In utero alcohol exposure increases mammary tumorigenesis in rats.
Findings in humans and animal models suggest that in utero hormonal and dietary exposures increase later breast cancer risk. Since alcohol intake by adult women consistently increases their breast cancer risk, we wondered whether maternal alcohol consumption during pregnancy increases female offspring's mammary tumorigenesis. In our study, pregnant female rats were pair-fed isocaloric diets containing either 0 (control), 16 or 25 g alcohol kg(-1) feed between days 7 and 19 of gestation. These alcohol exposures generate blood alcohol levels that correspond to low and moderate alcohol consumption and are lower than those that induce foetal alcohol syndrome. Serum oestradiol levels were elevated in pregnant rats exposed to alcohol (P<0.003). When adult, female offspring of alcohol-exposed dams developed significantly more 7,12-dimethylbenz[a]anthracene -induced mammary tumours, compared to the controls (tumour multiplicity; mean+/-s.e.m., controls: 2.0+/-0.3, 16 g alcohol: 2.7+/-0.4 and 25 g alcohol: 3.7+/-0.4; P<0.006). In addition, the mammary epithelial tree of the alcohol-exposed offspring was denser (P<0.004) and contained more structures that are susceptible for the initiation of breast cancer (P<0.001). Immunohistochemical assessment indicated that the mammary glands of 22-week-old in utero alcohol-exposed rats contained elevated levels of oestrogen receptor-alpha (P<0.04) that is consistent with the changes in mammary gland morphology. In summary, maternal alcohol intake during pregnancy increases female offspring's mammary tumorigenesis, perhaps by programming the foetal mammary gland to exhibit persistent alterations in morphology and gene expression. It remains to be determined whether an increase in pregnancy oestradiol levels mediated alcohol's effects on offspring's mammary tumorigenesis.
Hilakivi-Clarke
L
L
Lombardi Cancer Center and Department of Oncology, Georgetown University, 3970 Reservoir Road NW, Washington, DC 20007, USA. clarkel@georgetown.edu
Cabanes
A
A
de Assis
S
S
Wang
M
M
Khan
G
G
Shoemaker
W J
WJ
Stevens
R G
RG
D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000633:toxicity*; D004958:Estradiol / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D008321:Mammary Glands, Animal / Q000502:physiology; D015674:Mammary Neoplasms, Animal / Q000209:etiology*; D011247:Pregnancy / Q000502:physiology; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000032:analysis
D002492:Central Nervous System Depressants; D011960:Receptors, Estrogen; D000431:Ethanol; D004958:Estradiol