title: Effects of Citalopram on Sutural and Calvarial Cell Processes.
abstract: The use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression during pregnancy is suggested to increase the incidence of craniofacial abnormalities including craniosynostosis. Little is known about this mechanism, however based on previous data we propose a mechanism that affects cell cycle. Excessive proliferation, and reduction in apoptosis may lead to hyperplasia within the suture that may allow for differentiation, bony infiltration, and fusion. Here we utilized in vivo and in vitro analysis to investigate this proposed phenomenon. For in vivo analysis we used C57BL-6 wild-type breeders treated with a clinical dose of citalopram during the third trimester of pregnancy to produce litters exposed to the SSRI citalopram in utero. At post-natal day 15 sutures were harvested from resulting pups and subjected to histomorphometric analysis for proliferation (PCNA) and apoptosis (TUNEL). For in vitro studies, we used mouse calvarial pre-osteoblast cells (MC3T3-E1) to assess proliferation (MTS), apoptosis (Caspase 3/7-activity), and gene expression after exposure to titrated doses of citalopram. In vivo analysis for PCNA suggested segregation of effect by location, with the sagittal suture, showing a statistically significant increase in proliferative response. The coronal suture was not similarly affected, however there was a decrease in apoptotic activity at the dural edge as compared to the periosteal edge. No differences in apoptosis by suture or area due to SSRI exposure were observed. In vitro results suggest citalopram exposure increased proliferation and proliferative gene expression, and decreased apoptosis of the MC3T3-E1 cells. Decreased apoptosis was not confirmed in vivo however, an increase in proliferation without a concomitant increase in apoptosis is still defined as hyperplasia. Thus prenatal SSRI exposure may exert a negative effect on post-natal growth through a hyperplasia effect at the cranial growth sites perhaps leading to clinically significant craniofacial abnormalities.
authors.affiliation: Departments of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Durham
authors.affiliation: School of Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Serena
authors.initials: S
authors.lastname: Jen
authors.affiliation: Institute for Plastic Surgery, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oral Biology, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Nasworthy
authors.affiliation: Department of Oral Biology, Georgia Regents University, Augusta, Georgia, United States of America; Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, United States of America; Department of Oral Maxillofacial Surgery, Georgia Regents University, Augusta, Georgia, United States of America; Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Elsalanty
authors.affiliation: Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Seth
authors.initials: S
authors.lastname: Weinberg
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America; Department of Surgery, Division of Plastic Surgery, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Jack
authors.initials: J
authors.lastname: Yu
authors.affiliation: Departments of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Cray
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015283:Citalopram / Q000494:pharmacology*; D003393:Cranial Sutures / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D015283:Citalopram