Robert Lipinski, Ph.D.
University of Wisconsin-Madison
NIEHS grantees found that a chemical commonly used to make pesticides more effective, called piperonyl butoxide (PBO), can cause rare birth defects in the brains and faces of mice exposed in the womb. They examined how PBO exposure can interfere with a signaling pathway called sonic hedgehog (Shh), which is critical for many aspects of early development, including formation of the brain.
To uncover how PBO interferes with normal Shh signaling, the researchers exposed mouse and human cells to PBO and to two other compounds known to result in brain defects, cyclopamine and vismodegib. They also examined how PBO altered normal development by exposing pregnant mice to varying doses of PBO on gestational day 7.75, a critical period for normal brain development.
They reported that PBO inhibited Shh signaling in both mouse and human cells through a mechanism similar to that of cyclopamine, a known developmental toxin. However, PBO was found to be four times less potent. In fetal mice, the highest PBO exposure severely stunted forebrain development and caused facial abnormalities similar to a severe condition known as holoprosencephaly in humans. Lower doses of PBO disrupted forebrain development in more subtle ways that might be linked to altered neurodevelopment or behavior.
By focusing on changes to Shh signaling, the authors defined a lowest observable effect level ― more than 30 times lower than previously recognized for PBO developmental toxicity in mice. According to the authors, the results demonstrated that preventing PBO exposures in pregnant women might be important to protecting children’s neurodevelopment.
Citation: Everson JL, Sun MR, Fink DM, Heyne GW, Melberg CG, Nelson KF, Doroodchi P, Colopy LJ, Ulschmid CM, Martin AA, McLaughlin MT, Lipinski RJ. 2019. Developmental toxicity assessment of piperonyl butoxide exposure targeting sonic hedgehog signaling and forebrain and face morphogenesis in the mouse: an in vitro and in vivo study. Environ Health Perspect 127(10):107006.