# Developmental toxicity of pesticide synergist/Hedgehog inhibitor PBO

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $42,749

## Abstract

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...

## Key facts

- **NIH application ID:** 10530751
- **Project number:** 3R01ES026819-05S1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Robert Lipinski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $42,749
- **Award type:** 3
- **Project period:** 2017-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10530751

## Citation

> US National Institutes of Health, RePORTER application 10530751, Developmental toxicity of pesticide synergist/Hedgehog inhibitor PBO (3R01ES026819-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10530751. Licensed CC0.

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