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 birth defects through the identification and characterization of culpable and avoidable environmental agents.

Public Health Relevance

This project examines the effects of piperonyl butoxide on embryonic development of the brain and face, particularly in relation to structural birth defects and neurobehavioral disorders. This compound is present in pesticide formulations with increasing human exposure. The long-term goal is to lessen the incidence of these adverse outcomes through informed risk assessment and communication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES026819-03
Application #
9836852
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Mcallister, Kimberly A
Project Start
2017-12-01
Project End
2022-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715