{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,12,28]],"date-time":"2023-12-28T08:52:55Z","timestamp":1703753575654},"reference-count":32,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2013,8,23]],"date-time":"2013-08-23T00:00:00Z","timestamp":1377216000000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research Pt B"],"published-print":{"date-parts":[[2013,8]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>The present study was performed to evaluate the effect of methionine (<jats:styled-content style=\"fixed-case\">M<\/jats:styled-content>et) pretreatment on valproate (<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>) axial defects, induced in <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>1 mice by a single intraperitoneal (i.p.) injection of 400 mg\/kg <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> on <jats:styled-content style=\"fixed-case\">E<\/jats:styled-content>8 dams. This <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> dosage regimen has been in the past related to a specific pathogenic pathway cascade: (1) <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> in utero exposure, (2) <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>4 histone hyperacetylation (h<jats:styled-content style=\"fixed-case\">AC<\/jats:styled-content>) at the level of somites, (3) expression of pro\u2010apoptotic factors in somite tissues, (4) apoptosis of somite cells, and (5) axial defects in embryos (abnormal or fused somites) and fetuses (fusions, duplications, respecifications of vertebrae, and\/or ribs).<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>On the basis of literature suggestion, <jats:styled-content style=\"fixed-case\">E<\/jats:styled-content>8 <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>1 mice were i.p. injected with 70 mg\/kg <jats:styled-content style=\"fixed-case\">M<\/jats:styled-content>et 30 min before the i.p. injection with 400 mg\/kg <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>. Some females were sacrificed, 1 or 3 hr after the <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> injection, embryos explanted, and used to evaluate the <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>4 histone h<jats:styled-content style=\"fixed-case\">AC<\/jats:styled-content>. The remaining females were sacrificed at term (<jats:styled-content style=\"fixed-case\">E<\/jats:styled-content>18) and fetuses processed for external and skeletal examination.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The pretreatment with <jats:styled-content style=\"fixed-case\">M<\/jats:styled-content>et worsened the axial skeletal malformative picture in fetuses (we observed a larger number of affected segment per fetus in respect to the groups treated with <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> alone). In embryos, <jats:styled-content style=\"fixed-case\">M<\/jats:styled-content>et pretreatment increased the <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>4 h<jats:styled-content style=\"fixed-case\">AC<\/jats:styled-content> index and shifted the timing of the <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>4 h<jats:styled-content style=\"fixed-case\">AC<\/jats:styled-content> peak.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Our data suggest that <jats:styled-content style=\"fixed-case\">M<\/jats:styled-content>et pretreatment enhances the effects of <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> in deregulating the epigenetic control of gene expression in somites, and by consequence, induces more extended dysmorphogenic effects along the axial 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