Neonatal exposure to the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine via breast milk or directly induces intestinal tumors in multiple intestinal neoplasia mice

• Published in: Carcinogenesis (New York) 1999-07, Vol.20 (7), p.1277-1282
• Main Authors: Paulsen, Jan Erik, Steffensen, Inger-Lise, Andreassen, Åshild, Vikse, Rose, Alexander, Jan
• Format: Article
• Language: English
• Subjects: 2-amino-1-methyl-6-phenylimidazo; 5-b]pyridine; aberrant crypt foci; ACF; adenomatous polyposis coli gene (human/murine); Animals; Animals, Newborn; APC/Apc; Carcinogenicity Tests; Carcinogens - toxicity; Cell Division - drug effects; Dose-Response Relationship, Drug; Drug Administration Routes; familial adenomatous polyposis; FAP; Female; Heterozygote; Imidazoles - toxicity; Incidence; Intestinal Neoplasms - chemically induced; Intestinal Neoplasms - epidemiology; Intestinal Neoplasms - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Milk - adverse effects; Min; multiple intestinal neoplasia; Mutagens - toxicity; PhIP
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/20.7.1277

We examined whether the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) could increase intestinal tumorigenesis in neonatal C57BL/6J-Min/+ mice, a murine model for familial adenomatous polyposis. Min/+ mice are heterozygous for a nonsense mutation in the adenomatous polyposis coli gene and spontaneously develop multiple intestinal adenomas, primarily in the small intestine. Neonatal Min/+ mice (3–6 days old) were exposed to PhIP via breast milk from lactating dams given 8 s.c. injections of 50 mg/kg PhIP three times a week or to 8 s.c. injections of 25 or 50 mg/kg PhIP directly, over the same period. At the age of 11 weeks, the number, diameter and location of the intestinal tumors were scored. Remarkably, a 2- to 4-fold increase in the number of small intestinal tumors was seen in Min/+ mice exposed to PhIP via breast milk (P < 0.001). To our knowledge, this is the first time PhIP has been reported to induce tumors following exposure via breast milk from PhIP-exposed dams. Upon direct exposure to 50 mg/kg PhIP, a 6- to 9-fold increase in the number of small intestinal tumors was observed (P < 0.001). The diameter of the PhIP-induced small intestinal tumors was slightly increased (P < 0.001). In the colon, a 3- to 4-fold increase in the number of tumors was seen in Min/+ mice exposed to PhIP via breast milk (P = 0.004). Direct exposure to 50 mg/kg PhIP caused a 2- to 6-fold increase in the number of colonic tumors (P = 0.014). The PhIP-induced colonic tumors were located more distally and displayed a smaller diameter than the tumors from the controls (P < 0.05). In contrast to a previous study, where PhIP showed only a moderate tumorigenic effect in adult Min/+ mice, the present study demonstrates a strong tumorigenic effect of PhIP in neonatally exposed Min/+ mice, even after exposure via breast milk from PhIP-exposed dams.