leadsvul

571.
IntroductionSpermatogenesisisacyclicprocess,inwhichdiploidspermatogoniadifferentiateintomaturehaploidspermatozoa.
Spermatogoniaarediffer-entiatedtospermatocyteswhichundergotwomeioticdivisionstogenerateroundspermatids.
Duringspermiogenesisthehaploidroundsperma-tidsundergoanelongationphaseandarediffer-entiatedintomaturespermatozoa(Moldenhaueretal.
2003;Milleretal.
2005).
Microarrayanalysishasrevealedthepresenceofabout3000differenttranscriptsinejaculatedspermatozoa(Krawetz2005;MartinsandKrawetz2005).
AlthoughthestructureofspermRNAiswelldescribeditsroleinspermatogenesisandmaleinfertilityremainsun-SupportedbythePolishMinistryofScientificResearchandHigherEducation(GrantNo.
0233/IP1/2011/71"Iuven-tusPlus").
ThestructureandroleofmammalianspermRNA:areviewD.
Bukowska1,B.
Kempisty2,3,H.
Piotrowska4,P.
Sosinska5,M.
Wozna1,S.
Ciesiolka2,P.
Antosik1,J.
M.
Jaskowski1,K.
P.
Brüssow6,M.
Nowicki21DepartmentofVeterinary,PoznanUniversityofLifeScience,Poznan,Poland2DepartmentofHistologyandEmbryology,PoznanUniversityofMedicalScience,Poznan,Poland3DepartmentofAnatomy,PoznanUniversityofMedicalScience,Poznan,Poland4DepartmentofToxicology,PoznanUniversityofMedicalSciences,Poznan,Poland5InstituteofBioorganicChemistry,PolishAcademyofSciences,Poznan,Poland6DepartmentofReproductiveBiology,LeibnizInstituteforFarmAnimalBiology,Dummerstorf,GermanyABSTRACT:Themainroleofspermisthedeliveryofthepaternalgenomeintotheoocyteduringfertilisation.
However,severallinesofevidencehaveindicatedthatmammalianspermatozoacontributemorethanjusttheirDNA,namely,theyalsodeliveralargerangeofRNAmolecules.
Microarrayanalysishasrevealedacomplexpopulationof3000differentkindsofmessengerRNAthataredeliveredtooocytesbyspermandejaculatedspermatozoaareestimatedtocontainabout0.
015pgoftotalRNA.
Someofthetranscriptsencodeproteinscrucialforearlyembryodevelopment.
MessengerRNAsfromspermalsohelptoprotectthepaternalgenes,whichhaveanintegralrolesoonafterfertilisation.
Themolecularparticipationoftheoocyteduringfertilisationiswellunderstoodbutthefunctionofthesperminthisprocessremainsunclear.
Duringspermatogenesisthestructureofthemalehaploidgenomeispermanentlymodified.
Transitionproteins(TNPs),protamines(PRMs)andhistones(HILS-spermatidspecificlinkerhistone)playauniqueroleinspermatidchromatincompaction.
Inthisreview,thestructureandroleofspermRNAaswellaschromatinorganisationduringspermatogenesisarediscussed.
Keywords:sperm;spermatozoalRNA;fertilisationContents1.
Introduction2.
Chromatinstructureinmammaliansperm3.
Transcriptionalprocessesinmalegermcells4.
Processofspermchromatincompaction5.
RoleofspermRNA6.
Acknowledgements7.
References58clear.
Severalhypotheseshavebeenadvancedtotrytoexplaintheoriginandphysiologicalfunctionofthesetranscripts.
OnehypothesisisthattheRNAofspermatozoaistranscribedduringspermato-genesis.
However,atpresentthereisnoevidencetosuggesttranscriptionalactivityofspermatozoalRNA.
InanothertheoryitisproposedthatthepoolofspermatidRNAistheremainderoftheuntrans-latedmaterialduringspermatogenesis(KramerandKrawetz1997).
Thisissupportedbythefactthatthesametranscriptsdetectedinspermwerealsofoundinbothtestes.
Ifthistheorywasprovenbyexperimentaldata,spermatozoaltranscriptswouldrepresentthehistoricalentryofspermatogenesis.
TheidentifiedspermatozoalRNAencompass-esthetranscripts,whichmaybedeliveredtotheovumduringfertilisation.
Thetranscriptsdeliveredtotheooplasmcanplayacrucialroleinzygoticandearlyembryonicdevelopment(WrzeskaandRejduch2004;Ostermeieretal.
2004;Bukowskaetal.
2011a;Kempistyetal.
2011).
Asmentionedbe-fore,themolecularcontributionoftheovumdur-ingfertilisationiswellknown,whereastheroleofspermisstillunderdiscussion.
Itisawell-knowntheorythatthepaternalmolecularcontributionhasacrucialroleinearlyembryonicdevelopmentandindeterminingthehealthofachild(Lalande1996;SutovskyandSchatten2000;Kempistyetal.
2010).
Therefore,manyresearchgroupshaveshownthatmammalianspermatozoaplaymoreimportantrolesthanjustdelivertheirDNAintotheovum.
Duringspermatogenesis,thestructureofthemalehaploidgenomeispermanentlymodified.
Transitionproteins(TNPs),protamines(PRMs)andhistonesseemtoplayacrucialroleinthispro-cess.
Inparticular,proteinssuchasHILS1(sper-matidspecificlinkerhistone),TNPsandPRMsplaysanimportantroleinspermatidchromatincompaction(Dadoune2003;Meistrichetal.
2003).
Inhaploidroundspermatidshistonesarereplacedbytransitionproteins.
Thesecondstepofthispro-cessoccursinelongatingspermatidsandinvolvesreplacementofTNPswithprotamines(PRMs).
Asaresultofthesechangeschromatinbecomeshighlycondensedandtranscriptionallysilent.
2.
ChromatinstructureinmammalianspermTheidentifiedspermatozoalRNAsencompassthetranscriptsoftransitionproteins(TNPs),prota-mines(PRMs)andspermatid-specificlinkerhistone(HILS)(RothandAllis1992;Eddy2002).
Transitionproteinsandprotaminesareexpressedduringmam-malianspermiogenesis.
Duringchromatinremodel-linginlatespermatogenesismostsomatichistonesarereplacedbyDNApackagingproteinsthatarespecificforgermcelllines(Caronetal.
2005).
Thematurespermatozoahaveahighnumberofhistonevariantsincomparisontothesomaticcellsandthereexistdifferencesbetweenthesegermcell-specifichistonesandthosefromsomaticcells(BaarendsandGrootegoed2003;Churikovetal.
2004).
Forexample,thesynthesisofRNAisuncoupledfromDNAreplication.
Thereareseveraltypesofhistonevariants;testis-specifichistoneH4,whichcanhavedifferencesinamino-acidsequencefromthesomaticH4andH2A.
Xwithdifferentamino-acidsequenceandstructure.
Thetranscriptvariantshavealongerpoly-Atails,whichmayincreasetranscriptstability.
TheH3transcriptisspecificforspermatogoniaandlaterspermatids.
H3.
3AisavariantofhistoneH3andispresentinmalegermcelldevelopmentfromspermatogoniatospermatids.
InprophaseIhistoneH3isreplacedbyH3.
3AandthenH3.
3B(Burfeindetal.
1994;Fernandez-Capetilloetal.
2004).
TherearelittleexperimentaldataindicatingtheroleofH3his-toneanditstranscriptvariantsinthemechanismoftranscriptionactivationinspermatocytes.
H2AandH2BtranscriptvariantshaveadifferentstructureintheN-terminalchainofthetranscripts(Franketal.
2003).
TH2Bisatestis-specifictranscriptvariantoftheH2Bhistone,whichhasdifferencesinthestruc-tureofthreephosphorylationsites(Ser12,Thr23andThr34)(Green2001;Monardesetal.
2005).
Asaresulttherearedifferentcombinatorialinteractionsbetweenserineandthreonineresidueswhichcouldbeareasonforthespecificpatternofacetylationandmethylation(Rousseauxetal.
2005).
TheHistoneH1familyalsohasaseveralgerm-cellspecificvari-ants.
DifferencesinstructurehavebeenidentifiedmostlyintheC-terminiandpotentiallydeterminetheirbindingtochromatin.
TwotranscriptvariantsofthehistoneH1family,H1tandH1t2,exhibithighidentity.
Theremodellingofspermchromatinstruc-turestartsduringthemeioticprophase.
Atthattimehistone-likesomaticH1AandH1BarereplacedbyH1ttranscriptvariants.
Mutationsinthegenecod-ingH1tdonotaffectmalefertilityand,therefore,theroleofH1tseemstobelimitedtotherestruc-turingofchromatin.
H1t2transcriptvariantsplayanintegralroleintheestablishmentofcellpolarityandhighchromatincondensationduringspermato-genesis(Martianovetal.
2005;Tanakaetal.
2005).
59Thishistonevariantislocatedunderthenuclearmembraneandbasalacrosomeofroundspermatids.
Thepositionwherethetranscriptisidentifiedisthesamefortheinitiationofchromatincompaction.
ItisthussuggestedthatH1t2isacomponentofthechro-matinorganisingcentreintheheadofspermatozoa.
Hilsisamemberofthelinkerhistonefamilyandisspecificforlateelongatingspermatids(Yanetal.
2003;Iguchietal.
2004).
ThecellulardistributioninthenuclearmatrixofHils,transitionproteinsandprotaminesisalmostthesame,suggestingaroleforthishistoneinthechromatincompactionprocessinmaturingspermatids.
HistoneH1hasseveralSer/Thrcyclin/CDKsites,whichexertanimportantin-fluenceoncellmobilityandwhichareabsentintran-scriptvariantssuchasH1tandH1t2.
Theseresultssuggestafunctionalredundancyofthesetranscriptvariants.
Yanetal.
(2003)haveshownthatHilsex-hibitsseveralbiochemicalfunctionsincludingtheabilitytobindreconstitutedmononucleosomesandaroleinthechromatincompactionprocess.
Hils1isexpressedinlatematuringspermatidsthatdonotcontaincorehistonesinthisstage.
Forthisreason,ithasbeenproposedthatthemechanismofspermatidnuclearcondensationisdistinctfromthatspecificforsomaticlinkerhistones.
ThereisalsoatheoryinwhichitissuggestedthatHilsplaysaroleinregulat-inggenetranscription,DNArepairorotherchromo-someprocessesduringspermiogenesis.
3.
TranscriptionalprocessesinmalegermcellsSpermiogenesisisacomplexprocessbywhichpostmeioticmalegermcellsdifferentiateintomaturespermatozoa.
Thisprocessinvolvesstruc-turalandbiochemicalchangesincludingnuclearchromatincondensationandacrosomeformation(Ivelletal.
2004;RonfaniandBianchi2004).
Inmalegermcellstranscriptionisidentifiedinpost-mei-oticspermatids.
Theprocessofspermchromatinremodelling(regulationofprotamineexpressionandchromatincompaction)includesseveralnu-clearactivationfactorssuchasCREM,CREB,PAF-1,Y-boxproteinsp48/p52,nuclearfactor1,TLF,TFIID-TAF7andTFIID-TAF7L.
Transcriptionregulationinthespermnucleusoccursinseveralsteps;(i)methylationofspecificDNAsequences,(ii)bindingoftrans-actingfactorstoTATA-boxandCREsequencesinprotaminepromoters,and(iii)chromatinassociationinthenuclearmatrixintheheadofasperm.
CREMishighlyexpressedinpost-meioticsper-matidsandisprobablyresponsiblefortranscrip-tionalactivationofmanyhaploidgermcell-specificgenesincludedintherestructuringofthespermato-zoanchromatin(Monacoetal.
2004;Hogarthetal.
2005;Kempistyetal.
2008).
InactivationofCREMresultsinthelossofpostmeioticcell-specificgeneexpressionandleadstocompleteblockofspermio-genesis.
Thelatespermatidsarecompletelyabsentatthisstageandthereisanincreaseinthenumberofapoptoticmalegermcells.
CREM-responsetran-scriptionactivationinsomaticcellsisdependentonCREMphosphorylationandsubsequentCBPmobilisation.
Inmalegermcellsphosphorylationandhistoneacetyltranserasefunctionisdepend-entonthespecificco-activatorACT(activatorofCREMintestis)(DonandStelzer2002).
ACTisexpressedinroundspermatids,whereitcooperateswithCREMinregulatingthetranscriptionofvari-ouspost-meioticgenes.
Regulationoftranscrip-tionplaysanintegralroleintheearlystagesofspermatogenesis,whenthespermatogonialcellsaredifferentiated.
IthasbeenpostulatedthatcyclicAMP(cAMP)secondmessengerpathwaysplayacrucialroleincellulargrowthanddifferentiation(DeCesareandSassone-Corsi2000;DonandStelzer2002).
Inad-dition,cAMPcanbeoneoftheimportantfactorsindeterminingspermatidmobility.
AllcAMP-respon-sivegenepromotershaveincommonan8-baseenhancertermedthecAMP-responseelement(CRE),whichcontainsaconservedcoresequence,5'-TGACG-3',firstidentifiedinthesomatostatingenebyMontminyetal.
(1986).
Tayloretal.
(1990)mappedCREB1to2q32.
3-q34.
ThetranscriptionalactivityofCREBrequiresphosphorylationoftheproteinonaserineresidueatposition119.
TheCREelement(TGANNTCA)towhichCREBbindsispresentinanumberofT-cellspecificgenes,buttheroleofCREBinspermatiddifferentiationremainsunclear(Tamaietal.
1997).
PAF-1(protamineactivatingfactor1),activatesPRM2transcriptioninhaploidcellsbybindingtoaregulatorysequencelocatedatposition-64/-48.
YiuandHecht(1997)postulatedthatanyaltera-tioninthegenesequenceofthesebindingsitesleadtoinhibitionofPRM2transcription.
ThereareafewtranscriptionactivatingfactorssuchasTet-1andnuclearfactor1,whichbindtothePRM2promoter-specificsequenceandactivatetranscrip-tionofthesegenes(Tamuraetal.
1992;Kempistyetal.
2006,2007).
Sofar,therearenoregulatory60proteinsidentified,whichbybindingtothesese-quencesleadtoinhibitionoftranscriptionoftheprotaminegenes.
TheexpressionofHLAclassIIgenesisregulatedbycis-actingelementsandtransactingfactors.
Theidentifiedcis-actingelementsincludetheZ-box,X-box,Y-box,octamer,andTATAbox.
TheY-box-bindingprotein(YB-1)isthemostevolutionarilyconservednucleic-acid-bindingprotein(Torigoeetal.
2005).
Itissuggestedthattheseproteinsplayanimportantroleinseveralcellularprocessesin-cludingtranscriptionalregulationandDNArepair.
Kohnoetal.
(2003)postulatedthatYB-1playsaroleincellproliferationanddifferentiation.
Althoughthepresenceoftheseproteinsinspermatogenesisiswelldefined,theirfunctionsintheregulationoftranscriptioninitiationareyettobeelucidated.
Yangetal.
(2005)describedthefunctionoftheY-boxfamilyofDNA-/RNA-bindingproteinsasel-ements,whichregulatetranscriptioninthenucleusandwhichstabiliseandstorematernalandpaternalmRNAsinthecytoplasm.
MutationsofthegenesencodingY-boxproteinsleadtosterilityinmiceandtomanydisruptionsinspermatogensis.
Inthetestesofhomozygoteslevelsofpost-meioticmalegermcellmRNAwereobservedtobedecreasedwhilesmallerreductionswereseeninmeioticgermcelltranscripts.
ThestructureoftheTLFfactoriswellunderstoodbutitspossibleroleintheprocessoftranscriptionandfunctioninhumanspermatogenesisarenotyetunderstood.
TLFisamemberofthegeneraltranscriptionfactor(GTFs)family,whichincludesTATAbox-bindingprotein(TBP)importantforthetranscriptionalinitiationofeukaryoticgenes(Kimminsetal.
2004).
BothTBPandTLFfactorwerefoundtoplayacrucialroleinembryonicdevelop-ment.
ExperimentsusingratembryosasamodelhaveshownthatembryoswithoutdetectableTBPinitiatedgastrulationbutdiedbeforeitwascom-pleted.
MutationintheTLF-encodinggeneresultedinthenormaldevelopmentofspermatogoniaandspermatocytesbutinadecreasednumberofroundspermatids(Martianovetal.
2001).
AlthoughTLFisnotrequiredforembryonicdevelopment,ithasbeensuggestedthatitplaysanimportantroleintranscriptionalregulationofgenesessentialforsper-miogenesis.
TranscriptionfactorIID(TFIID)isaDNA-bindingproteincomplexrequiredforRNApolymeraseII-mediatedtranscriptionofmanygenesineukary-oticcells(Kleene2005).
TFIIDiscomposedoftheTATA-bindingprotein(TBP)andmultipleTBP-associatedfactors(TAFs)includingTAF1,TAF7andTAF7L(Falenderetal.
2005).
ThebindingofTBPtotheTATA-boxresultsintranscriptionalac-tivationofPRM1/PRM2promoters.
SeverallinesofexperimentaldatahaverevealedanimportantroleforTAFsfactorsintranscriptionalregulation.
TAF7hasalsobeenshowntoplayanimportantroleinpromoterrecognitionandtointeractwithspecifictranscriptionalactivators.
Mutationsinthissubunitcausecellcyclearrest,whichresultsinmaleinfertility(Pointudetal.
2003).
TAF7Lisatestis-andgerm-cell-specificproteinwithse-quencesimilaritytosomaticTAF7.
Theintracel-lularlocalisationofTAF7Lispermanentlychangedfromcytoplasmicinspermatogoniatonuclearinlatepachytenespermatocytesandhaploidroundspermatids.
TheprocessofintracellulartransportofTAF7LisconnectedwithdecreasedexpressionofTAF7,whichsuggestthatTAF7LreplacestheTAF7subunitinlatespermatocytes.
ExperimentaldatahaveshownthatTAFsaredifferentiallyex-pressedduringallstepsofmalegermcellmatura-tion(Hilleretal.
2001).
4.
ProcessofspermchromatincompactionThematurationofspermatidsintospermatozoainvolvesseveralimportantchangesinchromatinstructureandfunction.
Chromatinstructureinthespermnucleusissimilartothatinsomaticcells.
Theorganisationisbasedonloopeddomainsattachedattheirbasestothenuclearmatrix.
Theprocessofchromatinpackagingintohigherorderedstructureintheeukaryoticgenomeismediatedbyseveralmolecularinteractions,namely,DNA-DNA,DNA-histoneandprotein-proteininteractions(Rouxetal.
2004).
Spermiogenesisischaracterisedbytheex-pressionofseveralnuclearproteins,whicharecon-nectedwiththeprocessofchromatincondensation(Meistrichetal.
2003).
Thefirststepofchromatincondensationresultsintheappearanceofhaploidroundspermatidsandischaracterisedbythere-placementofsomatichistoneswithlowmolecularweighttransitionproteins(McLayandClarke2003).
Inthisstepthenucleusiselongatedandchromatinappearsassmoothfibres.
Inthenextstepofsperma-tidelongationtransitionproteinsarereplacedwithprotaminesinthenuclearmatrix.
DNAinspermchromatinisassociatedwith15%nucleohistonesand85%nucleoprotamines(Adhametal.
2001).
61Ithasbeenpostulatedthattheprocessofnor-malchromatincompactioninspermhasanim-portanteffectonearlyembryonicdevelopmentandtheproductionofviableoffspring.
Recentinvestigationshaverevealedanimportantroleforthestructureandfunctionoftransitionproteins1and2(TNP1andTNP2)onproperspermchro-matincondensation.
Therearetwotypesoftransitionproteins,tran-sitionprotein1(TNP1)andtransitionprotein2(TNP2)(Miller2000;Kempistyetal.
2006).
TNP1isaspermatid-specificprotein,whichreplacehis-tonesandthenisitselfreplacedbyprotaminesduringthelatterstepsofspermatogenesis.
Luerssenetal.
(1990)mappedhumanTNP1tochromosome2q35-q36.
Itwasshownthatmuta-tionoftheTNP1geneleadstoseveralabnormali-tiesinspermmorphology,althoughtestisweightandspermproductionwasnormal.
Micelack-ingTNP1exhibitedapronouncedreductioninspermmobility.
Yuetal.
(2000)postulatedthatTNP1wasnotessentialforhistonedisplacementandthatdecreasedlevelsofTNP1mightbepar-tiallycompensatedforbyTNP2andPRM2.
TheabsenceofTNP1canleadtodysregulationofspermproteinreplacement,whichresultsinanabnormalpatternofchromatincompactionandreducedfertility.
ThehumanTNP1geneislocatedonadifferentchromosomethanTNP2,PRM1andPRM2whichhaveallbeenmappedto16p13.
3(Viguieetal.
1990).
TheTNP2-PRM1-PRM2chromosomelo-cusspans28.
5kb.
Thespecificstructureandchro-mosomelocalisationfacilitatestheconcurrentexpressionofthesegenes.
ThestructuresofthePRM1andPRM2genesarehighlyconservedinthespermofallmammalianspecies(Hernandez-Ochoaetal.
2005).
ThestructuralorganisationofPRM1andPRM2genesimplicatesanimportantrolefortheirtranscriptionalregulation.
Theselociarelocatedinalargemethylateddomainthatisflankedbyamatrixattachmentregion(MAR).
Thisregioncontainsseveralalanine(Alu)ele-ments,whicharesitesofpotentialmethylation.
Theprocessofmethylationleadstosilenceofgeneexpressionwhilehypomethylationisresponsibleforchromatinbindingtothenuclearmatrix.
Inaddition,theprocessofchromatinbindingtothenuclearmatrixismediatedbyMARsequences.
Schmidetal.
(2001)postulatedthattheMARat-tachmentprocesshasanimportantroleintheregulationofgenetranscriptionbutisindepend-entofthestateofmethylation.
ThegenesencodingprotaminescontainTATA-sequences,whichplaycrucialrolesintheinitiationoftranscription.
ThepromotersofprotaminegenescontaincAMPre-sponseelements(CREs),whichplayanimportantroleinregulatingthetranscriptionofthesegenes.
Ithasbeenreportedthatprotamineexpressionandreplacementhasanimportantinfluenceonnormalspermatiddifferentiationduringspermatogenesis.
Therefore,anyaberrationsinPRM1orPRM2expres-sioncanleadtomaleinfertility.
Indeed,prematuretranslationofPRM1orPRM2resultsinprecociousnuclearchromatincompaction,whichblockstheprocessofspermatiddifferentiation(Bunicketal.
1990;OlivaandDixon1990).
Moreover,thespermofinfertilemenexhibitedanabnormalPRM1:PRM2ra-tio.
ItwashypothesisedthatanormalPRM1:PRM2ratiowasamoreimportantfactorformalefertilitythantheabsoluteconcentrationsofthesetwopro-teins.
Inconclusion,protaminesarearginine-richproteinsthatreplacehistonesinthenuclearmatrixintheheadofspermandplaycrucialrolesinDNAcondensation,DNAstabilisationandregulationofgeneexpression(Baroneetal.
1994).
5.
RoleofspermRNAThemolecularcontributionoftheovumduringfer-tilisationiswelldescribedbuttheroleofsperminthisprocessremainsunclear(Bukowskaetal.
2011b).
TheroleofspermatozoaliesfirstandforemostintheirdeliveryofDNAtotheoocyte.
However,experimen-taldatafromseverallaboratorieshaveshownthatspermcontributemorethanjusttheirhaploidge-nome.
Milleretal.
(2005)showedthathumansper-matozoacontainseveralmoleculesofmRNA,whichcouldbedefinedasaspecificgeneticfingerprintofeachstepofspermatogenesis.
Todateabout3000differenttranscriptscomprisingthepaternalhaploidgenomehavebeendescribed.
AlloftheseRNAsiden-tifiedinspermatozoahadpreviouslybeendetectedinbothtestes.
Althoughthesetranscriptswerewelldescribedtheirroleinmalespermatogenesisremainsunclear.
Krawetz(2005)suggestedthatsomeofthesemRNA,whichweredetectedinthespermnucleusweredeliveredintooocytesduringfertilisation.
Usingthezona-freehamsteregg/humanspermpenetrationassayMartinsandKrawetz(2005)identifiedonlypro-tamine-2(PRM2)andclusterin(CLU),whichwereconsistentlydetectedinspermatozoaandzygotesbutnotdetectedinunfertilisedhamsteroocytes.
Therole62ofthesetranscriptsisstilldiscussedbuttheyareim-plicatedinfertilisationaswellaszygoticandearlyembryonicdevelopment.
Ithasbeenpostulatedthatthepaternalcontributionplaysanimportantroleinseveraldevelopmentalprocessesandhasasignificantinfluenceonthehealthofoffspring.
Abetterunder-standingoftherolesofhumanspermRNAmayalsoholdthekeytomoresuccessfulsomaticcellnucleartransferaswellasprovidinginsightsintotheetiopa-thologyofmaleinfertility.
6.
AcknowledgementsTheauthorswishtoacknowledgeMScPiotrZawierucha(PoznanUniversityofMedicalScience,Poznan,Poland)fortechnicalsupport.
7.
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Received:2012–03–27Acceptedaftercorrections:2013–02–25CorrespondingAuthor:BartoszKempisty,PoznanUniversityofMedicalSciences,DepartmentofHistologyandEmbryology,6SwiecickiegoSt.
,60-781Poznan,PolandTel.
+48618546515,Fax+48618546510,E-mail:etok@op.
pl