Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Environ Health Perspect. 2019 Oct;127(10):107006. doi: 10.1289/EHP5260. Epub 2019 Oct 23.
BACKGROUND: Piperonyl butoxide (PBO) is a pesticide synergist used in residential, commercial, and agricultural settings. PBO was recently found to inhibit Sonic hedgehog (Shh) signaling, a key developmental regulatory pathway. Disruption of Shh signaling is linked to birth defects, including holoprosencephaly (HPE), a malformation of the forebrain and face thought to result from complex gene-environment interactions. OBJECTIVES: The impact of PBO on Shh signaling and forebrain and face development was examined. METHODS: The influence of PBO on Shh pathway transduction was assayed in mouse and human cell lines. To examine its teratogenic potential, a single dose of PBO () was administered by oral gavage to mice at gestational day 7.75, targeting the critical period for HPE. Gene-environment interactions were investigated using mice, which model human HPE-associated genetic mutations. RESULTS: PBO attenuated Shh signaling through a mechanism similar to that of the known teratogen cyclopamine. PBO exposure caused characteristic HPE facial dysmorphology including dose-dependent midface hypoplasia and hypotelorism, with a lowest observable effect level of . Median forebrain deficiency characteristic of HPE was observed in severely affected animals, whereas all effective doses disrupted development of Shh-dependent transient forebrain structures that generate cortical interneurons. Normally silent heterozygous null mutations exacerbated PBO teratogenicity at all doses tested, including . DISCUSSION: These findings demonstrate that prenatal PBO exposure can cause overt forebrain and face malformations or neurodevelopmental disruptions with subtle or no craniofacial dysmorphology in mice. By targeting Shh signaling as a sensitive mechanism of action and examining gene-environment interactions, this study defined a lowest observable effect level for PBO developmental toxicity in mice more than 30-fold lower than previously recognized. Human exposure to PBO and its potential contribution to etiologically complex birth defects should be rigorously examined. https://doi.org/10.1289/EHP5260.
背景：胡椒基丁醚 (PBO) 是一种在住宅、商业和农业环境中使用的杀虫剂增效剂。最近发现 PBO 抑制 Sonic hedgehog (Shh) 信号，这是一种关键的发育调节途径。Shh 信号的中断与出生缺陷有关，包括前脑和面部的 holoprosencephaly (HPE)，这是一种被认为是复杂基因-环境相互作用导致的前脑和面部畸形。 目的：研究 PBO 对 Shh 信号和前脑和面部发育的影响。 方法：在小鼠和人细胞系中检测 PBO 对 Shh 途径转导的影响。为了研究其致畸潜力，在妊娠第 7.75 天通过口服灌胃给予 PBO （）单一剂量，以靶向 HPE 的关键时期。使用 小鼠研究基因-环境相互作用，这些小鼠模拟人类 HPE 相关的遗传突变。 结果：PBO 通过类似于已知致畸剂环巴胺的机制减弱 Shh 信号。PBO 暴露导致特征性的 HPE 面部畸形，包括剂量依赖性的中面部发育不良和眼距过窄，最低可观察到的效应水平为 。在严重受影响的动物中观察到具有 HPE 特征的中脑前脑缺陷，而所有有效剂量均破坏了产生皮质中间神经元的 Shh 依赖性短暂前脑结构的发育。在所有测试剂量下，正常沉默的杂合 缺失突变都加剧了 PBO 的致畸性，包括 。 讨论：这些发现表明，产前 PBO 暴露可导致明显的前脑和面部畸形或神经发育障碍，而在小鼠中则无或无颅面畸形。通过靶向 Shh 信号作为敏感的作用机制，并研究基因-环境相互作用，本研究确定了 PBO 在小鼠中的发育毒性的最低可观察到效应水平，比以前认为的低 30 多倍。应该严格检查人类接触 PBO 及其对病因复杂的出生缺陷的潜在贡献。https://doi.org/10.1289/EHP5260.
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