Developmental toxicity of pesticide synergist/Hedgehog inhibitor PBO

农药增效剂/Hedgehog抑制剂PBO的发育毒性

基本信息

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
项目类别：
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

项目摘要

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.

出生缺陷会导致巨大的个人，家庭和社会伯恩（Burnen），但有针对性的发展预防策略在很大程度上被复杂性所困扰。这是由Holoprosencephaly（HPE）举例说明的，前脑的病态人类出生缺陷和面部被认为是由于易感性的相互作用而产生的基因突变和环境影响。 HPE在250个概念中发生1个，被认为是一个在最常见的人类畸形中，在幸存的患者中导致严重的残疾。我们最近证明大脑和面对HPE的畸形是由于声音的急性抑制作用而引起的刺猬（SHH）途径在早期胚胎发生期间的敏感性关键时期。此信号通路对小分子调节本质上是敏感的，但几乎没有努力识别和表征可能导致人类出生缺陷的环境SHH途径抑制剂。这最近证明了环境有毒的哌啶丁酰氧化物（PBO）可以抑制SHH途径，并且我们发现其产前暴露会导致小鼠中的HPE。 PBO是存在于数百种农业和家庭用品产品是室内尘埃中发现的十种化学物质，在75％的孕妇房屋中检测到75％的空气样品。与农药中的“活跃”成分不同公式，PBO的潜在发育毒性几乎没有受到关注。研究表明该申请测试中心假设，即PBO造成的SHH信号传导破坏可能导致公开前脑和面部的畸形，或者更难识别神经行为的定义具体结果取决于剂量以及相互作用的遗传和环境影响。测试这个假设，我们将定义PBO诱导的HPE的分子发病机理，并测试是否可以是 SHH途径的药物激活营救。然后，我们将检查临床上是否相关基因突变或环境因素与HPE起源中的PBO暴露相互作用。无论潜在的PBO暴露会导致神经行为定义，以及是否可以通过靶向检索然后将检查发育前脑中SHH途径的激活。最后，我们将确定 PBO浓度引起小鼠的发育毒性和浓度范围易感人口。预计此处提出的跨学科研究将揭示频谱由SHH途径抑制引起的PBO引起的不良结果，定义的关键窗口敏感性并确定高风险人群。明智的风险评估和化学的通信随着人类暴露的增加，目前对孕妇没有使用的用法可能会减少共同和病态的人类先天缺陷的负担。这些研究的完成将直接推动我们的长期的研究目标是通过识别和符合限制和可避免的环境代理的特征。