{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T20:00:31Z","timestamp":1788292831646,"version":"build-2803163510"},"reference-count":65,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2017,12,29]],"date-time":"2017-12-29T00:00:00Z","timestamp":1514505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Piperonyl butoxide (PBO) is a pesticide synergist used in residential, commercial, and agricultural settings. PBO was recently found to inhibit Sonic hedgehog (Shh) signaling, a key developmental regulatory pathway. Disruption of Shh signaling is linked to birth defects, including holoprosencephaly (HPE), a malformation of the forebrain and face thought to result from complex gene\u2013environment interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives:<\/jats:title>\n                    <jats:p>The impact of PBO on Shh signaling in vitro and forebrain and face development in\u00a0vivo was examined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>The influence of PBO on Shh pathway transduction was assayed in mouse and human cell lines. To examine its teratogenic potential, a single dose of PBO (22\u20131,800mg\/kg) was administered by oral gavage to C57BL\/6J mice at gestational day 7.75, targeting the critical period for HPE. Gene\u2013environment interactions were investigated using Shh+\/\u2212 mice, which model human HPE-associated genetic mutations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>PBO attenuated Shh signaling in vitro through a mechanism similar to that of the known teratogen cyclopamine. In utero PBO exposure caused characteristic HPE facial dysmorphology including dose-dependent midface hypoplasia and hypotelorism, with a lowest observable effect level of 67mg\/kg. Median forebrain deficiency characteristic of HPE was observed in severely affected animals, whereas all effective doses disrupted development of Shh-dependent transient forebrain structures that generate cortical interneurons. Normally silent heterozygous Shh null mutations exacerbated PBO teratogenicity at all doses tested, including 33mg\/kg.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion:<\/jats:title>\n                    <jats:p>These findings demonstrate that prenatal PBO exposure can cause overt forebrain and face malformations or neurodevelopmental disruptions with subtle or no craniofacial dysmorphology in mice. By targeting Shh signaling as a sensitive mechanism of action and examining gene\u2013environment interactions, this study defined a lowest observable effect level for PBO developmental toxicity in mice more than 30-fold lower than previously recognized. Human exposure to PBO and its potential contribution to etiologically complex birth defects should be rigorously examined. https:\/\/doi.org\/10.1289\/EHP5260<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1289\/ehp5260","type":"journal-article","created":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T09:07:26Z","timestamp":1571821646000},"source":"Crossref","is-referenced-by-count":41,"title":["Developmental Toxicity Assessment of Piperonyl Butoxide Exposure Targeting Sonic Hedgehog Signaling and Forebrain and Face Morphogenesis in the Mouse: An\n                    <i>in Vitro<\/i>\n                    and\n                    <i>in Vivo<\/i>\n                    Study"],"prefix":"10.1021","volume":"127","author":[{"given":"Joshua L.","family":"Everson","sequence":"first","affiliation":[{"name":"University of Wisconsin-Madison Department of Comparative Biosciences, School of Veterinary Medicine, , Madison, Wisconsin,","place":["USA"]},{"name":"University of 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