Journal Article

The Insecticide Synergist Piperonyl Butoxide Inhibits Hedgehog Signaling: Assessing Chemical Risks

Jiangbo Wang, Jiuyi Lu, Robert A. Mook, Min Zhang, Shengli Zhao, Larry S. Barak, Jonathan H. Freedman, H. Kim Lyerly and Wei Chen

in Toxicological Sciences

Volume 128, issue 2, pages 517-523
Published in print August 2012 | ISSN: 1096-6080
Published online May 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs165
The Insecticide Synergist Piperonyl Butoxide Inhibits Hedgehog Signaling: Assessing Chemical Risks

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The spread of chemicals, including insecticides, into the environment often raises public health concerns, as exemplified by a recent epidemiologic study associating in utero piperonyl butoxide (PBO) exposure with delayed mental development. The insecticide synergist PBO is listed among the top 10 chemicals detected in indoor dust; a systematic assessment of risks from PBO exposure, as for many toxicants unfortunately, may be underdeveloped when important biological targets that can cause toxicity are unknown. Hedgehog/Smoothened signaling is critical in neurological development. This study was designed to use novel high-throughput in vitro drug screening technology to identify modulators of Hedgehog signaling in environmental chemicals to assist the assessment of their potential risks. A directed library of 1408 environmental toxicants was screened for Hedgehog/Smoothened antagonist activity using a high-content assay that evaluated the interaction between Smoothened and βarrestin2 green fluorescent protein. PBO was identified as a Hedgehog/Smoothened antagonist capable of inhibiting Hedgehog signaling. We found that PBO bound Smoothened and blocked Smoothened overexpression–induced Gli-luciferase reporter activity but had no effect on Gli-1 downstream transcriptional factor–induced Gli activity. PBO inhibited Sonic Hedgehog ligand–induced Gli signaling and mouse cerebellar granular precursor cell proliferation. Moreover, PBO disrupted zebrafish development. Our findings demonstrate the value of high-throughput target-based screening strategies that can successfully evaluate large numbers of environmental toxicants and identify key targets and unknown biological activity that is helpful in properly assessing potential risks.

Keywords: piperonyl butoxide; Smoothened antagonist; Hedgehog signal transduction pathway; high throughput screening; chemical risk assessment.

Journal Article.  4854 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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