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. CONCLUSION: 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.
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. CONCLUSION: 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: Emily L Durham; R Nicole Howie; Laurel Black; Grace Bennfors; Trish E Parsons; Mohammed Elsalanty; Jack C Yu; Seth M Weinberg; James J Cray Journal: Birth Defects Res A Clin Mol Teratol Date: 2016-07-20
Authors: Madhurima Saha; Skylar A Rizzo; Manashwi Ramanathan; Rylie M Hightower; Katherine E Santostefano; Naohiro Terada; Richard S Finkel; Jonathan S Berg; Nizar Chahin; Christina A Pacak; Richard E Wagner; Matthew S Alexander; Isabelle Draper; Peter B Kang Journal: Hum Mol Genet Date: 2019-07-15 Impact factor: 6.150
Authors: Vivian Bradaschia-Correa; Anne M Josephson; Devan Mehta; Matthew Mizrahi; Shane S Neibart; Chao Liu; Oran D Kennedy; Alesha B Castillo; Kenneth A Egol; Philipp Leucht Journal: J Bone Miner Res Date: 2017-02-27 Impact factor: 6.741
Authors: Emily Durham; Serena Jen; Lin Wang; Joseph Nasworthy; Mohammed Elsalanty; Seth Weinberg; Jack Yu; James Cray Journal: PLoS One Date: 2015-10-02 Impact factor: 3.240
Authors: R Nicole Howie; Samuel Herberg; Emily Durham; Zachary Grey; Grace Bennfors; Mohammed Elsalanty; Amanda C LaRue; William D Hill; James J Cray Journal: Int J Oral Sci Date: 2018-09-03 Impact factor: 6.344