Developmental toxicity of pesticide synergist/Hedgehog inhibitor PBO

农药增效剂/Hedgehog抑制剂PBO的发育毒性

• 批准号: 10308002
• 负责人: Robert Lipinski
• 金额: $ 33.85万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308002
• 关键词: Acute; Adverse effects; Affect; Agriculture; Attention; Biological; Brain; Chemicals; Communication; Complex; Conceptus; Congenital Abnormality; DNA Sequence Alteration; Development; Disease Outbreaks; Dose; Drug Kinetics; Dysmorphology; Embryonic Development; Environmental Risk Factor; Erinaceidae; Etiology; Face; Female of child bearing age; Forebrain Development; Formulation; Foundations; Genetic; Goals; Holoprosencephaly; Home; Human; Incidence; Individual; Insecticides; Interdisciplinary Study; Investigation; Link; Molecular; Mosquito Control; Mus; Mutation; Outcome; Pathogenesis; Patients; Pesticides; Pharmacology; Plasma; Population; Predisposition; Pregnant Women; Prevention; Prevention strategy; Prosencephalon; Publishing; Research; Risk; Risk Assessment; Rural; SHH gene; Signal Pathway; Sonic Hedgehog Pathway; Structural Congenital Anomalies; Teratogenic effects; Teratogens; Testing; Time; Toxic Environmental Substances; Ursidae Family; Zika Virus; adverse outcome; air sampling; alcohol exposure; clinically relevant; cofactor; critical period; developmental toxicity; disability; environmental agent; exposed human population; gene environment interaction; high risk population; improved; indoor dust; inhibitor; malformation; mouse model; neurobehavioral; neurobehavioral disorder; novel; pesticide poisoning; prenatal; prenatal exposure; prevent; small molecule; smoothened signaling pathway

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.

出生缺陷造成巨大的个人、家庭和社会负担，但发展有针对性的 预防战略在很大程度上受到复杂性的阻碍。前脑无裂畸形（HPE）就是一例， 一种病态的人类前脑和脸部的先天缺陷，被认为是由于 基因突变和环境影响。每250个概念中就有一个，HPE被认为是其中之一。 最常见的人类畸形，并导致幸存患者严重残疾。我们最近 表明HPE的大脑和面部畸形是由于急性抑制声波引起的。 Hedgehog（Shh）途径在早期胚胎发生过程中敏感的关键时期。这个信号通路 本质上对小分子调节敏感，但很少努力鉴定和 表征可能导致人类出生缺陷的环境Shh通路抑制剂。的 环境毒物胡椒基丁醚（PBO）最近被证明可以抑制Shh通路， 我们发现它的产前暴露会导致小鼠的HPE。PBO是一种杀虫剂， 数百种农业和家用产品，在室内灰尘中发现的十大化学物质中， 在孕妇家中的空气样本中检测到75%。与农药中的“活性”成分不同， 尽管PBO的潜在发育毒性已被广泛应用于各种制剂中，但其潜在的发育毒性却很少受到关注。这些研究包括 该应用测试了中心假设，即PBO对Shh信号传导的破坏可以导致明显的 前脑和面部畸形，或更难以识别神经行为缺陷， 具体结果取决于剂量和相互作用的遗传和环境影响。为了验证这一 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 通过药理学激活Shh通路来拯救。然后我们将检查是否有临床意义 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 subteratogenic PBO暴露导致神经行为缺陷，以及是否可以通过靶向治疗来挽救这些缺陷。 然后检查发育中的前脑中Shh通路的激活。最后，我们将确定 在小鼠中引起发育毒性的PBO浓度和在小鼠中的浓度范围 易感人群。本文提出的跨学科研究有望揭示一个光谱 PBO诱导的Shh通路抑制导致的不良结局，定义了 易感性，并确定高风险人群。知情的化学品风险评估和通报 随着人类接触越来越多，目前没有孕妇使用警告， 常见和病态人类出生缺陷的负担。完成这些研究将直接推动我们的 长期的研究目标是通过鉴定和预防病因复杂的人类出生缺陷， 应受谴责和可避免的环境因素的特征。