Dose effect of gestational ethanol exposure on placentation and fetal growth.
BACKGROUND
Prenatal ethanol exposure compromises fetal growth by impairing placentation. Invasive trophoblastic cells, which mediate placentation, express the insulin-IGF regulated gene, aspartyl-asparaginyl β-hydroxylase (ASPH), which has a critical role in cell motility and invasion. The aims of this study were to characterize effects of ethanol on trophoblastic cell motility, and assess ethanol dose-dependent impairments in placentation and fetal development.


METHODS
Pregnant Long Evans dams were fed with isocaloric liquid diets containing 0%, 8%, 18% or 37% ethanol (caloric content) from gestation day (GD) 6 to GD18. Fetal development, placental morphology, density of invasive trophoblasts at the mesometrial triangle, as well as placental and mesometrial ASPH and Notch-1 protein expression were evaluated. Directional motility of control and ethanol-exposed HTR-8/SVneo cells was assessed by ATP Luminescence-Based assay.


RESULTS
Severity of fetal growth impairment correlated with increasing doses of ethanol. Ethanol exposure produced dose-dependent alterations in branching morphogenesis at the labyrinthine zone, and inhibited physiological transformation of maternal arteries. ASPH and Notch-1 protein expression levels were reduced, corresponding with impairments in placentation.


CONCLUSIONS
Prenatal ethanol exposure compromises fetal growth and placentation in a dose-responsive manner. Ethanol's adverse effects on placental development are mediated by: (1) altered branching morphogenesis in labyrinthine zone; (2) suppression of invasive trophoblastic precursor cells; and (3) inhibition of trophoblastic cell adhesion and motility, corresponding with reduced ASPH and Notch-1 protein expression.
Department of Pathology, Women and Infants Hospital, Providence, RI, 02905, USA; Alpert Medical School at Brown University, Providence, RI, 02905, USA.
F
F
Gundogan
Department of Medicine, Liver Research Center, Rhode Island Hospital, Providence, RI, 02905, USA.
J
J
Gilligan
Department of Medicine, Liver Research Center, Rhode Island Hospital, Providence, RI, 02905, USA.
W
W
Qi
Department of Medicine, Liver Research Center, Rhode Island Hospital, Providence, RI, 02905, USA.
E
E
Chen
Department of Pathology, Women and Infants Hospital, Providence, RI, 02905, USA.
R
R
Naram
Department of Pathology, Rhode Island Hospital, Providence, RI, 02905, USA; Department of Medicine, Liver Research Center, Rhode Island Hospital, Providence, RI, 02905, USA; Alpert Medical School at Brown University, Providence, RI, 02905, USA. Electronic address: Suzanne_DeLaMonte_MD@Brown.edu.
S M
SM
de la Monte
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000009:adverse effects*; D010064:Embryo Implantation / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D006801:Humans; D018811:Maternal Exposure / Q000009:adverse effects; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010929:Placentation / Q000187:drug effects; D011247:Pregnancy; D020318:Rats, Long-Evans; D051881:Receptor, Notch1 / Q000378:metabolism; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism
D002492:Central Nervous System Depressants; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D000431:Ethanol; D006899:Mixed Function Oxygenases; C058291:aspartic acid 2-oxoglutarate-dependent dioxygenase
Aspartyl-asparaginyl β-hydroxylase; Fetal alcohol spectrum disorders; Fetal growth; Placental morphology; Placentation; Trophoblast