Piperonyl butoxide (PBO) is a semisynthetic chemical present in hundreds of pesticide formulations used in agricultural, commercial, and residential settings. PBO acts as a pesticide synergist by inhibiting insect cytochrome P450 enzymes and is often present at much higher concentrations than active insecticidal ingredients. PBO was recently discovered to also inhibit Sonic hedgehog (Shh) signaling, a key molecular pathway in embryonic development and in brain and face morphogenesis. Recent animal model studies have shown that in utero PBO exposure can cause overt craniofacial malformations or more subtle neurodevelopmental abnormalities. Related adverse developmental outcomes in humans are etiologically heterogeneous, and, while studies are limited, PBO exposure during pregnancy has been linked to neurodevelopmental deficits. Contextualized in PBO’s newly recognized mechanism as a Shh signaling inhibitor, these findings support more rigorous examination of the developmental toxicity of PBO and its potential contribution to etiologically complex human birth defects. In this review, we highlight environmental sources of human PBO exposure and summarize existing animal studies examining the developmental impact of prenatal PBO exposure. Also presented are critical knowledge gaps in our understanding of PBO’s pharmacokinetics and potential role in gene-environment and environment-environment interactions that should be addressed to better understand the human health impact of environmental PBO exposure.

胡椒基丁醚 (PBO) 是一种半合成化学物质，存在于农业、商业和住宅环境中使用的数百种农药制剂中。PBO 通过抑制昆虫细胞色素 P450 酶作为杀虫剂增效剂，并且通常以比活性杀虫成分高得多的浓度存在。最近发现 PBO 还可以抑制 Sonic Hedgehog (Shh) 信号传导，这是胚胎发育以及大脑和面部形态发生中的关键分子途径。最近的动物模型研究表明，在子宫内PBO 暴露可导致明显的颅面畸形或更细微的神经发育异常。人类相关的不良发育结果在病因学上是异质的，虽然研究有限，但怀孕期间的 PBO 暴露与神经发育缺陷有关。在 PBO 新发现的作为 Shh 信号传导抑制剂的机制中，这些发现支持对 PBO 的发育毒性及其对病因复杂的人类出生缺陷的潜在贡献进行更严格的检查。在这篇综述中，我们强调了人类 PBO 暴露的环境来源，并总结了现有的动物研究，这些研究检查了产前 PBO 暴露对发育的影响。