Environmental influence on gametes and embryos

哺乳动物受精的一个普遍特征是，精子在卵中引起一系列重复的钙振荡，持续数小时，并以原核形成终止。小鼠中的这种钙振荡模式对于响应于受精的卵激活的早期事件和发生的足月子宫内发育都是必不可少的。精子内负责诱导这些钙振荡的因子是睾丸特异性磷脂酶C，PLC zeta，其在精卵质膜融合后从精子头部释放，并且在迄今为止研究的所有哺乳动物精子中发现，包括人类。我们正在研究PLC zeta功能在人类精子样本中获得完成临床体外受精程序。我们假设缺乏足够的PLC zeta活性来诱导卵子激活所需的适当钙振荡可以解释不孕夫妇的失败，包括受精失败，植入前胚胎发育不良，甚至临床妊娠后流产。我们在研究中招募了154对不孕夫妇，并从80多个程序中获得了精子样本。收集的数据将在2013年秋季完成数据报告时进行分析。 钙的波动也受鸡蛋内因素的控制。正在使用小鼠模型进行其他研究，以检查卵子内负责控制钙振荡行为和钙再吸收的分子，这些过程对于受精时钙振荡的持续至关重要。我们产生了磷脂酶C β 1基因的条件性小鼠敲除。该基因正在从小鼠卵中删除，以确定卵蛋白是否是产生功能性钙振荡所必需的。我们预计，通过更好地了解卵子激活过程中钙振荡行为的分子和细胞调节模式，我们可以了解早期胚胎发育如何被环境因素和疾病状态改变。 许多必需分子由休眠直到卵母细胞成熟的母体mRNA编码。这些分子之一是介体复合物的组成部分，有助于调节胚胎DNA的转录。我们目前正在研究的功能，调解人复合物亚基在编程基因表达在早期植入前胚胎发育。这些研究将揭示暴露于环境化学品可能会破坏的基本遗传过程，并可能影响人类生育能力。

A universal feature of fertilization in mammals is that the fertilizing sperm evokes a series of repetitive calcium oscillations in the egg that persist for several hours and terminate with pronucleus formation. This pattern of calcium oscillations in mice is essential for both early events of egg activation in response to fertilization and for full term intrauterine development to occur. The factor within sperm responsible for inducing these calcium oscillations is a testis-specific phospholipase C, PLC zeta, which is released from the sperm head after sperm-egg plasma membrane fusion, and is found in all mammalian sperm studied to date, including human. We are studying PLC zeta function in human sperm samples obtained at completion of clinical in vitro fertilization procedures. We hypothesize that a lack of sufficient PLC zeta activity to induce appropriate calcium oscillations required for egg activation could explain a spectrum of failure for the infertile couple, including failed fertilization, poor preimplantation embryo development, and even clinical pregnancy followed by miscarriage. We enrolled 154 infertile couples in the study and obtained sperm samples from over 80 procedures. The data collected will be analyzed when data reporting is complete in the fall, 2013. Calcium oscillations are also controlled by factors within the egg. Additional studies are being performed using the mouse model to examine molecules within the egg that are responsible for controlling calcium oscillation behavior and calcium reuptake, processes that are essential for the continuation of calcium oscillations at fertilization. We generated a conditional mouse knockout of the phospholipase C beta 1 gene. This gene is in the process of being genetically deleted from mouse eggs to determine if the egg protein is needed for production of functional calcium oscillations. We anticipate that by achieving a better understanding of the molecular and cellular modes of regulation of calcium oscillatory behavior during egg activation, we can learn how early embryo development is altered by environmental factors and by disease states. A number of essential molecules are encoded by maternal mRNAs that are dormant until oocyte maturation. One of these molecules is a component of the Mediator complex that helps regulate transcription from the embryonic DNA. We are currently examining the function of a mediator complex subunit in programming gene expression during early preimplantation embryo development. These studies will shed light on basic genetic processes that can be disrupted by exposure to environmental chemicals and could impact on human fertility.