS diseases. Toxicol Sci, 2013; 135(1):218–228; doi: 10.1093/toxsci/kft146
41.
KobayashiK, KurodaJ, ShibataN, et al.Induction of metallothionein by manganese is completely dependent on interleukin-6 production. J Pharmacol Exp Ther, 2007; 320(2):112912; doi: 10.1124/jpet.106.112912
42.
MilatovicD, Zaja-MilatovicS, GuptaRC, et al.Oxidative damage and neurodegeneration in manganese-induced neurotoxicity. Toxicol Appl Pharmacol, 2009; 240(2):219–225; doi: 10.1016/j.taap.2009.07.004
43.
van der WalT, van AmerongenR. Walking the tight wire between cell adhesion and WNT signalling: A balancing act for β-catenin. Open Biol, 2020; 10(12):200267; doi: 10.1098/rsob.200267
44.
FeitosaNM, ZhangJ, CarneyTJ, et al.Hemicentin 2 and Fibulin 1 are required for epidermal-dermal junction formation and fin mesenchymal cell migration during zebrafish development. Dev Biol, 2012; 369(2):235–248; doi: 10.1016/j.ydbio.2012.06.023
45.
MaB, HottigerMO. Crosstalk between Wnt/β-Catenin and NF-ΚB signaling pathway during inflammation. Front Immunol, 2016; 7:00378; doi: 10.3389/fimmu.2016.00378
46.
MolagodaIMN, KarunarathneWAHM, ParkSR, et al.GSK-3β-targeting fisetin promotes melanogenesis in B16F10 melanoma cells and zebrafish larvae through β-catenin activation. Int J Mol Sci, 2020; 21(1):312; doi: 10.3390/ijms21010312
47.
MolagodaIMN, JayasinghaJACC, ChoiYH, et al.Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock. Sci Rep, 2021; 11(1):1–17; doi: 10.1038/s41598-021-87257-0
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
