title: Selective serotonin reuptake inhibitor exposure alters osteoblast gene expression and craniofacial development in mice.
abstract: BACKGROUND
  Selective serotonin reuptake inhibitor (SSRI) use in pregnancy has been linked to craniofacial birth defects. Little is known about the effects of serotonin or SSRIs on craniofacial development. Here, we provide evidence that citalopram (SSRI) alters the osteogenic profile of murine calvarial cells and leads to craniofacial dysmorphology.
  
  
  METHODS
  We used mouse calvarial pre-osteoblast cells (MC3T3-E1) to study the biochemical profile (microarray and quantitative reverse transcription polymerase chain reactions) after treatment with a titrated dose of citalopram. We used C57BL-6 wild-type breeders to produce litters treated with a clinical dose of citalopram during the third trimester of pregnancy. We used micro-computed tomography and morphometric measures to determine effects on craniofacial development.
  
  
  RESULTS
  Controls included untreated cells and age matched untreated litters. We observed decreases in proliferation and increases in alkaline phosphatase activity after citalopram exposure. We confirmed altered expression of genes linked to osteogenesis including Ocn and significant increase in expression of Alp after 7 days of treatment. Our data suggest altered expression of several genes related to craniofacial development (Fgf2, Fgfr2, Tgfβr2 Irs1, Igf1) and statistically significant changes in expression for (Col2a1, Gdf6, Hmox1, and Notch1). We also observed changes in regulation of the serotonin pathway (Sert, Tph1, Tph2, Htr2a, Lrp5) after treatment with citalopram. After in utero exposure to citalopram, mice displayed shorter narrow snouts, more globular skulls and several craniofacial anomalies.
  
  
  CONCLUSIONS
  Our results provide confirmatory evidence that citalopram exposure is associated with cellular and morphological alterations of the craniofacial complex, which may have important implications for use during pregnancy.
authors.affiliation: Departments of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cray
authors.forename: Seth M
authors.initials: SM
authors.lastname: Weinberg
authors.forename: Trish E
authors.initials: TE
authors.lastname: Parsons
authors.forename: R Nicole
authors.initials: RN
authors.lastname: Howie
authors.forename: Mohammed
authors.initials: M
authors.lastname: Elsalanty
authors.forename: Jack C
authors.initials: JC
authors.lastname: Yu
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002478:Cells, Cultured; D015283:Citalopram / Q000494:pharmacology*; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000187:drug effects*; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D015283:Citalopram; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors
keywords: SLC6A4 inhibitor; craniosynostosis; depression; osteoblast; osteogenesis; serotonin