The mutagenic potential of duodenoesophageal reflux.
BACKGROUND
Duodenogastric-esophageal reflux disease is directly linked to Barrett's esophagus and to the development of esophageal adenocarcinoma. Despite this link, little is known about the mutagenic potential of refluxed material on the esophageal mucosa. We hypothesize that the reflux of gastric and duodenal content causes mutations in esophageal mucosa in vivo.


METHODS
Seven Sprague Dawley/Big Blue F1 lacI transgenic rats underwent esophagoduodenostomy (ED) to surgically create duodeno-gastric-esophageal reflux. Fourteen nonoperated rats served as negative (n = 7) and as positive (n = 7/methyl-N-amyl-nitrosamine [MNAN] intraperitoneally) controls. The animals were killed 16 weeks after operation or injection, the entire esophageal mucosa was harvested, and mutation frequency was determined through standard Big Blue Mutagenesis Assay.


RESULTS
Gross esophagitis was evident in all operated animals. The frequency of lacI mutations in esophageal mucosal cells of animals with ED was significantly higher, nearly 1.5-fold, than that of nonoperated animals. Nitrosamine administration resulted in a nearly 20-fold increase of lacI mutation frequency. Thirteen mutations were successfully sequenced, 46% occurred at CpG dinucleotide sites and 61% were either C to T or G to A transitions.


CONCLUSIONS
The data provide preliminary evidence of the mutagenic potential of bile reflux on esophageal epithelium. The specific mutations are markedly higher than would be expected by chance and are similar to that found in p53 mutations of human esophageal adenocarcinoma, providing a link to human esophageal cancer.
Theisen
Jörg
J
Department of Surgery, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany.
Peters
Jeffrey H
JH
Fein
Martin
M
Hughes
Michael
M
Hagen
Jeffrey A
JA
Demeester
Steven R
SR
Demeester
Tom R
TR
Laird
Peter W
PW
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D004383:Duodenogastric Reflux / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D004941:Esophagitis / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D004947:Esophagus / Q000473:pathology*; D007413:Intestinal Mucosa / Q000473:pathology; D007763:Lac Operon / Q000235:genetics; D051379:Mice; D023421:Models, Animal; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley