Abstract
Amorphous silica nanoparticles (SiO2NPs) have been widely used in medicine including targeted drug/DNA delivery, cancer therapy, and enzyme immobilization. Nevertheless, SiO2NPs should be used with caution due to safety concerns associated with unique physical and chemical characteristics. The objective of this study was to determine the effects of SiO2NPs on genotoxic and non-genotoxic mechanisms associated with abnormal gap junctional intercellular communication (GJIC) in multistage carcinogenesis. The SiO2NPs exhibited negative responses in standard genotoxicity tests including the Ames test, chromosome aberration assay, and micronucleus assay. In contrast, the SiO2NPs significantly induced DNA breakage in comet assay. Meanwhile, SiO2NPs inhibited GJIC based on the results of scrape/loading dye transfer assay for the identification of non-genotoxic tumor-promoting potential. The reduction in expression and plasma membrane localization of Cx43 was detected following SiO2NP treatment. Particularly, SiO2NP treatment increased Cx43 phosphorylation state, which was significantly attenuated by inhibitors of extracellular signal-regulated kinases 1/2 (ERK1/2) and threonine and tyrosine kinase (MEK), but not by protein kinase C (PKC) inhibitor. Taken together, in addition to a significant increase in DNA breakage, SiO2NP treatment resulted in GJIC dysregulation involved in Cx43 phosphorylation through the activation of mitogen-activated protein kinase (MAPK) signaling. Overall findings of the genotoxic and non-genotoxic carcinogenic potential of SiO2NPs provide useful toxicological information for clinical application at an appropriate dose.
Highlights
Nanoparticles are materials measuring less than 100 nm in at least one dimension
As a nanoparticle is characterized by less than 100 nm at least in one dimension, the size and morphology of SiO2NPs were verified by transmission electron microscope (TEM)
For the confirmation of elemental analysis, SiO2NPs was subjected to the energy dispersive X-ray detection (EDX) analysis
Summary
Nanoparticles are materials measuring less than 100 nm in at least one dimension. Due to the unique physical and chemical properties of nanomaterials compared with their micro-sized counterparts, nanotechnology is one of the most rapidly growing technologies in various fields including food, agriculture, energy, materials, healthcare, and medicine [1,2,3]. Pharmaceutics 2020, 12, 826 Pharmaceutics 2020, 12, 826. 2 of 17 2 of 17 wnitahnmopaajortriscalefsetayrceoanscseorcnisatfeodllowwitinhgmbarojoardsearfheutymcaonnecxeprnossuforell.oSwinicnegthberoualdtrear-shmuamllasnizeexopfonsaunroem. Saitnecreial fatchielitualttersa-istms dalilffusiszieonofacnraonsosmbaiotelorigailcafalcbilairtariteerssi[ts4]d, sifmfuasliloenr paacrrotiscslebsiowloitghicaallabragrerriesrusr[f4a]c,esamreaallearre mpoarretitcolxeiscwwiitthhaalhariggherersuabrfsaocrepatiroena raarteemthoarne tthoexilcarwgietrhoanhesig[h5e,6r]a. BInsodrepetdio, nWraartheetiht aent athl.e[7la]rfgoeurnodntehsat nfoap[u5nu,no6ldm]s.ctoIahnnlaedaterTsyeiiOdlivn,2esWritninaldlarauhnticeooeiptnsaetirtnrtaiarcnlal.set[iss7e.t]nKrftiiogimungnfleerdatmoatxlhm.iad[t8aa]tntoifavornyeuonscstedcrlaeltlsshesaaTiftntiseOihrl2vupiemnurdlanmunaconhenoesapptraaryartotniinmcsslieeatisnlcltteariltinlgisofg.lnaeRmrianogmxrhaiaudttsnoa.tariyKtvheicamesnltlreesettasaasfllt..ien[[r89]] rehpuomrtaend hcheproamtoemnaanceolplsa.rRtiacgleh-uinndauthcaedn getenaol.to[9x]icrietpyobryteidndchurcoinmgerenaacntoivpearotxicylgee-inndspuecceidesg.eEnxoptooxsiucrietyto zibgnyecnoionxtdoidxueiccinintaygn, oarpenadacrtitinivcfleleasmolxmeydgatteoonrcyysprteoestcopiexosin.csiEteysx,pignoesnhuuortmeoxatinocintzyai,snaacnl mdoxiuindcfloeasmanacmneloalstpoa[r1ry0ti]rc.elMesspeoalenndswesthoiilnec,hyMutomatogaxaniycneitaeyst,al maul.c[o1s1a] creepllosr[t1e0d].gMeneoatnowxichiitlye,aMndagcaaryceineotgaeln. [i1ci1t]yroefpcoorbteadlt,gneinckoetol,xaicnidtycoanpdpecra-brcaisneodgneannicoiptyarotficcloesb.alt, nickel,Sailnicdoncodpipoexrid-bea, saeldsonkannoowpanrtaicslesisl.ica, exists in three forms: crystalline, amorphous, and fused silicSai.liAcomnodnigoxthideem, a, ltshoerkenioswenxtaesnssiilviecae,veixdiestnscientthhartecerfyosrtmalsli:ncerysisltiaclaliinset,oaxmico. Acmryosntagltlihneems,iltihcaerheaiss beexetennksnivoewenvitdoeinncceretahsaet tchryesrtiaslklionfepsuillimcaoinsatoryxidc.isEeaxsceessssiuvceheaxsposisluicroestios acnrydsltualnligne sicliacnacheras[b1e2e].n Fkunsoewdnstiolicinacrpeaarsteictlhese raisrke orfeppourlmtedonatoryidndisueacesesinstuecrlheuaskisnil-i1cβosi(sILa-n1dβ)lurnegleacasencefrro[m12]. I[O202N] dPesminonvsitroa.ted cytotoxicity and genotoxicity of SiO2NPs in vitro Rbyeeunectoanl.s[i1d9e]reddidtonobtefainldesasntyoxtiocxficoirtmy o, irtschtoanxigceitiynis stoilrlghaingshflyoldloiswpiuntgedex. pRoysuureet atol. a[1m9o] rdpidhonuost sfiilnicdaannayntoopxaicrittiycleosr (cShiaOn2gNePisn).oUrgbaonlds ifoeltloawl. [in15g]eaxlpsooshuarveeto amshoorwpnhotuhsatsiSliicOa2nNaPnsopdaidrtincoletsi(nSdiOuc2eNcPyst)o. tUoxbiociltdyi, ecteall. t[r1a5n]safolsromhaativoen,shoorwgnenthotaotxSiciOity2NinPsmdoidusneot infdiburcoeblcaysttocteolxlsic. iItny,ccoenltlrtarsatn, sSfioOr2mNaPtsioanr,eokrngoewnnottooxciaciutyseincymtootouxsiecifityb,rorebslualsttincegllisn. oIxnidcoantitvreast,reSsiOs a2nNdPs araepkonpotowsins tofcaeupsiethceyltiaoltocxeilclisty,inreshuulmtinagn inskoinxidaantdivelusntrgess[1a6n].dGapuoicphtaorsdis oetf eapl.ith[2e0li]aldceemllsoninsthrautmedan skciyntoatnodxilcuitnyga[n1d6]g. eGnuoitcohxaicrdityetoaflS. i[O202N] dPesminonvsitroa.ted cytotoxicity and genotoxicity of SiO2NPs in vitro
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