Effects of pesticides on the ratio of 16 alpha/2-hydroxyestrone: a biologic marker of breast cancer risk.
Xenobiotic estrogens are external compounds with estrogenic activity that may thereby affect the risk of breast cancer. This paper describes a mechanism by which xeno-estrogens may affect the development of breast cancer. Estradiol metabolism proceeds by hydroxylation at one of two mutually exclusive sites at C-2 and C-16 alpha. The catechol pathway yields the weakly estrogenic 2-hydroxyestrone (2-OHE1), which inhibits breast cell proliferation. In contrast, the alternative pathway yields the genotoxic 16 alpha-hydroxyestrone (16 alpha-OHE1), which enhances breast cell growth, increases unscheduled DNA synthesis, and oncogene and virus expression, and increases anchorage-independent growth. Using a radiometric assay that measures the relative formation of 16 alpha-OHE1 versus 2-OHE1 from specifically tritiated estradiol in (ER+) MCF-7 cells, we compared the ratio of 16 alpha-OHE1/2-OHE1 observed after treatment with the known rodent carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) with the ratios after treatment with DDT, atrazine, gamma-benzene hexachloride, kepone, coplanar PCBs, endosulfans I and II, linoleic and eicosapentenoic acids, and indole-3-carbinol (I3C). These pesticides significantly increase the ratio of 16 alpha-OHE1/2-OHE1 metabolites to values comparable to or greater than those observed after DMBA. In contrast, the antitumor agent I3C increased 2-OHE1 formation and yielded ratios that are 1/3 of those found in unexposed control cells and 1/10th of those found in DMBA-treated cells. Thus the ratio of 16 alpha-OHE1/2-OHE1 may provide a marker for the risk of breast cancer. Assays of this ratio, which can be measured in spot urines, may prove useful for a variety of in vitro and in vivo studies bearing on breast cancer risk.
Bradlow
H L
HL
Strang-Cornell Cancer Research Laboratory, New York, NY 10021, USA.
Davis
D L
DL
Lin
G
G
Sepkovic
D
D
Tiwari
R
R
D015415:Biomarkers / Q000737:chemistry; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D002393:Estrogens, Catechol / Q000378:metabolism*; D006801:Humans; D006894:Hydroxyestrones / Q000378:metabolism*; D007306:Insecticides / Q000009:adverse effects*; D014407:Tumor Cells, Cultured
D015415:Biomarkers; D002393:Estrogens, Catechol; D006894:Hydroxyestrones; D007306:Insecticides; C026702:16-hydroxyestrone; D004958:Estradiol; C024980:2-hydroxyestrone