Epigenetic Defects in Human Spermatozoa: Biomarker of Infertility and Sperm Toxic
Epigenetic Defects in Human Spermatozoa: Biomarker of Infertility and Sperm Toxic
批准号:
8059093
负责人:
Victoria K Cortessis
金额:
$19.44万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-05-10 至 2011-04-30
关键词:
AccountingAffectAmericanAnimalsBase SequenceBiologicalBiological MarkersBiologyCategoriesChildCouplesDNADNA MethylationDataDefectDevelopmentDiagnosisDisciplineDiseaseDistressEpigenetic ProcessEtiologyFertilityFunctional disorderGene ExpressionGenesGerm CellsGerm LinesHealthHumanInfertilityLaboratoriesLeadLifeLightMale InfertilityModificationMorphologyOutcomePathogenesisPatternPhysiologicalPregnancyPreventionProcessResearchRoleScreening procedureSeminal fluidSperm Count ProcedureSpermatogenesisTechniquesTestingToxicant exposurecell motilitydaughter celldesignfrontierimprovedmalemennovel strategiesprogramssperm cellsperm function
中文摘要
大多数男人都认为他们能毫不费力地怀上孩子。然而,10-20%的夫妇
英文摘要
Most men assume they will be able to conceive a child with no difficulty. However, 10-20% of all couples
attempting pregnancy are infertile, with male factor infertility accounting for 40-50% of the cases. For most
male infertility cases, the etiology is unknown and specific therapy is not available. Diagnosis of infertility can
be a distressing life crisis, and the absence of a clear understanding of the pathophysiology of the disease and
the corresponding lack of efficacious treatment for most male-factor infertility underscores the need for novel
approaches to better understand this condition. This proposal seeks to improve the understanding of the
pathophysiology of male factor infertility and the ability to diagnose male infertility by investigating the
epigenetic state of human spermatozoa and defining its physiologic role in male infertility. Epigenetic
programming (altering heritable biological information without changing DNA nucleotide sequence) is a normal
process that leads to modifications of gene activity that can be transmitted to daughter cells. Extensive
epigenetic reprogramming occurs during normal maturation of germ cells and spermatogenesis. However,
improper epigenetic programming can have adverse health effects. Our preliminary data indicate that levels of
one epigenetic indicator, DNA methylation, are elevated in spermatozoa of men who have abnormal sperm
numbers, motility and morphology. This pattern may be expected if disrupted epigenetic programming
predisposes to male infertility. This is particularly intriguing in light of preliminary animal studies suggesting that
toxic exposures that negatively affect semen parameters also alter sperm DNA methylation. We propose that
assessment of DNA methylation profiles in the male germ line provides the opportunity to better understand
the physiologic mechanisms leading to idiopathic male infertility and to develop sensitive biomarkers of
disrupted epigenetic programming. We anticipate that these markers will provide a mechanistic explanation for
a category of idiopathic infertility and improve the diagnosis of and ultimately the treatment of male infertility by
allowing us to study the epigenetic state of the germ cell and its relationship to fertility outcomes. This project
should improve our ability to diagnose male factor infertility by identifying an epigenetic role in the
pathogenesis of male factor infertility and lead to the development of a biomarker of abnormal sperm function
that can be used as 1) a screening test for male factor infertility; 2) a predictor of fertility outcomes in an ART
setting, and 3) a marker/predictor of adverse fertility outcomes following toxic exposures.
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