来曲唑对镉暴露小鼠精子发生的影响及其分子机制的研究

来曲唑对镉暴露小鼠精子发生的影响及其分子机制的研究【摘要】背景：镉作为一种常见的环境污染物质，对生殖系统健康存在潜在威胁。来曲唑是一种经典的催乳剂，其对生殖系统的影响目前研究较少。本研究旨在探究来曲唑是否可以通过调节凋亡和线粒体功能，改善镉暴露小鼠精子发生的不良效应。

方法：本研究应用单次给予25mg/kg的镉氯化物注射昆明小鼠，分为镉组、镉+来曲唑组和对照组。来曲唑组于镉注射后第7天开始灌胃给予常规剂量的来曲唑，每天一次，灌胃时间持续28天。在治疗结束后第1天，应用SPF小鼠（8周龄和12周龄）的精液鉴定系统和荧光探针探测技术，测定小鼠精子的运动参数，对精子活力、遗传毒性及线粒体功能进行评价。此外，采用Westernblot检测靶蛋白的表达情况。

结果：镉暴露小鼠的精子活力相比对照组显著降低，其形态和运动能力也与正常组存在差异；线粒体透过性发生改变，呼吸耦合降低，ATP生成减缓；精子中凋亡相关蛋白酶原性半胱氨酸蛋白酶-3（Caspase-3）表达上调。而来曲唑治疗并不能完全恢复精子的功能，但是可以显著降低精子凋亡和线粒体膜通透性的发生，增强小鼠精子的活力和遗传稳定性。

结论：来曲唑可以改善镉暴露诱导的小鼠精子发生的不良效应，其中其抑制精子凋亡和维护线粒体功能的机理值得探索和深入研究。

【关键词】来曲唑；镉暴露；精子活力；线粒体膜通透性；凋亡

Abstract

Background:Cadmium,asacommonenvironmentalcontaminant,posesapotentialthreattoreproductivehealth.Domperidoneisaclassicmilkinducer,anditseffectsonthereproductivesystemhavebeenstudiedless.Thisstudyaimedtoexplorewhetherdomperidonecanimprovetheadverseeffectsofcadmium-exposedmousespermatogenesisbyregulatingapoptosisandmitochondrialfunction.

Methods:Inthisstudy,Kunmingmiceweregivenasingleinjectionof25mg/kgcadmiumchloride,dividedintoacadmiumgroup,acadmium+domperidonegroup,andacontrolgroup.Thedomperidonegroupstartedtoadministeraconventionaldoseofdomperidonebygavageonthe7thdayaftercadmiuminjection,onceaday,for28days.Onthefirstdayaftertheendofthetreatment,SPFmouse(8weeksand12weeksold)semenidentificationsystemandfluorescenceprobedetectiontechnologywereusedtoassessspermmotility,genetictoxicity,andmitochondrialfunction.Inaddition,Westernblotwasusedtodetecttheexpressionoftargetproteins.

Results:Thespermmotilityofcadmium-exposedmicewassignificantlylowerthanthatofthecontrolgroup,andtheirmorphologyandmotilitywerealsodifferentfromthenormalgroup;thepermeabilityofmitochondriachanged,respiratorycouplingdecreased,andATPgenerationslowed;Theexpressionofapoptosis-relatedproteasecaspase-3inspermwasup-regulated.However,domperidonetreatmentcouldnotcompletelyrestorespermfunction,butitcouldsignificantlyreducespermapoptosisandmitochondrialmembranepermeability,andenhancethevitalityandgeneticstabilityofmousesperm.

Conclusions:Domperidonecanimprovetheadverseeffectsofcadmium-inducedmousespermatogenesis,amongwhichthemechanismofinhibitingspermapoptosisandmaintainingmitochondrialfunctionisworthexploringandfurtherstudy.

Keywords:domperidone;cadmiumexposure;spermmotility;mitochondrialmembranepermeability;apoptosisCadmiumexposurecanhaveanegativeimpactonthereproductivesystem,particularlyonthequalityandquantityofsperm.Thepresentstudydemonstratedthatdomperidonecaneffectivelyreversetheadverseeffectsofcadmiumexposureonmousespermatogenesis.

Oneofthemajorfindingsofthisstudyisthatdomperidonecansignificantlyimprovespermmotility,whichisessentialforfertility.Spermmotilityisdependentontheintegrityofthemitochondrialmembrane,whichprovidestheenergyrequiredforthemovementoftheflagellum.Cadmiumexposurecancompromisethemitochondrialmembrane,leadingtoreducedmotility.However,domperidonetreatmentcanpreservetheintegrityofthemitochondrialmembrane,therebyenhancingspermmotility.

Anotherimportantfindingofthisstudyisthatdomperidonecaninhibitspermapoptosis.Apoptosisisaprogrammedcelldeathprocessthatplaysacrucialroleinspermatogenesis.However,excessiveapoptosiscanleadtoreducedspermcountandmotility.Cadmiumexposurecaninduceapoptosisinsperm,butdomperidonetreatmentcaneffectivelyinhibitthisprocess,therebypreservingspermquantityandquality.

Finally,thisstudydemonstratedthatdomperidonecanenhancethegeneticstabilityofmousesperm.Cadmiumexposurecaninducegeneticabnormalitiesinsperm,whichcanleadtoinfertilityandbirthdefects.However,domperidonetreatmentcansignificantlyreducetheincidenceofgeneticabnormalities,therebyimprovingthegeneticqualityofthesperm.

Overall,theresultsofthisstudysuggestthatdomperidonecaneffectivelyimprovetheadverseeffectsofcadmium-inducedmousespermatogenesis,particularlybyinhibitingspermapoptosisandmaintainingmitochondrialfunction.FurtherstudiesarewarrantedtoelucidatetheunderlyingmechanismsandpotentialclinicalapplicationsofdomperidoneinthetreatmentofmaleinfertilitycausedbyenvironmentaltoxinsInadditiontothepotentialuseofdomperidoneinthetreatmentofmaleinfertilitycausedbyenvironmentaltoxins,itisimportanttoconsiderotherfactorsthatcanimpactspermatogenesisandmalefertility.Onesuchfactorislifestylehabits,suchassmokingandalcoholconsumption,whichhavebeenshowntohavenegativeeffectsonspermqualityandquantity.

Researchhasalsosuggestedalinkbetweenobesityandmaleinfertility,withincreasedbodymassindex(BMI)associatedwithdecreasedspermcountandmotility.Therefore,weightmanagementandhealthylifestylehabitsmayplayaroleinimprovingmalefertility.

Anotherconsiderationinmaleinfertilityistheuseofassistedreproductivetechnologies(ART),suchasinvitrofertilization(IVF)andintracytoplasmicsperminjection(ICSI).Thesetechniquescanhelpovercomeissueswithspermqualityandquantity,buttheyalsocomewiththeirownsetofrisksandlimitations.

Overall,whiletheuseofdomperidoneshowspromiseinimprovingspermqualityincasesofenvironmentaltoxinexposure,itisimportanttotakeacomprehensiveapproachtomaleinfertilitytreatment,addressingvariouspossiblecontributingfactorsandconsideringallavailabletreatmentoptions.FurtherresearchisnecessarytofullyunderstandthepotentialbenefitsandlimitationsofdomperidoneandothertreatmentsinmaleinfertilityInadditiontomedicaltreatments,therearealsolifestylechangesthatcanimprovemalefertility.Maintainingahealthyweight,avoidingheavyalcoholanddruguse,quittingsmoking,andreducingstressareallimportantfactorsthatcanpositivelyimpactfertility.

Dietisanotherimportantfactortoconsider.Studieshaveshownthatadietrichinfruits,vegetables,wholegrains,andleanproteincanimprovespermquality.Conversely,adiethighinprocessedfoods,sugarydrinks,andredmeathasbeenlinkedtolowerspermcountandmotility.

Alternativetherapies,suchasacupuncture,mayalsobeeffectiveinimprovingmalefertility.Researchhasshownthatacupuncturecanimprovespermmotility,morphology,andconcentration.

Itisimportantformentodiscussfertilityconcernswiththeirhealthcareproviderandundergoathoroughevaluationtoidentifyposs