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.