ContraPest-an oral bait for fertility management of rodent pests

描述（由申请人提供）：啮齿类害虫已经吃了我们的食物，并将疾病传播给我们数千年。据估计，美国有3亿只引进的挪威或棕色老鼠，每年造成270亿美元的经济损失。 历史上的策略一直是通过各种方法杀死老鼠害虫，但主要是通过使用抗凝血灭鼠剂毒饵。除了与使用毒饵相关的所有问题之外，例如毒害非目标动物/宠物、6岁以下的儿童以及污染环境，毒药不能解决问题。一个非致命的战略，具有显着的潜力，以管理啮齿动物害虫的数量是生育控制。但迄今为止，尚未实现对自由放养的野生动物（如小型夜行啮齿动物）的有效控制，因为必须通过口服途径向大鼠分配剂量。工业化学品4-乙烯基环己烯二环氧化物（VCD）加速闭锁的自然过程，导致大鼠卵巢卵泡耗竭，导致卵巢衰竭和永久性不育。当VCD每日重复腹膜内给药时，发生卵泡耗竭，平均而言，原始/初级卵泡完全消除，在给药开始后第58天发生卵巢早衰，在小鼠中导致不育。迄今为止，VCD诱导的卵泡耗竭已通过腹膜内给药实现。然而，为了开发和商业化一种导致野鼠不育的产品，它必须在诱饵中口服。这个第一阶段的应用程序旨在测试以下三个具体目标的假设。大鼠经口给予VCD将导致卵泡群完全耗竭，导致不育，证明了开发大鼠生育控制诱饵的可行性。目标1。确定通过经口暴露于VCD消耗大鼠原始卵泡所需的剂量。目标二。确定VCD完全消耗卵泡群的时间进程。目标3：测定VCD排泄的药代动力学。I期实验的结果将确定导致卵泡完全耗竭所需的VCD暴露剂量和持续时间。这些结果将使我们能够获得足够的信息，以进入第二阶段应用，开发口服诱饵和诱饵方案来管理野生动物啮齿动物种群。这些研究以大鼠为目标，因为大鼠比小鼠对VCD更具抵抗力。因此，在大鼠身上取得的成功，很容易就能应用到小鼠身上。此外，老鼠是主要的目标害虫物种，这是基于它们通过污染和破坏我们的食物供应以及目前用于管理老鼠种群的危险灭鼠剂控制方法而造成的巨大经济和重大公共卫生风险。PHS 398/2590（Rev. 11/07） 公共卫生相关性：管理野鼠对于最大限度地减少农业和财产损失以及传染病的传播至关重要。致命的方法将毒物引入环境中，因此正成为从非处方药中去除的目标。该项目的目标是提供数据支持使用工业化学品4-乙烯基环己烯二环氧化物（VCD）的可行性，以最终开发一种环境中性的永久性啮齿动物生育控制诱饵来管理野生大鼠种群

DESCRIPTION (provided by applicant): Rodent pests have eaten our food and transmitted diseases to us for millennia. There are an estimated 300 million introduced Norway or brown rats in the U.S. that cause $27 billion of economic losses annually. Historically the strategy has been to kill rat pests through a variety of methods but primarily by using poison baits that are anticoagulant rodenticides. In addition to all of the problems associated with using poison bait, e.g. poisoning nontarget animals/pets, children under the age of 6, and contaminating the environment, poison does not address the problem. A non-lethal strategy that has significant potential to manage rodent pest number is fertility control. But thus far effective control of free-ranging wildlife, such as small, nocturnal rodents, has not been achieved because distribution to dose rats must be via an oral route. The industrial chemical 4-vinylcyclohexene diepoxide (VCD) accelerates the natural process of atresia leading to depletion of rat ovarian follicles causing ovarian failure and permanent sterility. Follicle depletion occurs when VCD is given in repeated intraperitoneal daily doses and on average, complete elimination of primordial/primary follicles and premature ovarian failure occur by day 58 following the onset of dosing and in mice causes infertility. To date VCD induced follicle depletion has been achieved by intraperitoneal administration. However to develop and commercialize a product to cause wild rat infertility it must be given orally in a bait. This Phase I application aims to test the following hypothesis in three specific aims. Oral administration of VCD to rats will lead to complete depletion of ovarian follicle populations, resulting in infertility demonstrating feasibility for development of a fertility control bait for rats. Aim 1. Determine the dose needed to deplete primordial ovarian follicles in rats by oral exposures to VCD. Aim 2. Determine the time course over which VCD completely depletes ovarian follicle populations. Aim 3. Determine the pharmacokinetics of VCD excretion. Results from Phase I experiments will define the dose and duration of VCD exposure necessary to cause complete ovarian follicle depletion. These results will enable us to obtain sufficient information to progress to a Phase II application to develop an oral bait and baiting protocol to manage wildlife rodent populations. Rats are being targeted in these studies, with the understanding that rats are more resistant to VCD than mice. Thus, success with rats, can easily be translated to mice. Furthermore, rats are the primary target pest species based on the enormous economic and significant public health risks they pose both by their contamination and destruction of our food supplies and the dangerous rodenticide control approaches currently being used to manage rat populations. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Management of wild rats is critical to minimize agriculture and property damage and the spread of infectious diseases. Lethal approaches introduce poison into the environment and consequently are being targeted for removal from over the counter availability. The goal of this project is to provide data to support the feasibility of using the industrial chemical 4-vinylcyclohexene diepoxide (VCD) to ultimately develop an environmentally neutral permanent rodent fertility control bait to manage wild rat populations