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组织化和受调控的过程，易受环境毒物的影响，如干扰内分泌的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暴露的损害可导致精子发生受损，或在最坏的情况下导致不育。了解某些化学物质如何在不同的敏感窗口（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能力受损至关重要。此外，这些有毒物质可能会诱导表观遗传改变，导致后代的疾病表型，从而产生跨代后果，如产生神经系统疾病、心脏畸形、肢体缺陷和其他发育缺陷的后代的风险增加，导致衰弱性疾病。迄今为止，用于探索环境因素对生殖毒性和多代缺陷的影响的最广泛使用的模型是啮齿动物模型。虽然信息丰富，但这些模型很难概括人类精子发生，因为与人类精子发生相比，啮齿动物精子发生以明显不同的方式进行。因此，开发用于生殖毒性测试的人类体外模型对于推进该领域和理解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。该提案旨在利用我最近发表的新的体外人类精子发生模型来研究已知和未知/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.