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: 10197508
• 负责人: Robert Lipinski
• 金额: $ 3.05万
• 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 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197508
• 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; Dust; Dysmorphology; Embryonic Development; Environmental Risk Factor; Erinaceidae; Etiology; Face; Female of child bearing age; Forebrain Development; Formulation; Foundations; Genetic; Goals; Holoprosencephaly; Home environment; 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; inhibitor/antagonist; 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，但有针对性的发展 预防策略在很大程度上因复杂性而受到阻碍。前脑无裂畸形 (HPE) 就是一个例子， 人类前脑和面部的一种病态先天缺陷，被认为是由诱发因素相互作用造成的 基因突变和环境影响。 HPE 被认为是每 250 个概念中就有 1 个出现的案例之一 最常见的人类畸形，并导致幸存患者严重残疾。我们最近 证明 HPE 的大脑和面部畸形是由声波的急性抑制引起的 Hedgehog (Shh) 通路处于早期胚胎发生过程中敏感的关键时期。该信号通路 本质上对小分子调节敏感，但很少有人努力去识别和 表征可能导致人类出生缺陷的环境 Shh 通路抑制剂。这 最近证明环境毒物胡椒基丁醚 (PBO) 可以抑制 Shh 通路，并且 我们发现其产前暴露会导致小鼠发生 HPE。 PBO 是一种杀虫增效剂，存在于 数百种农产品和家用产品，属于室内灰尘中发现的十大化学物质，以及 孕妇家中 75% 的空气样本中均检测到了这种物质。与农药中的“活性”成分不同 制剂中，PBO 的潜在发育毒性很少受到关注。研究包括 该应用程序测试了中心假设，即 PBO 干扰 Shh 信号传导可能会导致明显的 前脑和面部畸形，或者更难以识别的神经行为缺陷， 具体结果取决于剂量以及相互作用的遗传和环境影响。为了测试这个 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 通过药物激活 Shh 途径来拯救。然后我们将检查是否有临床相关性 在 HPE 的发生过程中，基因突变或环境因素与 PBO 暴露相互作用。无论 亚致畸性 PBO 暴露会导致神经行为缺陷，以及是否可以通过针对性治疗来挽救这些缺陷 然后将检查发育中前脑中 Shh 通路的激活情况。最后，我们将确定 引起小鼠发育毒性的 PBO 浓度及其浓度范围 易感人群。这里提出的跨学科研究预计将揭示一系列 的 PBO 诱导的由 Shh 通路抑制引起的不良后果，定义了关键窗口 易感性，识别高危人群。化学品的知情风险评估和沟通 随着人类暴露量的增加，目前没有针对孕妇的使用警告，可能会减少 常见和病态人类出生缺陷的负担。完成这些研究将直接推进我们的 长期研究目标是通过识别和预防病因复杂的人类出生缺陷 有罪和可避免的环境因素的特征。