Spontaneous mutation frequency and pattern in Big Blue (R) mice fed a vitamin E-supplemented diet

Endogenous oxidative DNA damage caused by normal cellular processes may pla y a vital role in carcinogenesis. To directly test the hypothesis that anti oxidants will protect DNA from oxidative damage in vivo, Big Blue(TM) mice were fed either a control diet (66 IU vitamin E/kg diet) or a high-dose vit amin E diet containing 1000 IU vitamin E/kg diet of racemic d,l-alpha-tocop herol acetate from conception until 3 months of age. Using the standard Big Blue(R) protocol, 15.5 million plaque Forming units (pfu) were examined fr om five tissues (heart, liver, adipose tissue, thymus, and testis) of three control and three high-dose vitamin E supplemented male mice generating 43 3 mutants, which represented 373 independent mutations upon sequencing the loci transgene. The alpha-tocopherol tissue concentration increased with hi gh-dose vitamin E supplementation. In four of the tissues, individually or combined, mutation frequency changed little if any with vitamin E supplemen tation. In adipose tissue, which accumulated the highest levels of vitamin E, mutation frequency was significantly reduced with high-dose vitamin E su pplementation (P = 0.047). Within the constraints of sample size, the patte rn of mutation in adipose tissue was not altered significantly (P = 0.40). When data from all tissues were combined, a reduction in G:C --> T:A transv ersions was observed (P = 0.044). These results may have implications For c ancer chemoprevention and provide insight into the efficacy of vitamin E su pplementation in reducing spontaneous oxidative DNA damage in vivo. More dr amatic alterations of mutation Frequency and pattern may be observed with h igher doses of vitamin E and substitution of the racemic supplement with d- alpha-tocopherol acetate. (C) 1999 Wiley-Liss, Inc.