Altered p53 response and enhanced transgenerational transmission of carcinogenic risk upon exposure of mice to betel nut.

Alteration of p53 protein level, and possible mutation of the p53 gene during carcinogenesis in mice exposed chronically (P) and transgenerationally to 2mg/ml aqueous extract of betel nut (AEBN) in drinking water, were studied. Exons 5 and 7 of the p53 gene were not mutated under both chronic and transgenerational exposure, but, p53 protein response was altered. In P mice, p53 protein was initially upregulated in comparison to age-matched controls, reaching 2.5 folds in the liver after 6 weeks of exposure. Subsequently, p53 protein declined to control level after 16 weeks, with concomitant preneoplastic nodulation of the liver. After 24 weeks, p53 protein was below control level, and preneoplastic nodules were well-developed. The level of p53 protein in transgenerationally exposed mice remained invariant in comparison to age-matched controls. Liver nodulation was significantly advanced, developing in F1 mice after 8 weeks, F2 mice after 6 weeks and F3 mice after 4 weeks of exposure. Anomalies not observed in P mice, developed in transgenerationally exposed mice, albeit, non-significantly. Thus, AEBN exposure enhanced transgeneration transmission of carcinogenic risk.