Ethanol-induced oxidative stress and mitochondrial dysfunction in rat placenta: relevance to pregnancy loss.
BACKGROUND
Ethanol consumption during pregnancy increases the risk of early pregnancy loss and causes intrauterine growth restriction. We previously showed that chronic gestational exposure to ethanol impairs placentation, and that this effect is associated with inhibition of insulin and insulin growth factor signaling. Since ethanol also causes oxidative stress and DNA damage, we extended our investigations to assess the role of these pathological processes on placentation and placental gene expression.


METHODS
Pregnant Long Evans rats were pair-fed liquid diets containing 0% or 24% ethanol by caloric content. Placentas harvested on gestation day 16 were used to examine DNA damage, lipid peroxidation, apoptosis, mitochondrial gene/protein and hormonal gene expression in relation to ethanol exposure.


RESULTS
Gestational exposure to ethanol increased fetal resorption, and trophoblast apoptosis/necrosis, oxidative stress, DNA damage, and lipid peroxidation. These adverse effects of ethanol were associated with increased expression of pro-apoptotic (Bax and Bak) and reduced levels of the anti-apoptotic Bcl-2 protein. In addition, increased trophoblast apoptosis proneness was associated with p53-independent activation of p21, reduced mitochondrial gene and protein expression, and dysregulated expression of prolactin (PRL) family hormones that are required for implantation and pregnancy-related adaptations.


CONCLUSIONS
Chronic gestational exposure to ethanol increases fetal demise due to impaired survival and mitochondrial function, increased oxidative stress, DNA damage and lipid peroxidation, and dysregulated expression of prolactin family hormones in placental trophoblasts.
Gundogan
Fusun
F
Department of Pathology, Women and Infants Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.
Elwood
Gwen
G
Mark
Princess
P
Feijoo
Adrian
A
Longato
Lisa
L
Tong
Ming
M
de la Monte
Suzanne M
SM
D000428:Alcohol Drinking / Q000009:adverse effects* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D004249:DNA Damage; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D005786:Gene Expression Regulation / Q000187:drug effects; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy / Q000187:drug effects* / Q000378:metabolism / Q000523:psychology; D011388:Prolactin / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans
D002492:Central Nervous System Depressants; D000431:Ethanol; D011388:Prolactin