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Serotonin as a regulator of
craniofacial morphogenesis: site specific malformations following
exposure to serotonin uptake inhibitors.
Shuey DL,
Sadler TW, Lauder JM.
Curriculum in Toxicology, University of
North Carolina, Chapel Hill 27599.
During craniofacial
development in the mouse embryo (days 9-12 of gestation; plug day = day
1), transient expression of serotonin (5-HT) uptake in epithelial
structures of this region correlates with critical morphogenetic events
(Lauder et al., '88; Shuey, '91; Shuey et al., '89, '92). The purpose of
the present investigation was to assess the possible functional
significance of these uptake sites by examination of patterns of
dysmorphology following exposure of embryos to selective 5-HT uptake
inhibitors. Exposure of mouse embryos in whole embryo culture to
sertraline, at a concentration (10 microM) which produced no evidence of
general embryotoxicity, caused craniofacial malformations consistent
with direct action at 5-HT uptake sites. Two other 5-HT uptake
inhibitors, fluoxetine and amitriptyline, produced similar defects. The
critical period of sertraline exposure occurred on days 10-11. The
observed craniofacial defects were associated with decreased
proliferation and extensive cell death in mesenchyme located 5-6 cell
layers deep from the overlying epithelium. In contrast, the
subepithelial mesenchymal layers showed normal or elevated levels of
proliferation. From these results it appears that inhibition of 5-HT
uptake into craniofacial epithelia may produce developmental defects by
interference with serotonergic regulation of epithelial-mesenchymal
interactions important for normal craniofacial
morphogenesis.
PMID: 1412065 [PubMed - indexed for MEDLINE]
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