The link between the insecticide heptachlor epoxide, estradiol, and breast cancer Report DOI:
Cite this article as: Cassidy, R.A., Natarajan, S. & Vaughan, G.M. Breast Cancer Res Treat (2005) 90: 55. doi:10.1007/s10549-004-2755-0 Summary
Given the suspected effects of estrogens on breast cancer, xenoestrogenic insecticides may be a risk factor. Studies of the weak xenoestrogen, 1,1-dichloro-2,2-bis(
p-chlorophenyl)ethylene (DDE), have failed to demonstrate a causal relationship, though another estrogenic organochlorine insecticide, dieldrin, belonging to the cyclodiene family, has recently been linked to breast cancer. Other cyclodienes such as heptachlor epoxide (HE) and oxychlordane (OC) present in breast tissue have not been evaluated as rigorously, presumably due to their lower concentration and lower recovery using solvent extraction procedures. We used sparging extraction coupled with gas chromatography to determine the levels of HE, OC, and DDE in adipose tissue within breast biopsies in a series of 34 women evaluated for breast abnormality. Of the three insecticides tested, only HE ( p=0.007) was positively associated with prevalence of breast cancer in the biopsies. In rapid, non-genomic studies using isolated human leukocytes, flow cytometric methods were used to measure HE-induced oxidants and DNA damage. These studies indicated that HE, at concentrations similar to those in breast biopsies, induced an inverted-U increase in intracellular oxidants and DNA strand breaks [both blocked by specific nitric oxide- (NO-) synthesis blockade with l-NMMA] in human polymorphonuclear leukocytes (PMNs). HE-treated PMNs also induced damage to surrounding lymphocytes in mixed-leukocyte incubations (also inhibited by NO blockade). The HE-induced changes in NO were inhibited by 17 β-estradiol-(17 β-E 2) receptor antagonists and were mimicked by similar concentrations of 17 β-E 2. The addition of tumor necrosis factor- α (TNF- α) increased intracellular oxidants and DNA damage and shifted the responses to lower HE concentrations. This study, along with others, suggests that HE-induced NO production may contribute to initiation, promotion, and progression of cancer. Keywords breast cancer DDE DNA damage estradiol heptachlor epoxide nitric oxide oxidant oxychlordane tamoxifen References Miller, BA, Feuer, EJ, Hankey, BF 1994 The significance of the rising incidence of breast cancer in the United States. Devita, VT Hellman, S Rosenburg, SA eds. [Important Advances in Oncology] J B Lippincott Company Philadelphia 193 207 Google Scholar
American Cancer Society. Cancer Facts and Figures, 1996. Publication no. 5008.96. American Cancer Society, Atlanta, Georgia, 1996
Ziegler, RG, Hoover, RN, Pike, MC, Hildesheim, A, Nomura, AM, West, DW, Wu-Williams, AH, Kolonel, LN, Horn-Ross, PL, Rosenthal, JF, Hyer, MB 1993 Migration patterns and breast cancer risk in Asian–American women J Natl Cancer Inst 85 1819 1827 PubMed Google Scholar
National Cancer Institute. SEER Cancer Statistics Review 1973–1999. Rockville, Maryland, 2002.
Chu, KC, Tarone, RE, Kessler, LG, Ries, LA, Hankey, BF, Miller, BA, Edwards, BK 1996 Recent trends in US breast cancer incidence, survival, and mortality rates J Natl Cancer Inst 88 1571 1579 PubMed Google Scholar Kelsey, JL 1993 Breast cancer epidemiology:summary and future directions Epidemiol Rev 15 256 263 PubMed Google Scholar Steinberg, KK, Thacker, SB, Smith, SJ, Stroup, DF, Zack, MM, Flanders, WD 1991 A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer JAMA 265 1985 1990 PubMed Google Scholar Cummings, SR, Duong, T, Kenyon, E, Cauley, JA, Whitehead, M, Krueger, KA 2002 Serum estradiol level and the risk of beast cancer during treatment with raloxifene JAMA 287 216 220 CrossRef PubMed Google Scholar Cauley, JA, Lucas, FL, Kuller, LH, Stone, K, Browner, W, Cummings, SR 1999 Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer Ann Intern Med 130 270 277 PubMed Google Scholar Wolff, MS, Collman, GW, Barett, JC, Huff, J 1996 Breast cancer and environmental risk factors: epidemiological and experimental findings Annu Rev Pharmacol Toxicol 35 573 596 Google Scholar Hoyer, AP, Grandjean, P, Jorgensen, T, Brock, JW, Hartvig, HB 1998 Organochlorine exposure and risk of breast cancer Lancet 352 1816 1820 PubMed Google Scholar Kutz, FW, Wood, PH, Bottimore, DP 1991 Organochlorine pesticides and polychlorinated biphenyls in human adipose tissue Rev Environ Contam Toxicol 120 1 82 PubMed Google Scholar Steffey, KL, Reynolds, JD, Petty, HB 1984 An eleven-year study of chlorinated hydrocarbon insecticide residues in bovine fat in Illinois, 1972–1982. J Environ Sci Health B19 773 783 Google Scholar Steffey, KL, Mack, J, MacMonegle, CW, Petty, HB 1984 A ten-year study of chlorinated hydrocarbon insecticide residues in bovine milk in Illinois, 1972–1981. J Environ Sci Health B19 49 65 Google Scholar Salman, MD, Reif, JS, Rupp, L, Aaronson, MJ 1990 Chlorinated hydrocarbon insecticides in Colorado beef cattle serum–a pilot environmental monitoring system J Toxicol Environ Health 3 125 132 Google Scholar
Toxicilogical Profile for Chlordane. Agency for Toxic Substances and Diesease Registry, Public Health Services. US Department of Health and Human Services. Atlanta, Georgia, 1994.
US EPA. Chlordane, Heptachlor, Aldrin, and Dieldrin. Technical Support Document. Office of Pesticide and Toxic Substances. US Environmental Protection Agency, Washington, DC, 1987.
Adeshina, F, Todd, EL 1990 Organochlorine compounds in human adipose tissue from North Texas J Toxicol Environ Health 29 147 156 CrossRef PubMed Google Scholar Wassermann, M, Nogueira, DP, Tomatis, L, Mirra, AP, Shibata, H, Arie, G, Cucos, S, Wassermann, D 1976 Organochlorine compounds in neoplastic and adjacent apparently normal breast tissue Bull Environm Contamin Toxicol 15 478 484 Google Scholar Mussalo-Rauhamaa, H, Hasanen, E, Pyysalo, H, Antervo, K, Kauppila, R, Pantzar, P 1990 Occurrence of beta-hexachlorocyclohexane in breast cancer patients Cancer 66 2124 2128 PubMed Google Scholar Zheng, T, Holford, TR, Tessari, J, Mayne, ST, Zahm, SH, Owens, PH, Zhang, B, Ward, B, Carter, D, Zhang, Y, Zhang, W, Dubrow, R, Boyle, P 2000 Oxychlordane and trans-nonachlor in breast adipose tissue and the risk of female breast cancer J Epidemiol Biostat 5 153 160 PubMed Google Scholar Falck, F, Ricci, A, Wolff, MS, Godbold, J, Deckers, P 1992 Pesticides and polychlorinated biphenyl residues in human breast lipids and their relation to breast cancer Arch Environ Health 47 143 146 PubMed Google Scholar Cassidy, RA, Vorhees, CV, Minnema, DJ, Hastings, L 1994 The effects of chlordane exposure during pre- and post-natal periods at environmentally relevant levels on sex steroid-mediated behaviors and functions in the rat Toxicol Appl Pharmacol 126 326 337 PubMed Google Scholar Shekhar, PV, Werdell, J, Basrur, VS 1997 Environmental estrogen stimulation of growth and estrogen receptor function in preneoplastic and cancerous human breast cell lines J Natl Cancer Inst 89 1774 1782 PubMed Google Scholar Massaad, C, Coumoui, X, Sabbah, M, Garlatti, M, Redeuilh, G, Barouki, R 1998 Properties of overlapping EREs: synergistic activation of transcription and cooperative binding of ER Biochemistry 37 6023 6032 PubMed Google Scholar Welch, RM, Levin, W, Kuntzman, R, Jacobson, M, Conney, AH 1971 Effect of halogenated hydrocarbon insecticides on the metabolism and uterotropic action of estrogens in rats and mice Toxicol Appl Pharmacol 19 234 246 PubMed Google Scholar Welch, RM, Levin, W, Conney, AH 1967 Insecticide inhibition and stimulation of steroid hydroxylases in rat liver J Pharmacol Exp Thera 155 167 173 Google Scholar Oduma, JA, Wango, EO, Oduor-Okelo, D, Makawiti, DW, Odongo, H 1995 In vivo and in vitro effects of graded doses of the pesticide heptachlor on female sex steroid hormone production in rats Comp Biochem Physiol C Pharmacol Toxicol Endrocrinol 111 191 196 Google Scholar Elston, CW, Ellis, IO 1991 Pathological prognostic factors in breast cancer The value of histological grade in breast cancer: experience from a large study with long term-term follow-up. Histopathol 19 403 140 PubMed Google Scholar Cassidy, RA, Burleson, DG, Delgado, AV, Kohler, DJ, Salin, ML, Pruitt, BA, Jr 2000 Effects of heme proteins on nitric oxide levels and cell viability in isolated PMNs: a mechanism of toxicity J Leukoc Biol 67 357 68 PubMed Google Scholar Fleiss, JL eds. 1981Sampling method I: naturalistic or cross-sectional studies. Statistical Methods for Rates and Proportions, 2nd edn. John Wiley & Sons New York 64 74 Google Scholar
Carcinogenicity Assessment of Chlordane and Heptachlor/Heptachlor Epoxide. Office of Pesticide and Toxic Substances. US Environmental Protection Agency, Washington, DC, 1986.
Guillette, LJ, Vonier, PM, McLachlan, JA 2002 Affinity of the alligator estrogen receptor for serum pesticide contaminants. Toxicol 181–182 151 154 Google Scholar James, RA, Hertz-Picciotto, I, Willman, E, Keller, JA, Charles, MJ 2002 Determinants of serum polychlorinated biphenyls and organochlorine pesticides measured in women from the child health and development study cohort, 1963–1967 Environ Health Perspect 110 617 624 PubMed Google Scholar Hergenrather, J, Hlady, G, Wallace, B, Savage, E 1981 Pollutants in breast milk of vegetarians. New Eng J Med 304 792 PubMed Google Scholar Dagnelie, PC, van Staveren, WA, Roos, AH, Tuinstra, LG, Burema, J 1992 Nutrients and contaminants in human milk from mothers on macrobiotic and omnivorous diets Eur J Clin Nutr 46 355 366 PubMed Google Scholar Beral, V, Bull, V, Doll, R, Peto, R, Reeves, G 2002 Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50,302 women with breast cancer and 96,973 women without the disease Lancet 360 187 195 Google Scholar Jensen, AA 1983 Chemical Contaminants in Human Milk Residue Rev 89 1 128 PubMed Google Scholar Sim, M, Forbes, A, McNeil, J, Graham, R 1998 Termite control and other determinants of high body burdens of cyclodienes insecticides Arch Environ Health 53 114 121 PubMed Google Scholar Taguchi, S, Yakushiji, T 1988 Influence of termite treatment in the home on the concentration of chlordane concentration in human milk Arch Environ Contamin Toxicol 17 65 71 Google Scholar Foidart, J, Colin, C, Denoo, X, Desreux, J, Beliard, A, Fournier, S, de Lignieres, B 1998 Estradiol and progesterone regulate the proliferation of human breast epithelial cells Fertil Steril 69 963 969 PubMed Google Scholar Chang, F, Lee, TY, Linares-Cruz, G, Fournier, S, de Lignieres, B 1995 Influences of percutaneous administration of estradiol and progesterone on the human breast epithelial cell cycle in vivo Fertil Steril 63 785 791 PubMed Google Scholar
Toxicological Profile for Heptachlor/Heptachlor epoxide. Agency for Toxic Substances and Diesease Registry, Public Health Services. US Department of Health and Human Services. Atlanta, Georgia, 1993.
Okoumassoun, L, Averill-Bates, D, Marion, M, Denizeau, F 2003 Possible mechanisms underlying the mitogenic action of heptachlor in rat hepatocytes Toxicol Appl Pharmacol 193 356 369 PubMed Google Scholar Calabrese, EJ 2001 Estrogen and related compounds: Biphasic dose responses Crit Rev Toxicol 31 503 515 PubMed Google Scholar Stefano, GB, Prevot, V, Beauvillain, J, Fimiani, C, Welters, I, Cadet, P, Breton, C, Pestel, J, Salzet, M, Bilfinger, TV 1999 Estradiol coupling to human monocyte nitric oxide release is dependent on intracellular calcium transients: Evidence for an estrogen surface receptor J Immunol 163 3758 3763 PubMed Google Scholar Stefano, GB, Cadet, P, Breton, C, Goumon, Y, Prevot, V, Dessaint, JP, Beauvillain, J, Roumier, AS, Welters, I, Salzet, M 2000 Estradiol-stimulated nitric oxide release in human granulocytes is dependent on intracellular calcium transients: evidence of a cell surface estrogen receptor Blood 95 3951 3958 PubMed Google Scholar Fulton, D, Gratton, J, McCabe, TJ, Fontana, J, Fujio, Y, Walsh, K, Franke, TF, Papapetropoulos, A, Sessa, WC 1999 Regulation of endothelium-derived nitric oxide production by the protein kinase Akt Nature 399 597 601 CrossRef PubMed Google Scholar Simoncini , T, Rabkin, E, Liao, JK 2003 Molecular basis of cell membrane estrogen receptor interact with phosphatidylinositol 3-kinase in endothelial cells Arterioscler Thromb Vascular Biol 23 198 207 Google Scholar Chen, D, Bird, IM, Zheng, J, Magness, RR 2003 Membrane estrogen receptor-dependent extracellular signal-regulated kinase pathway mediates acute activation of endothelial nitric oxide synthase by estrogen in uterine artery endothelial cells Endocrinol 145 113 125 Google Scholar Sak, K, Everaus, H 2004 Nongenomic effects of 17beta-estrodiol-diversity of membrane binding sites J Steroid Biochem Mol Biol 88 323 325 PubMed Google Scholar Li, L, Haynes, P, Bender, JR 2003 Plasma membrane localization and function of the estrogen receptor α variant in human endothelial cells PNAS 100 4807 4812 PubMed Google Scholar Nadal, A, Ropero, AB, Laribi, O, Maillet, M, Fuentes, E, Soria, B 2000 Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor α and estrogen receptor β PNAS 97 11603 11608 PubMed Google Scholar Nguyen, T, Brunson, D, Crespi, CL, Penman, BW, Wishnok, JS, Tannenbaum, SR 1992 DNA damage and mutation in human cells exposed to nitric oxide in vitro PNAS 89 3030 3034 PubMed Google Scholar Tamir, S, Tannenbaumm, SR 1996 The role of nitric oxide (NO) in the carcinogenic process. Biochim Biophys Acta 1288 F31 F36 PubMed Google Scholar Monson, RR, Yen, S, MacMahon, B, Warren, S 1976 Chronic mastitis and carcinoma of the breast Lancet 2 224 226 PubMed Google Scholar Reveneau, S, Arnold, L, Jolimoy, G, Hilpert, S, Lejeune, P, Saint-Giorgio, V, Belichard, C, Jeannin, J 1999 Nitric oxide synthase in human breast cancer is associated with tumor grade, proliferation rate, and expression of progesterone receptors Lab Invest 79 1215 1225 PubMed Google Scholar Thomsen, LL, Miles, DW, Happerfield, L, Bobrow, LG, Knowles, RG, Moncada, S 1995 Nitric oxide synthase activity in human breast cancer Br J Cancer 72 41 44 PubMed Google Scholar Tschugguel, W, Knogler, W, Czerwenka, K, Mildner, M, Weninger, W, Zeillinger, R, Huber, JC 1996 Presence of endothelial calcium-dependent nitric oxide synthase in breast apocrine metaplasia Br J Cancer 74 1423 1426 PubMed Google Scholar Thamrongwittawatpong, L, Sirivatanauksorn, Y, Batten, JJ, Williamson, RC, Kakkar, AK, Mathie, RT 2001 The effect of N G-monomethyl- L-arginine and tamoxifen on nitric oxide production in breast cancer cells stimulated by oestrogen and progesterone Eur J Surg 167 484 489 PubMed Google Scholar Jenkins, DC, Charles, IG, Thomsen, LL, Moss, DW, Holmes, LS, Baylis, SA, Rhode, P, Westmore, K, Emson, PC, Moncada, S 1995 Role of nitric oxide in tumor growth PNAS 92 4392 4396 PubMed Google Scholar Iscan, M, Coban, T, Cok, I, Bulbul, D, Eke, BC, Burgaz, S 2002 The organochlorine pesticide residues and antioxidant enzyme activities in human breast tumors: is there any association Breast Cancer Res Treatm 72 173 182 Google Scholar