title: Effects of long-term ethanol consumption and Aldh1b1 depletion on intestinal tumourigenesis in mice.
abstract: Ethanol and its metabolite acetaldehyde have been classified as carcinogens for the upper aerodigestive tract, liver, breast, and colorectum. Whereas mechanisms related to oxidative stress and Cyp2e1 induction seem to prevail in the liver, and acetaldehyde has been proposed to play a crucial role in the upper aerodigestive tract, pathological mechanisms in the colorectum have not yet been clarified. Moreover, all evidence for a pro-carcinogenic role of ethanol in colorectal cancer is derived from correlations observed in epidemiological studies or from rodent studies with additional carcinogen application or tumour suppressor gene inactivation. In the current study, wild-type mice and mice with depletion of aldehyde dehydrogenase 1b1 (Aldh1b1), an enzyme which has been proposed to play an important role in acetaldehyde detoxification in the intestines, received ethanol in drinking water for 1 year. Long-term ethanol consumption led to intestinal tumour development in wild-type and Aldh1b1-depleted mice, but no intestinal tumours were observed in water-treated controls. Moreover, a significant increase in DNA damage was detected in the large intestinal epithelium of ethanol-treated mice of both genotypes compared with the respective water-treated groups, along with increased proliferation of the small and large intestinal epithelium. Aldh1b1 depletion led to increased plasma acetaldehyde levels in ethanol-treated mice, to a significant aggravation of ethanol-induced intestinal hyperproliferation, and to more advanced features of intestinal tumours, but it did not affect intestinal tumour incidence. These data indicate that ethanol consumption can initiate intestinal tumourigenesis without any additional carcinogen treatment or tumour suppressor gene inactivation, and we provide evidence for a role of Aldh1b1 in protection of the intestines from ethanol-induced damage, as well as for both carcinogenic and tumour-promoting functions of acetaldehyde, including increased progression of ethanol-induced tumours. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: University of Edinburgh, Division of Pathology, Centre for Comparative Pathology, Cancer Research UK Edinburgh Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XR, UK.
authors.forename: Mike F
authors.initials: MF
authors.lastname: Müller
authors.affiliation: University of Edinburgh, Division of Pathology, Centre for Comparative Pathology, Cancer Research UK Edinburgh Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XR, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: University of Edinburgh, Division of Pathology, Centre for Comparative Pathology, Cancer Research UK Edinburgh Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XR, UK.
authors.forename: Mark J
authors.identifier: 0000-0002-6826-8770
authors.initials: MJ
authors.lastname: Arends
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism / Q000633:toxicity*; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects*; D002273:Carcinogens; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D002273:Carcinogens; D000431:Ethanol; D000080924:Aldehyde Dehydrogenase 1 Family; C578830:ALDH1B1 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde
keywords: Aldh; DNA damage; EUCOMM; acetaldehyde; alcohol; colorectal cancer; intestine; proliferation