Effects of Pesticides on the Ratio of 16 Alpha/2-hydroxyestrone: a Biologic Marker of Breast Cancer Risk

Overview

Journal Environ Health Perspect

Date 1995 Oct 1

PMID 8593862

Citations 35

Authors

H L Bradlow

D L Davis

G Lin

D Sepkovic

R Tiwari

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Xeno-Estrogenic Pesticides and the Risk of Related Human Cancers.

Kumar V, Yadav C, Banerjee B J Xenobiot. 2022; 12(4):344-355.

PMID: 36412768 PMC: 9680220. DOI: 10.3390/jox12040024.

The Anticancer Potential of Plant-Derived Nutraceuticals via the Modulation of Gene Expression.

Vranceanu M, Galimberti D, Banc R, Dragos O, Cozma-Petrut A, Heghes S Plants (Basel). 2022; 11(19).

PMID: 36235389 PMC: 9571524. DOI: 10.3390/plants11192524.

Effects of menopausal hormone therapy-based on the role of estrogens, progestogens, and their metabolites in proliferation of breast cancer cells.

Deng Y, Jin H Cancer Biol Med. 2021; .

PMID: 34779589 PMC: 9088189. DOI: 10.20892/j.issn.2095-3941.2021.0344.

Toxicoproteomics Disclose Pesticides as Downregulators of TNF-α, IL-1β and Estrogen Receptor Pathways in Breast Cancer Women Chronically Exposed.

Pizzatti L, Kawassaki A, Fadel B, Nogueira F, Evaristo J, Woldmar N Front Oncol. 2020; 10:1698.

PMID: 32984049 PMC: 7483484. DOI: 10.3389/fonc.2020.01698.

Urinary Estrogen Metabolites and Long-Term Mortality Following Breast Cancer.

Wang T, Nichols H, Nyante S, Bradshaw P, Moorman P, Kabat G JNCI Cancer Spectr. 2020; 4(3):pkaa014.

PMID: 32455334 PMC: 7236781. DOI: 10.1093/jncics/pkaa014.

References

Zhu B, Bui Q, Weisz J, Liehr J . Conversion of estrone to 2- and 4-hydroxyestrone by hamster kidney and liver microsomes: implications for the mechanism of estrogen-induced carcinogenesis. Endocrinology. 1994; 135(5):1772-9. DOI: 10.1210/endo.135.5.7956900. View

Schneider J, Kinne D, FRACCHIA A, Pierce V, Anderson K, Bradlow H . Abnormal oxidative metabolism of estradiol in women with breast cancer. Proc Natl Acad Sci U S A. 1982; 79(9):3047-51. PMC: 346346. DOI: 10.1073/pnas.79.9.3047. View

Yu S, Fishman J . Interaction of histones with estrogens. Covalent adduct formation with 16 alpha-hydroxyestrone. Biochemistry. 1985; 24(27):8017-21. DOI: 10.1021/bi00348a027. View

Goldin B, Gorbach S . Effect of diet on the plasma levels, metabolism, and excretion of estrogens. Am J Clin Nutr. 1988; 48(3 Suppl):787-90. DOI: 10.1093/ajcn/48.3.787. View

Swaneck G, Fishman J . Covalent binding of the endogenous estrogen 16 alpha-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization. Proc Natl Acad Sci U S A. 1988; 85(21):7831-5. PMC: 282290. DOI: 10.1073/pnas.85.21.7831. View

Vandewalle B, Lefebvre J . Opposite effects of estrogen and catecholestrogen on hormone-sensitive breast cancer cell growth and differentiation. Mol Cell Endocrinol. 1989; 61(2):239-46. DOI: 10.1016/0303-7207(89)90135-4. View

Telang N, Bradlow H, Kurihara H, Osborne M . In vitro biotransformation of estradiol by explant cultures of murine mammary tissues. Breast Cancer Res Treat. 1989; 13(2):173-81. DOI: 10.1007/BF01806529. View

Niwa T, Bradlow H, Fishman J, Swaneck G . Determination of estradiol 2- and 16-alpha-hydroxylase activities in MCF-7 human breast cancer cells in culture using radiometric analysis. J Steroid Biochem. 1989; 33(2):311-4. DOI: 10.1016/0022-4731(89)90309-9. View

Lustig R, Mobbs C, Pfaff D, Fishman J . Temporal actions of 16 alpha-hydroxyestrone in the rat: comparisons of lordosis dynamics with other estrogen metabolites and between sexes. J Steroid Biochem. 1989; 33(3):417-21. DOI: 10.1016/0022-4731(89)90332-4. View

10.

Bradlow H, Michnovicz J, Telang N, Osborne M . Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis. 1991; 12(9):1571-4. DOI: 10.1093/carcin/12.9.1571. View

11.

Telang N, Suto A, Wong G, Osborne M, Bradlow H . Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. J Natl Cancer Inst. 1992; 84(8):634-8. DOI: 10.1093/jnci/84.8.634. View

12.

Falck Jr F, Ricci Jr A, Wolff M, Godbold J, Deckers P . Pesticides and polychlorinated biphenyl residues in human breast lipids and their relation to breast cancer. Arch Environ Health. 1992; 47(2):143-6. View

13.

Harris J, Lippman M, Veronesi U, Willett W . Breast cancer (1). N Engl J Med. 1992; 327(5):319-28. DOI: 10.1056/NEJM199207303270505. View

14.

Wolff M, Toniolo P, Lee E, Rivera M, Dubin N . Blood levels of organochlorine residues and risk of breast cancer. J Natl Cancer Inst. 1993; 85(8):648-52. DOI: 10.1093/jnci/85.8.648. View

15.

Pike M, Spicer D, Dahmoush L, Press M . Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev. 1993; 15(1):17-35. DOI: 10.1093/oxfordjournals.epirev.a036102. View

16.

Osborne M, Bradlow H, Wong G, Telang N . Upregulation of estradiol C16 alpha-hydroxylation in human breast tissue: a potential biomarker of breast cancer risk. J Natl Cancer Inst. 1993; 85(23):1917-20. DOI: 10.1093/jnci/85.23.1917. View

17.

Dewailly E, Dodin S, Verreault R, Ayotte P, Sauve L, Morin J . High organochlorine body burden in women with estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1994; 86(3):232-4. DOI: 10.1093/jnci/86.3.232. View

18.

Suto A, Bradlow H, Wong G, Osborne M, Telang N . Experimental down-regulation of intermediate biomarkers of carcinogenesis in mouse mammary epithelial cells. Breast Cancer Res Treat. 1993; 27(3):193-202. DOI: 10.1007/BF00665689. View

19.

Davis D, Bradlow H, Wolff M, Woodruff T, Hoel D, Anton-Culver H . Medical hypothesis: xenoestrogens as preventable causes of breast cancer. Environ Health Perspect. 1993; 101(5):372-7. PMC: 1519851. DOI: 10.1289/ehp.93101372. View

20.

Kojima T, Tanaka T, Mori H . Chemoprevention of spontaneous endometrial cancer in female Donryu rats by dietary indole-3-carbinol. Cancer Res. 1994; 54(6):1446-9. View