Impaired placentation in fetal alcohol syndrome.
Intrauterine growth restriction (IUGR) is one of the key features of fetal alcohol syndrome (FAS), and IUGR can be mediated by impaired placentation. Insulin-like growth factors (IGF) regulate placentation due to stimulatory effects on extravillous trophoblasts, which are highly motile and invasive. Previous studies demonstrated that extravillous trophoblasts express high levels of aspartyl-(asparaginyl) beta-hydroxylase (AAH), a gene that is regulated by IGF and has a critical role in cell motility and invasion. The present study examines the hypothesis that ethanol impaired placentation is associated with inhibition of AAH expression in trophoblasts. Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 37% ethanol by caloric content. Placentas harvested on gestation day 16 were used for histopathological, mRNA, and protein studies to examine AAH expression in relation to the integrity of placentation and ethanol exposure. Chronic ethanol feeding prevented or impaired the physiological conversion of uterine vessels required for expansion of maternal circulation into placenta, a crucial process for adequate placentation. Real-time quantitative RT-PCR analysis demonstrated significant reductions in IRS-1, IRS-2, and significant increases in IGF-II and IGF-II receptor mRNA levels in ethanol-exposed placentas. These abnormalities were associated with significantly reduced levels of AAH expression in trophoblastic cells, particularly within the mesometrial triangle (deep placental bed) as demonstrated by real time quantitative RT-PCR, Western blot analysis, ELISA, and immunohistochemical staining. Ethanol-impaired placentation is associated with inhibition of AAH expression in trophoblasts. This effect of chronic gestational exposure to ethanol may contribute to IUGR in FAS.
Department of Pathology and Medicine, Women and Infants Hospital, Providence, RI 02903, USA.
F
F
Gundogan
G
G
Elwood
L
L
Longato
M
M
Tong
A
A
Feijoo
R I
RI
Carlson
J R
JR
Wands
S M
SM
de la Monte
D000818:Animals; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005865:Gestational Age; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000235:genetics; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D010922:Placenta Diseases / Q000209:etiology* / Q000235:genetics; D010929:Placentation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D020318:Rats, Long-Evans; D017526:Receptor, IGF Type 1 / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics; D013997:Time Factors
D000431:Ethanol; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D006899:Mixed Function Oxygenases; C058291:aspartic acid 2-oxoglutarate-dependent dioxygenase; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin