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

二十二碳六烯酸 (DHA) 在精子形态发生和男性生育能力中的作用

• 批准号: 10228609
• 负责人: Benjamin Joseph Hale
• 金额: $ 2.92万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-16 至 2022-01-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228609
• 关键词: Acrosome; Acyl Coenzyme A; Address; Award; Biology; Cell membrane; Cellular Membrane; Cellular Metabolic Process; Coenzyme A; Coenzyme A Ligases; Data; Defect; Development; Diet; Discipline; Docosahexaenoic Acids; Endoplasmic Reticulum; Enzymes; Exhibits; Fatty Acids; Fertility; Flagella; Foundations; Genetic; Germ Cells; Goals; Graduate Education; Head; Heat shock proteins; Human; Impairment; Knock-out; Knockout Mice; Knowledge; Link; Lipids; Male Infertility; Membrane Fluidity; Membrane Lipids; Membrane Proteins; Metabolism; Mitochondria; Modeling; Morphogenesis; Morphology; Omega-3 Fatty Acids; Organelles; Oxidative Stress; Phenotype; Polyunsaturated Fatty Acids; Population; Predisposition; Process; Production; Publishing; Reporting; Reproductive Biology; Research; Risk; Role; Seminal fluid; Series; Solid; Somatic Cell; Sperm Motility; Spermatids; Spermatocytes; Spermatogenesis; Spermatogenic Cell; Spermiogenesis; Supplementation; Testing; Testis; Training; Work; dietary; experimental study; improved; lipid metabolism; male; male fertility; mitochondrial membrane; mouse model; post-doctoral training; reproductive; sperm cell; sperm function; subfertility; tool; western diet

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.

项目摘要/摘要 二十二碳六烯酸是一种欧米茄-3(ω-3)膳食来源的必需多不饱和脂肪酸。 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 它调节膜的流动性，对氧化应激的敏感性，以及膜与蛋白质的相互作用。多重 使用小鼠模型或分析人类种群的研究清楚地表明，DHA缺乏是负面的 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，西方饮食明显缺乏w-3脂肪酸，因此大多数 世界人口面临DHA缺乏症的风险。尽管DHA和DHA之间存在这些明确的联系 男性生育能力、DHA在生精细胞中的作用和作用机制尚不清楚。为了解决这个问题， 盖尔实验室(精子发生专家)与埃利斯实验室(脂代谢专家)合作，这 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。这次培训 将使黑尔博士能够追求长期目标，以确定多不饱和脂肪酸在生殖细胞新陈代谢和 精子的形成和功能。这里提出的项目是我们小组工作的结果，描述了 一种新的不依赖饮食的DHA缺乏症遗传小鼠模型 6‘(Acsl6)，编码细胞DHA代谢所必需的一种酶。我们最近报道了全身 Acsl6基因敲除(KO)小鼠睾丸DHA水平显著降低，精子发生多处缺陷， 并且是严重不育的。这些Acsl6 KO小鼠是定义特定机制的理想工具 DHA在精子发生中的作用。我们将直接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。我们将测试ACSL6需要合并的中心假设 DHA进入生殖细胞脂膜，促进精子形态发生。这一假设将在 目的如下：1)确定Acsl6 KO精子如何有缺陷；2)确定DHA在精子发育过程中的作用。 精子发生。这些目标的完成将提供一个前所未有的了解如何 将DHA掺入生殖细胞可促进精子的形态发生和功能。