Intestinal tumorigenesis in multiple intestinal neoplasia mice induced by the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine: perinatal susceptibility, regional variation, and correlation with DNA adducts.

In our previous experiments, multiple injections with the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were used to induce intestinal tumors in C57BL/6J-multiple intestinal neoplasia (Min)/+ mice. To define the period of highest susceptibility to PhIP perinatally, we first determined the effect of a single s.c. injection. Ten or 50 mg/kg PhIP increased the number and diameter of small intestinal tumors dose-dependently in 3-day-old Min/+ mice. In the colon, only 50 mg/kg PhIP increased the incidence and number of tumors. The number of dysplastic aberrant crypt foci decreased from weeks 7 to 11. In the same period, an increase in the number of tumors was seen, indicating that over time the dysplastic aberrant crypt foci develop into tumors. Min/+ mice were then exposed in utero through their dams being given one s.c. injection of 50 mg/kg PhIP 3 days before giving birth or were exposed directly to the same dose on day 3, 12, or 36 after birth. Remarkably, the most susceptible period for tumorigenesis in the small intestine was between days 3-12 after birth, whereas in the colon it was from day 3 before to day 3 after birth. Furthermore, we examined whether the formation of DNA adducts determined after 24 h could explain the observed time-dependent and regional susceptibility to PhIP. A higher level of PhIP-DNA adducts was found after exposure on day 12 after birth, compared with day 36 after birth, in all parts of the small intestine but not in the colon, which was in close accordance with the numbers of tumors present. The levels of PhIP-DNA adducts along the intestines were highest in the middle and distal parts of the small intestine, where tumor numbers were also the highest. In conclusion, Min/+ mice are most susceptible to intestinal tumor induction by PhIP from day 3 before to day 12 after birth, and this susceptibility could at least partly be explained by the formation of PhIP-DNA adducts.