Examining the developmental toxicity of piperonyl butoxide as a Sonic hedgehog pathway inhibitor.
Examining the developmental toxicity of piperonyl butoxide as a Sonic hedgehog pathway inhibitor.
复制标题
检查胡椒基丁醚作为Sonic hedgehog通路抑制剂的发育毒性。
DOI：
10.1016/j.chemosphere.2020.128414
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发表时间：
2021-03
期刊：
影响因子：
8.8
通讯作者：
Lipinski, Robert J.
中科院分区：
文献类型：
--
作者：
Rivera-Gonzalez, Kenneth S.;Beames, Tyler G.;Lipinski, Robert J.
丁醚双壬酯（PBO）是一种半合成化学品，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，并且通常以比活性杀虫成分高得多的浓度存在。PBO最近被发现还抑制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，宫内PBO暴露可导致明显的颅面畸形或更微妙的神经发育异常。人类的相关不良发育结局在病因上是异质性的，虽然研究有限，但妊娠期间暴露于PBO与神经发育缺陷有关。在PBO作为Shh信号传导抑制剂的新认识机制的背景下，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产前PBO暴露对发育的影响。还提出了关键的知识差距，我们的理解PBO的药代动力学和潜在的作用，基因-环境和环境-环境的相互作用，应解决更好地了解环境PBO暴露对人类健康的影响。
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.
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