Reversal of Spermatogonial Arrest in Mice

逆转小鼠精原细胞停滞

• 批准号: 8041059
• 负责人: Marvin L. Meistrich
• 金额: $ 30万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8041059
• 关键词: Adolescent; Affect; Androgens; Biological; Body Temperature; Cell Differentiation process; Cells; Defect; Development; Event; Experimental Animal Model; Genes; Genetic; Germ Cells; High temperature of physical object; Hormones; Human; In Vitro; Infertility; Lead; Link; Male Infertility; Metabolic; Metabolism; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Oligospermia; Process; Publications; Publishing; RNA Processing; Regulation; Research; Ribosomal RNA; Sperm Count Procedure; Spermatocytes; Spermatogenesis; Spermatogonia; Staging; Temperature; Testing; Testosterone; Toxicant exposure; Toy; in vivo; insight; men; soy; sperm cell; spermatogonial arrest; toxicant

DESCRIPTION (provided by applicant): Genetic defects or toxicant exposure often result in blocks in early germ cell development, but in some cases elevation of temperature or lowering testosterone levels can overcome this block. This suggests that the low scrotal temperatures and high intratesticular testosterone may not be optimal for spermatogonial and spermatocyte development in these pathological cases, and that effects restorative of testosterone suppression and elevated temperature might be mechanistically linked. We hypothesize that suppression of testosterone elevates testicular temperature, which then enhances general or specific metabolic events to overcome genetic or toxicant induced blocks. The juvenile spermatogonial depletion (jsd) mutant mouse is one model to study the mechanisms by which elevated temperature and hormone suppression can alleviate the block in spermatogonial differentiation. Jsd is a mutation in the Utp14b gene, which is involved in ribosomal RNA processing. Utp14b is a copy of the widely expressed (except spermatocytes) X linked Utp14a gene. Utp14b is mainly expressed in germ cells. We propose that in jsd mice, testosterone suppression leads to a gradual temperature increase, which restores ribosomal RNA processing by upregulating Utp14a in spermatogonia and/or spermatocytes. We will test between this model and alternatives with the following Specific Aims: (I) Determine whether testosterone suppression elevates testicular temperature in vivo, whether testosterone inhibits spermatogonial differentiation by acting on cells involved in temperature regulation, and whether temperature but not testosterone affects differentiation in vitro. (II) Determine if 18S ribosomal RNA processing is defective in both spermatogonia and spermatocytes of jsd mice at scrotal temperatures, and if processing is more efficient at body temperature. (III) Determine the specific or general metabolic processes that are altered by elevation of temperature to overcome the defects in germ cell differentiation. If temperature elevation restores 18S rRNA processing in jsd mice, then increases in Utp14a levels in germ cells will be examined as a specific compensatory mechanism. In addition, (IV) we will evaluate the application of testosterone suppression and elevated temperature to enhance spermatogonial development in irradiated mice, a toxicant induced model of hypospermatogenesis. These results will provide insight into the molecular mechanisms underlying aspects of temperature and androgen effects on spermatogenesis and reveal a direct mechanistic link between these two modulators. This information would significantly contribute to both our basic understanding of the biological mechanisms involved in spermatogenesis, and to possible treatments for oligospermia or azoospermia in men. Partial or complete blocks at the early stages of spermatogenesis results in low or zero sperm counts, a problem that appears to be increasing in men. Elucidation of the causes of such blocks and the mechanisms by which temperature elevation and hormone suppression can reverse them in experimental animal models could apply to treatment of genetically or environmentally caused male infertility in humans. Further, proof of our hypothesis that the effects of testosterone suppression and temperature elevation are mechanistically linked would lead to new insights and interpretations of published research.

描述（由申请人提供）：遗传缺陷或毒性暴露通常会导致生殖细胞早期发育的阻滞，但在某些情况下，温度升高或降低睾丸激素水平可以克服该障碍。这表明在这些病理病例中，阴囊温度低和高静脉内睾丸激素可能对精子和精子细胞发育而言可能不是最佳的，并且可能会恢复睾丸激素抑制和升高的温度。我们假设抑制睾丸激素会升高睾丸温度，然后增强了一般或特定的代谢事件，以克服遗传或毒性诱导的块。少年精子耗竭（JSD）突变小鼠是研究温度升高和激素抑制可以减轻精子分化中块的机制的一种模型。 JSD是UTP14B基因中的突变，它参与了核糖体RNA加工。 UTP14B是广泛表达的（精子细胞除外）X链接的UTP14A基因的副本。 UTP14B主要在生殖细胞中表达。我们提出，在JSD小鼠中，睾丸激素抑制会导致逐渐升高，从而通过上调精子症和/或精子细胞来恢复核糖体RNA加工。我们将在该模型和以下特定目的之间进行测试：（i）确定睾丸激素抑制在体内是否升高睾丸温度，睾丸激素是否通过作用于参与温度调节的细胞以及温度和睾丸激素不影响体内分化的细胞来抑制精子分化。 （ii）确定在阴囊温度下的JSD小鼠的精子和精子细胞中，18S核糖体RNA加工是否有缺陷，以及在体温下加工是否更有效。 （iii）确定因温度升高而改变的特定或一般代谢过程，以克服生殖细胞分化的缺陷。如果温度升高恢复了JSD小鼠中的18S rRNA处理，则将检查生殖细胞中UTP14A水平的增加作为特定的补偿机制。此外，（iv）我们将评估睾丸激素抑制和升高温度的应用，以增强辐射小鼠的精子发育，这是一种毒性诱导的性衰竭模型。这些结果将为温度和雄激素对精子发生的影响的分子机制提供洞察力，并揭示这两个调节剂之间的直接机械联系。这些信息将大大有助于我们对涉及精子发生的生物学机制的基本理解，以及对男性寡头植物的可能治疗方法。 精子发生的早期阶段的部分或完整块导致精子计数低或零，这一问题似乎正在增加。在实验动物模型中阐明了这种块的原因以及温度升高和激素抑制可以逆转它们的机制，可以应用于人类遗传或环境造成的男性不育症的治疗。此外，我们的假设证明了睾丸激素抑制和温度升高的作用是机械上联系的，这将导致对已发表研究的新见解和解释。