Developmental toxicity of pesticide synergist/Hedgehog inhibitor PBO

出生缺陷会造成巨大的个人、家庭和社会负担，但有针对性地发展 预防战略在很大程度上受到复杂性的阻碍。这一点以无前脑畸形(HPE)为例， 一种人类前脑和面部的病态先天缺陷，被认为是由易感的相互作用造成的 基因突变和环境影响。每250个胚胎中就有1个发生HPE，这被认为是 是最常见的人类畸形之一，并会导致幸存患者的严重残疾。我们最近 证明HPE的脑和面部畸形是由于Sonic的急性抑制所致 Hedgehog(Shh)途径在胚胎发育早期的敏感期。这条信号通路 本质上对小分子调节很敏感，但几乎没有努力识别和 描述可能导致人类出生缺陷的环境Shh途径抑制物。这个 环境毒物胡椒基丁醚(PBO)最近被证明能抑制Shh途径，并且 我们发现，它在出生前暴露在小鼠身上会引起HPE。PBO是一种杀虫剂增效剂，存在于 在室内粉尘中发现的前十种化学物质中，有数百种农业和家用产品，以及 在75%的孕妇家中空气样本中检测到。与农药中的“活性”成分不同 在配方中，PBO的潜在发育毒性几乎没有受到关注。这些研究包括 这个应用程序验证了中心假设，即PBO对Shh信号的干扰会导致 前脑和面部畸形，或更难识别的神经行为缺陷，与 具体结果取决于剂量和相互作用的遗传和环境影响。为了测试这一点 假设，我们将定义PBO诱导的HPE的分子发病机制，并测试这是否可以 通过Shh通路的药理激活而被拯救。然后我们将检查临床上是否相关 在HPE的发生中，基因突变或环境因素与PBO暴露相互作用。是否 亚致畸PBO暴露会导致神经行为障碍，以及是否可以通过有针对性的治疗来挽救这些缺陷 然后将检测发育中的前脑中Shh通路的激活情况。最后，我们将确定 对小鼠造成发育毒性的PBO浓度和 易感人群。这里提出的跨学科研究有望揭示一种光谱 Shh途径抑制导致的PBO诱导的不良后果，定义关键窗口 易感性，并确定高危人群。化学品的知情风险评估和沟通 随着目前对孕妇没有使用警告的人类接触的增加，可能会减少 常见的和病态的人类出生缺陷的负担。这些研究的完成将直接推动我们的 通过鉴定和鉴定预防病因复杂的人类出生缺陷的长期研究目标 应受责备和可避免的环境因素的特征。

Birth defects cause tremendous individual, familial, and societal burden but development of targeted prevention strategies has been largely stymied by complexity. This is exemplified by holoprosencephaly (HPE), a morbid human birth defect of the forebrain and face thought to result from the interaction of predisposing genetic mutations and environmental influences. Occurring in 1 in 250 conceptuses, HPE is thought to be one of the most common human malformations and causes severe disability in surviving patients. We recently demonstrated that the brain and face malformations of HPE result from acute inhibition of the Sonic Hedgehog (Shh) pathway at a critical period of sensitivity during early embryogenesis. This signaling pathway is intrinsically sensitive to small molecule modulation but little effort has been made to identify and characterize environmental Shh pathway inhibitors that may contribute to human birth defects. The environmental toxicant piperonyl butoxide (PBO) was recently demonstrated to inhibit the Shh pathway, and we found that its prenatal exposure causes HPE in the mouse. PBO is an insecticide synergist present in hundreds of agricultural and home-use products, among the top 10 chemicals found in indoor dust, and detected in 75% of air samples from homes of pregnant women. Unlike “active” components in pesticide formulations, the potential developmental toxicity of PBO has received little attention. The studies comprising this application test the central hypothesis that Shh signaling disruption by PBO can result in overt malformations of the forebrain and face, or more difficult to recognize neurobehavioral deficits, with the specific outcome dependent upon dose and interacting genetic and environmental influences. To test this hypothesis, we will define the molecular pathogenesis of PBO-induced HPE, and test whether this can be rescued by pharmacological activation of the Shh pathway. We will then examine whether clinically relevant genetic mutations or environmental factors interact with PBO exposure in the genesis of HPE. Whether subteratogenic PBO exposure causes neurobehavioral deficits, and whether these can be rescued by targeted activation of the Shh pathway in the developing forebrain will then be examined. Finally, we will determine the PBO concentrations that cause developmental toxicity in the mouse and the range of concentrations in susceptible human populations. The inter-disciplinary studies proposed here are expected to reveal a spectrum of PBO-induced adverse outcomes resulting from Shh pathway inhibition, define critical windows of susceptibility, and identify high-risk populations. Informed risk assessment and communication of a chemical with increasing human exposure that currently bears no usage warning for pregnant women could lessen the burden of common and morbid human birth defects. Completion of these studies will directly advance our long term research goal of preventing etiologically complex human birth defects through the identification and characterization of culpable and avoidable environmental agents.