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

 描述(由申请人提供) 人类男性生殖发育是一个高度有组织和受管制的过程，容易受到环境毒物的影响，如干扰内分泌的化学品和医疗。在发育早期或青春期后暴露生殖毒物对环境的影响和侮辱可能会导致精子发生受损，最糟糕的是，会导致不育。了解某些化学物质如何在不同的敏感性窗口(WOS)期间干扰精子发生，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，从而导致后代的疾病表型，从而产生跨代后果，如增加生下患有神经疾病、心脏畸形、肢体缺陷和其他导致衰弱疾病的发育缺陷的后代的风险。到目前为止，在探索环境因素对生殖毒性和多代缺陷的影响方面应用最广泛的模型是啮齿动物模型。虽然信息丰富，但这些模型不能很好地概括人类的精子发生，因为啮齿动物的精子发生与人类精子发生的方式截然不同。因此，开发用于生殖毒性测试的人体体外模型对于推动该领域的发展和了解WOS以及可能导致这些人类精子发生中断的细胞和分子机制至关重要。这项建议试图利用我最近发表的人类精子发生的体外模型来检查已知和未知/预测的生殖毒物对精子发生过程中各种易感性窗口的影响并确定亚细胞机制。

 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.