Combined subcarcinogenic benzo[a]pyrene and UVA synergistically caused high tumor incidence and mutations in H-rasgene, but notp53,in SKH-1 hairless mouse skin

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Combined subcarcinogenic doses of benzo[a]pyrene (BaP) and UVA induced H-ras,but notp53,gene mutations 8 weeks before tumor emergence in SKH-1 mice. Neither UVA (40 kJ/m2) nor BaP (8 nmol) induced any tumors after mice were topically treated 3 times/week for 25 weeks. However, combined BaP-UVA treatment synergistically increased tumor incidence and multiplicity. All tumors induced by BaP-UVA were malignant. The epidermis was collected from mice treated for 2, 6 and 10 weeks. DNA from UVB- (0.3 kJ/m2) or BaP-UVA-(8 nmol and 40 kJ/m2-induced tumors was isolated and screened for H-rasandp53mutations. Four types of point mutation, GGC→GAC, GCC, GTC and CGC, occurred in UVB-induced tumors at H-rascodon 13; and one type of point mutation, GGA→GAA, at codon 12. Treatment with either BaP alone or BaP-UVA for 10 weeks caused GGA→GAA mutation at codon 12 or GGC→GAC mutation at codon 13 in nontumor skin, respectively, as well as in tumors induced by BaP-UVA. All of the 10-week samples treated with either BaP or BaP-UVA showed detectable mutations at codons 12 and 13, but the genetic load was significantly higher in BaP-UVA-treated mice than in those exposed only to BaP. UVA alone induced mutations at codon 12 in only one-third of samples. G→A mutations induced by BaP or BaP-UVA at position 38 of codon 13 have not been reported previously. C→T transitions were detected inp53hot spots of exon 8 in 2 of 19 BaP-UVA-induced tumors but were not found in nontumor skin.

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