Characterization of a major aromatic DNA adduct detected in human breast tissues

Abstract

A bulky DNA adduct (Spot 1) was previously detected in normal adjacent breast tissues of 41% (36/87) of women with breast cancer and in none (0/29) of the noncancer controls by 32 P-postlabeling. To characterize this adduct, it was chromatographically compared with DNA adduct profiles generated in several in vitro and in vivo experimental systems. First, MCF-7 cells were exposed to a number of chemical carcino- [a,h]anthracene, 3-methylcholanthrene, and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine. Spot 1 was detected as a minor adduct in cells treated with B[a]P but not other compounds. Second, to determine whether Spot 1 is derived from lipid peroxidation products or estrogen metabolites, it was compared with adduct profiles of cells or DNAs exposed to 17␤-estradiol, 4-hydroxy estradiol, 4-hydroxynonenal, or oxidized oat oil. Spot 1 was not detectable in these samples. In addition, Spot 1 did not comigrate with the 1,N 2 -ethenodeoxyguanosine adduct standard. Third, to explore the mechanism of Spot 1 formation, it was compared with adduct profiles detected in DNA or mononucleotides reacted with BPDE, 1-OH-7,8-dihydrodiol of B[a]P, and 3-OH-7,8-dihydrodiol of B[a]P as well as in rats orally treated with B[a]P. Spot 1 comigrated with a minor adduct in BPDEtreated DNA during anion exchange rechromatography but these two adducts were separated by partition chromatography. Spot 1 also behaved in a manner that was very similar to that of the polar B[a]P adducts detected in rat liver, but the two adducts were separated by HPLC. Fourth, Spot 1 was compared with CD1 mice exposed to 7H-benzo[c]fluorene (B[c]F). Spot 1 from some patients comigrated with a major adduct induced by B[c]F. Finally, we found that the presence of Spot 1 in human breast tissues was not related to smoking status but, rather, with CYP1A1 MspI polymorphism. The CYP1A1 mutant carriers had a significantly higher frequency of this adduct than did the wild-type genotypes. Furthermore, individuals with Spot 1 had a significantly higher staining intensity for BPDE-PAH adducts in their tissue sections than those without it. These results demonstrate that this major bulky DNA adduct detected in human breast tissues is related to PAH exposure. Environ. Mol. Mutagen. 39:193-200, 2002.

Associations between Smoking, Polymorphisms in Polycyclic Aromatic Hydrocarbon (PAH) Metabolism and Conjugation Genes and PAH-DNA Adducts in Prostate Tumors Differ by Race

“…In lung tumor tissue, the variant alleles of the CYP1A1 1*/2* (includes CYP1A1 Ile 462 Val) and the GSTM1 null deletion polymorphisms have been positively associated with (+)anti -BPDE -DNA adduct levels, and the effect was more pronounced in individuals with both polymorphisms (48). In addition, carrying the GSTM1 null deletion has been shown to be positively associated with PAH-DNA adducts in tumor and adjacent nontumor cells obtained from breast cancer cases (49), but this effect was not found in another study (50). We did not find an effect with the GSTM1 null deletion polymorphism; however, we did observe significant individual and joint gene associations with the GSTP1 105 Val allele which may be more efficient than GSTM1 in conjugating the most reactive PAH-diolepoxides (33).…”

“…Although associations between a few of the aforementioned polymorphisms in metabolism and conjugation genes and PAH-DNA adduct levels have been examined in human lung (48) and breast (49,50) cancer tissues and differences in PAH-DNA adduct levels by race in mononuclear cells have been reported (51), no prior studies have evaluated effects of these polymorphisms on adduct levels in human prostate cancer tissues. Therefore, in this study, we extend our earlier work …”

Exposure to traffic emissions throughout life and risk of breast cancer: the Western New York Exposures and Breast Cancer (WEB) study

“…Although studies have found that higher concentrations of PAH-DNA adducts are present in human breast tissues of cancer cases than noncancer controls [23][24][25] and that higher levels of PAH-DNA adducts in blood were associated with increased risk of breast cancer [26], PAHs have not been strongly linked to breast cancer risk in epidemiological studies. Although cigarette smoking is one of the major sources of PAH exposure, most studies have not found an association between adult smoking and breast cancer risk [27].…”

Active and passive smoking and breast cancer risk in middle‐aged Japanese women

“…16 Although they do not directly contact mammary cells, many studies utilizing biomarkers have demonstrated that tobacco-related carcinogens reach human breast tissue. [17][18][19] On the other hand, antiestrogenic effects of tobacco smoke have been suggested by many published observations. 20 -23 Thus, the exposure may decrease the breast cancer risk, especially in postmenopausal women.…”