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

大多数男人认为他们能够毫无困难地怀上孩子。然而，10-20%的夫妇 试图怀孕的妇女是不育的，其中男性因素不育占40-50%。对于大多数 男性不育病例，病因不明，没有具体的治疗方法。不孕症的诊断可以 是一个令人痛苦的生活危机，缺乏对疾病的病理生理学的明确理解， 对大多数男性因素不育症缺乏有效的治疗，这就强调了对新的治疗方法的需要。 方法来更好地了解这种情况。这项建议旨在增进对 男性因素不育症的病理生理学和通过调查男性不育症的发病率来诊断男性不育症的能力。 人类精子的表观遗传状态，并确定其在男性不育中的生理作用。后生 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。 这一过程导致基因活性的改变，可以传递给子细胞。广泛 表观遗传重编程发生在生殖细胞和精子发生的正常成熟过程中。然而，在这方面， 不适当的表观遗传编程会对健康产生不利影响。我们的初步数据表明， 精子异常的男性精子中的一个表观遗传指标DNA甲基化水平升高 数量、运动性和形态学。如果表观遗传编程被破坏， 容易导致男性不育鉴于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 对男性生殖系DNA甲基化谱的评估提供了更好地了解 导致特发性男性不育的生理机制，并开发敏感的生物标志物， 破坏了表观遗传程序我们预期这些标记物将为 一类特发性不育症，并通过以下方式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 应该通过确定表观遗传作用来提高我们诊断男性因素不育症的能力。 男性因素不育的发病机制，并导致精子功能异常的生物标志物的发展 可用作1）男性因素不孕症的筛查试验; 2）ART中生育结果的预测因子 环境，以及3）毒性暴露后不良生育结果的标志物/预测因子。

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.