The role of docosahexaenoic acid (DHA) in sperm morphogenesis and male fertility

项目总结/摘要 二十二碳六烯酸（DHA）是一种ω-3（ω-3）膳食衍生的必需多不饱和脂肪酸（PUFA） 在睾丸中含量特别高。DHA是线粒体和细胞膜的重要组成部分 调节膜流动性、对氧化应激的敏感性和膜-蛋白质相互作用。多 使用小鼠模型或分析人群的研究清楚地表明， 影响精子发生导致男性不育，补充DHA可改善精液质量 和生育能力。不幸的是，西方饮食中明显缺乏w-3脂肪酸，因此大多数人都缺乏w-3脂肪酸。 全世界的人都有患DHA缺乏症的危险。尽管DHA和 男性生育力，DHA的作用和机制的作用，在生精细胞仍然是未知的。为了解决这个问题， 盖耶实验室（精子发生专家）与埃利斯实验室（脂质代谢专家）合作， 独特的合作伙伴关系为申请人（本黑尔博士）提供了这两个学科的正式培训。本次培训 将使黑尔博士能够追求长期目标，以确定PUFA在生殖细胞代谢中的作用， 精子的形成和功能本文中提出的项目是我们小组工作的产物， 一种新的非饮食依赖性的DHA缺乏遗传小鼠模型，通过整体缺失酰基辅酶A合成酶 6'（Acsl 6），其编码细胞DHA代谢所必需的酶。我们最近报告说， Acsl 6敲除（KO）小鼠具有显著降低的睾丸DHA水平，精子发生的多重缺陷， 而且生育能力严重不足这些Acsl 6 KO小鼠是定义潜在的特定机制的理想工具。 DHA在精子发生中的作用。我们将精子功能和形态发生的缺陷与 生殖细胞脂质分布的变化。我们将检验中心假设，即ACSL 6需要纳入 DHA进入生殖细胞脂质膜，促进精子形态发生。这一假设将在 以下目的：1）确定Acsl 6 KO精子是如何有缺陷的，以及2）确定DHA在精子发育过程中的作用。 精子发生这些目标的完成将使人们前所未有地了解 DHA掺入生殖细胞促进精子形态发生和功能。

PROJECT SUMMARY/ABSTRACT Docosahexaenoic acid (DHA) is an omega-3 (ω-3) dietary-derived essential polyunsaturated fatty acid (PUFA) present in particularly high levels in testes. DHA is a critical component of mitochondrial and cellular membranes that regulates membrane fluidity, susceptibility to oxidative stress, and membrane-protein interactions. Multiple studies using mouse models or analyzing human populations have clearly shown that DHA deficiency negatively impacts spermatogenesis to cause male infertility, and that supplementation with DHA improves semen quality and fertility. Unfortunately, Western diets are remarkably deficient in w-3 fatty acids, and therefore a majority of the world’s population is at risk for DHA-deficiency. Despite these clearly established links between DHA and male fertility, DHA’s role and mechanism of action in spermatogenic cells remain unknown. To address this, the Geyer lab (experts in spermatogenesis) has partnered with the Ellis lab (experts in lipid metabolism), and this unique partnership has provided the applicant (Dr. Ben Hale) with formal training in both disciplines. This training will enable Dr. Hale to pursue the long-term goals to define the roles of PUFAs in germ cell metabolism and sperm formation and function. The proposed project herein is an outgrowth of work from our group characterizing a new diet-independent genetic mouse model of DHA deficiency by whole-body deletion of ‘acyl-CoA synthetase 6’ (Acsl6), which encodes an enzyme essential for cellular DHA metabolism. We recently reported whole-body Acsl6 knockout (KO) mice have significantly reduced testicular DHA levels, multiple defects in spermatogenesis, and are severely subfertile. These Acsl6 KO mice are the ideal tool to define the specific mechanisms underlying DHA function in spermatogenesis. We will directly correlate defects in sperm function and morphogenesis to changes in germ cell lipid distribution. We will test the central hypothesis that ACSL6 is required to incorporate DHA into germ cell lipid membranes to facilitate sperm morphogenesis. This hypothesis will be tested in the following Aims: 1) Determine how Acsl6 KO sperm are defective, and 2) determine the roles of DHA during spermatogenesis. The completion of these Aims will provide an unprecedented understanding of how incorporation of DHA into the germ cell facilitates sperm morphogenesis and function.