Assessing Reproductive Toxicity of Various Environmental Toxicants with a Novel in vitro Spermatogenesis Model

用新型体外精子发生模型评估各种环境毒物的生殖毒性

• 批准号: 8870008
• 负责人: Charles A. Easley
• 金额: $ 13.58万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870008
• 关键词: Affect; Applications Grants; Biological Models; Cell Lineage; Cell Proliferation; Cell physiology; Chemicals; Congenital Heart Defects; DNA Methylation; Defect; Development; Disease; Endocrine Disruptors; Environmental Risk Factor; Epigenetic Process; Fertility; Future; Genomic Imprinting; Germ Cells; Haploidy; Human; In Vitro; Infertility; Lead; Limb structure; Medical; Meiosis; Methods; Mitosis; Modeling; Molecular; Parents; Pluripotent Stem Cells; Predisposition; Process; Proliferating; Puberty; Publishing; Risk; Rodent; Rodent Model; Signal Pathway; Spermatids; Spermatocytes; Spermatogenesis; Spermatogonia; Spermiogenesis; Stem cells; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Toxicity Tests; base; disease phenotype; embryonic stem cell; genetic manipulation; human embryonic stem cell; human male; in vitro Model; induced pluripotent stem cell; innovation; male; men; nervous system disorder; novel; offspring; public health relevance; reproductive; reproductive development; sperm cell; toxicant

 DESCRIPTION (provided by applicant) Human male reproductive development is a highly organized and regulated process that is susceptible to environmental toxicants such as endocrine-disrupting chemicals and medical treatments. Environmental influences and insults by reproductive toxicant exposure during early development or post-puberty can lead to impaired spermatogenesis or, at worst, infertility. Understanding how certain chemicals disrupt spermatogenesis during various Windows of Susceptibility (WOS) is critical for determining how environmental and industrial toxicants contribute to impaired fertility. Furthermore, these toxicants can potentially induce epigenetic alterations that contribute to disease phenotypes in offspring and thus have transgenerational consequences such as increased risk of producing offspring with neurological disorders, cardiac malformations, limb defects, and other developmental deficiencies that lead to debilitating disorders. To date, the most widely used models for exploring the effects of environmental factors on reproductive toxicity and multigenerational defects are rodent models. While informative, these models poorly recapitulate human spermatogenesis as rodent spermatogenesis proceeds in a distinctly different fashion compared to human spermatogenesis. Thus, developing human in vitro models for reproductive toxicity testing is paramount for advancing the field and for understanding WOS as well as the cellular and molecular mechanisms that may underlie these disruptions in human spermatogenesis. This proposal seeks to utilize my recently published, novel in vitro model of human spermatogenesis to examine the effects and identify sub-cellular mechanisms of known and unknown/predicted reproductive toxicants on various windows of susceptibility during spermatogenesis.

 描述（由申请人提供） 人类男性生殖发育是一个高度组织和调节的过程，容易受到环境毒物的影响，例如内分泌干扰化学物质和药物治疗。在发育早期或青春期后，环境影响和生殖毒物接触可能导致精子发生受损。最糟糕的是，不孕不育。了解某些化学物质如何在不同的易感性窗口（WOS）期间破坏精子发生对于确定环境和工业毒物如何导致生育力受损至关重要。此外，这些毒物可能会引起表观遗传改变，从而导致生育能力下降。导致后代出现疾病表型，从而产生跨代后果，例如增加后代患神经系统疾病、心脏畸形、肢体缺陷和其他导致衰弱性疾病的发育缺陷的风险。迄今为止，最广泛使用的模型是用于探索其影响。环境因素对生殖毒性和多代缺陷的影响是啮齿动物模型，虽然信息丰富，但这些模型很难概括人类精子发生，因为啮齿动物精子发生的方式与人类精子发生明显不同，因此，开发人类生殖毒性体外模型。测试对于推进该领域和了解 WOS 以及可能导致人类精子发生中断的细胞和分子机制至关重要。本提案旨在利用我最近发表的新型人类精子发生体外模型来检查其影响并确定其影响。已知和未知/预测的生殖毒物对精子发生过程中各种易感性窗口的亚细胞机制。