Coexposure to Ethanol with N-Nitrosodimethylamine or 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone during Lactation of Rats: Marked Increase in O6-Methylguanine–DNA Adducts in Maternal Mammary Gland and in Suckling Lung and Kidney

Abstract

Use of alcoholic beverages increases risk of cancer at several target sites, including the breast. Of several possible mechanisms for this effect, competitive inhibition by ethanol of hepatic clearance of nitrosamines, resulting in increased dose delivery to posthepatic tissues, gives the quantitatively most pronounced enhancement. We investigated whether this effect would pertain to the mammary gland, and to ethanol and nitrosamines delivered translactationally to sucklings. Ethanol (1.6 g/kg) was administered by gavage to nursing Sprague–Dawley rats 10 min before 5 mg/kg N-nitrosodimethylamine (NDMA) or 50 mg/kg 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); treatment was on postnatal days 1, 7, or 14. Tissues taken 4 h later for analysis of O6-methylguanine in DNA were liver, blood, and mammary glands from the mothers, and liver, lung, kidney, and blood from the sucklings. Ethanol cotreatment resulted in a marked, 10-fold increase in O6-methylguanine adducts from NDMA in mammary gland, as well as smaller but significant increases in this tissue from NNK and in maternal blood cells from both chemicals; adducts in maternal liver decreased slightly. In the sucklings, ethanol cotreatment also lowered adducts in liver after NDMA or NNK treatment. After NDMA, adducts were also detected in suckling lung and kidney and were increased five- to 10-fold after ethanol coexposure. Adducts from either chemical, with or without ethanol, decreased markedly in all suckling tissues with development from postnatal day 1 to day 14. Thus ethanol coexposure with nitrosamines increases O6-methylguanine DNA adducts in mammary gland and strongly influences adduct formation in suckling tissues after translactational delivery.