{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T01:45:26Z","timestamp":1791164726466,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2008,3,12]],"date-time":"2008-03-12T00:00:00Z","timestamp":1205280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2008,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>In humans, fetal ethanol exposure can cause holoprosencephaly (HPE), one of the most common birth defects that is characterized by brain, facial, and oral abnormalities. However, the pathogenesis of HPE is not clear. In the present study, we investigated the teratogenic mechanism of ethanol\u2010induced brain and facial malformations in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Pregnant C57BL\/6J mice were administered ethanol on E7 and facial and brain malformations were characterized on E10.5. We examined the effect of fetal ethanol exposure on\n                      <jats:italic>Shh<\/jats:italic>\n                      expression and activation of protein kinase A (PKA) because mutations in the human\n                      <jats:italic>Shh<\/jats:italic>\n                      gene are the most frequent cause of autosomal\u2010dominant inherited HPE and PKA is a potent endogenous antagonist of Shh signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Fetal ethanol exposure on E7 induced severe midline defects characteristic of HPE. Ethanol exposure impaired\n                      <jats:italic>Shh<\/jats:italic>\n                      expression and induced excessive apoptosis only along the anterior edge of the prechordal mesendoderm (PME). In addition, ethanol activated PKA in anterior PME cells. Pretreatment of embryos with antioxidants, such as vitamins C or E, prevented the development of ethanol\u2010induced HPE.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Shh<\/jats:italic>\n                      expression in PME cells is involved in the pathogenesis of ethanol\u2010induced HPE. Ethanol may impair\n                      <jats:italic>Shh<\/jats:italic>\n                      expression indirectly by activating PKA. The inhibition of excessive apoptosis in PME cells by antioxidants implies that oxidative stress may underlie the teratogenic actions of ethanol. Thus, antioxidant treatment may be a simple preventative measure that could reduce the incidence of HPE following fetal ethanol exposure. Birth Defects Research (Part A), 2008. \u00a9 2008 Wiley\u2010Liss, Inc.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bdra.20447","type":"journal-article","created":{"date-parts":[[2008,3,12]],"date-time":"2008-03-12T17:37:11Z","timestamp":1205343431000},"page":"224-231","source":"Crossref","is-referenced-by-count":92,"title":["Fetal ethanol exposure activates protein kinase a and impairs\n                    <i>Shh<\/i>\n                    expression in prechordal mesendoderm cells in the pathogenesis of holoprosencephaly"],"prefix":"10.1002","volume":"82","author":[{"given":"Kazushi","family":"Aoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayoi","family":"Shikata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Higashiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Shiota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Motoyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,3,12]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1086\/394504"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.162356199"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.301.1.66"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1196-353"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1998.8995"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-1878(200006)22:6<499::AID-BIES1>3.0.CO;2-F"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604751103"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/383407a0"},{"key":"e_1_2_5_10_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/oso\/9780199630882.003.0002","volume-title":"Mammalian 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