Epigenetic Defects in Human Spermatozoa: Biomarker of Infertility and Sperm Toxic

大多数男人认为他们可以毫无困难地怀上孩子。然而，10%-20%的夫妇 尝试怀孕是不育的，其中男性因素不孕不育占40%-50%。对大多数人来说 男性不育病例，病因不明，也没有特效治疗方法。不孕症的诊断可以 是一种令人痛苦的生活危机，对疾病的病理生理学和 相应地，缺乏对大多数男性因素不育症的有效治疗，突显了创新的必要性 更好地了解这种情况的方法。这项建议旨在提高对 男性因素不育症的病理生理学及对男性不育的诊断能力 人类精子的表观遗传状态及其在男性不育中的生理作用。表观遗传 编程(在不改变DNA核苷酸序列的情况下改变可遗传的生物信息)是正常的 导致基因活性改变的过程，基因活性可以传递给子细胞。广泛性 表观遗传重编程发生在生殖细胞的正常成熟和精子发生过程中。然而， 不适当的表观遗传编程可能会对健康产生不利影响。我们的初步数据表明， 一种表观遗传学指标DNA甲基化在精子异常的男性精子中升高 数量、运动性和形态。如果表观遗传编程中断，这种模式是可以预期的 容易导致男性不育。这一点特别耐人寻味，因为初步的动物研究表明 对精液参数产生负面影响的毒性暴露也会改变精子DNA甲基化。我们建议 对雄性生殖系DNA甲基化情况的评估提供了更好地了解 特发性男性不育的生理机制及开发敏感的生物标志物 打乱了表观遗传程序。我们预计这些标记物将为 一类特发性不育症，通过以下方法改善男性不育症的诊断和最终治疗 使我们能够研究生殖细胞的表观遗传状态及其与生育结果的关系。这个项目 应该提高我们诊断男性因素不育症的能力，通过确定表观遗传学在 男性因素不育症的发病机制和导致精子功能异常的生物标志物的发展 这可以被用作1)男性因素不育症的筛查试验；2)ART中生育结局的预测指标 环境，以及3)有毒暴露后不良生育后果的标记/预测因素。

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.