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 withl-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 17β-estradiol-(17β-E2) receptor antagonists and were mimicked by similar concentrations of 17β-E2. 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.
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References
BA Miller EJ Feuer BF Hankey (1994) The significance of the rising incidence of breast cancer in the United States. VT Devita S Hellman SA Rosenburg (Eds) [Important Advances in Oncology] J B Lippincott Company Philadelphia 193–207
American Cancer Society. Cancer Facts and Figures, 1996. Publication no. 5008.96. American Cancer Society, Atlanta, Georgia, 1996
RG Ziegler RN Hoover MC Pike A Hildesheim AM Nomura DW West AH Wu-Williams LN Kolonel PL Horn-Ross JF Rosenthal MB Hyer (1993) ArticleTitleMigration patterns and breast cancer risk in Asian–American women J Natl Cancer Inst 85 1819–1827 Occurrence Handle1:STN:280:DyaK2c%2FkslWgsQ%3D%3D Occurrence Handle8230262
National Cancer Institute. SEER Cancer Statistics Review 1973–1999. Rockville, Maryland, 2002.
KC Chu RE Tarone LG Kessler LA Ries BF Hankey BA Miller BK Edwards (1996) ArticleTitleRecent trends in US breast cancer incidence, survival, and mortality rates J Natl Cancer Inst 88 1571–1579 Occurrence Handle1:STN:280:DyaK2s%2FlslGitA%3D%3D Occurrence Handle8901855
JL Kelsey (1993) ArticleTitleBreast cancer epidemiology:summary and future directions Epidemiol Rev 15 256–263 Occurrence Handle1:STN:280:DyaK2c%2FgvFCisw%3D%3D Occurrence Handle8405209
KK Steinberg SB Thacker SJ Smith DF Stroup MM Zack WD Flanders (1991) ArticleTitleA meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer JAMA 265 1985–1990 Occurrence Handle1:STN:280:DyaK3M7nvVykuw%3D%3D Occurrence Handle1826136
SR Cummings T Duong E Kenyon JA Cauley M Whitehead KA Krueger (2002) ArticleTitleSerum estradiol level and the risk of beast cancer during treatment with raloxifene JAMA 287 216–220 Occurrence Handle10.1001/jama.287.2.216 Occurrence Handle1:CAS:528:DC%2BD38XisVSmtg%3D%3D Occurrence Handle11779264
JA Cauley FL Lucas LH Kuller K Stone W Browner SR Cummings (1999) ArticleTitleElevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer Ann Intern Med 130 270–277 Occurrence Handle1:CAS:528:DyaK1MXhsleiu7w%3D Occurrence Handle10068384
MS Wolff GW Collman JC Barett J Huff (1996) ArticleTitleBreast cancer and environmental risk factors: epidemiological and experimental findings Annu Rev Pharmacol Toxicol 35 573–596
AP Hoyer P Grandjean T Jorgensen JW Brock HB Hartvig (1998) ArticleTitleOrganochlorine exposure and risk of breast cancer Lancet 352 1816–1820 Occurrence Handle1:STN:280:DyaK1M%2Fms1OjtQ%3D%3D Occurrence Handle9851382
FW Kutz PH Wood DP Bottimore (1991) ArticleTitleOrganochlorine pesticides and polychlorinated biphenyls in human adipose tissue Rev Environ Contam Toxicol 120 1–82 Occurrence Handle1:CAS:528:DyaK3MXktVamt7k%3D Occurrence Handle1899728
KL Steffey JD Reynolds HB Petty (1984) ArticleTitleAn eleven-year study of chlorinated hydrocarbon insecticide residues in bovine fat in Illinois, 1972–1982. J Environ Sci Health B19 773–783 Occurrence Handle1:CAS:528:DyaL2MXptFWjsA%3D%3D
KL Steffey J Mack CW MacMonegle HB Petty (1984) ArticleTitleA ten-year study of chlorinated hydrocarbon insecticide residues in bovine milk in Illinois, 1972–1981. J Environ Sci Health B19 49–65 Occurrence Handle1:CAS:528:DyaL2cXhtlOmt7k%3D
MD Salman JS Reif L Rupp MJ Aaronson (1990) ArticleTitleChlorinated hydrocarbon insecticides in Colorado beef cattle serum–a pilot environmental monitoring system J Toxicol Environ Health 3 125–132
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.
F Adeshina EL Todd (1990) ArticleTitleOrganochlorine compounds in human adipose tissue from North Texas J Toxicol Environ Health 29 147–156 Occurrence Handle10.1080/15287399009531379 Occurrence Handle1:CAS:528:DyaK3cXhsleku7w%3D Occurrence Handle1688952
M Wassermann DP Nogueira L Tomatis AP Mirra H Shibata G Arie S Cucos D Wassermann (1976) ArticleTitleOrganochlorine compounds in neoplastic and adjacent apparently normal breast tissue Bull Environm Contamin Toxicol 15 478–484 Occurrence Handle1:CAS:528:DyaE28Xkt12htbg%3D
H Mussalo-Rauhamaa E Hasanen H Pyysalo K Antervo R Kauppila P Pantzar (1990) ArticleTitleOccurrence of beta-hexachlorocyclohexane in breast cancer patients Cancer 66 2124–2128 Occurrence Handle1:CAS:528:DyaK3MXitVClu7k%3D Occurrence Handle1699651
T Zheng TR Holford J Tessari ST Mayne SH Zahm PH Owens B Zhang B Ward D Carter Y Zhang W Zhang R Dubrow P Boyle (2000) ArticleTitleOxychlordane and trans-nonachlor in breast adipose tissue and the risk of female breast cancer J Epidemiol Biostat 5 153–160 Occurrence Handle1:STN:280:DC%2BD3crgt1Klug%3D%3D Occurrence Handle11051111
F Falck A Ricci MS Wolff J Godbold P Deckers (1992) ArticleTitlePesticides and polychlorinated biphenyl residues in human breast lipids and their relation to breast cancer Arch Environ Health 47 143–146 Occurrence Handle1567239
RA Cassidy CV Vorhees DJ Minnema L Hastings (1994) ArticleTitleThe 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 Occurrence Handle1:CAS:528:DyaK2cXksFaitrk%3D Occurrence Handle8209386
PV Shekhar J Werdell VS Basrur (1997) ArticleTitleEnvironmental estrogen stimulation of growth and estrogen receptor function in preneoplastic and cancerous human breast cell lines J Natl Cancer Inst 89 1774–1782 Occurrence Handle1:CAS:528:DyaK2sXotVSnt7w%3D Occurrence Handle9392618
C Massaad X Coumoui M Sabbah M Garlatti G Redeuilh R Barouki (1998) ArticleTitleProperties of overlapping EREs: synergistic activation of transcription and cooperative binding of ER Biochemistry 37 6023–6032 Occurrence Handle1:CAS:528:DyaK1cXislGhtbc%3D Occurrence Handle9558340
RM Welch W Levin R Kuntzman M Jacobson AH Conney (1971) ArticleTitleEffect of halogenated hydrocarbon insecticides on the metabolism and uterotropic action of estrogens in rats and mice Toxicol Appl Pharmacol 19 234–246 Occurrence Handle1:CAS:528:DyaE3MXlsFSltrY%3D Occurrence Handle4105824
RM Welch W Levin AH Conney (1967) ArticleTitleInsecticide inhibition and stimulation of steroid hydroxylases in rat liver J Pharmacol Exp Thera 155 167–173 Occurrence Handle1:CAS:528:DyaF2sXjs1yjsg%3D%3D
JA Oduma EO Wango D Oduor-Okelo DW Makawiti H Odongo (1995) ArticleTitleIn 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 Occurrence Handle1:STN:280:DyaK287ivFWnsA%3D%3D
CW Elston IO Ellis (1991) ArticleTitlePathological 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 Occurrence Handle1:STN:280:DyaK38%2FpvVSltw%3D%3D Occurrence Handle1757079
RA Cassidy DG Burleson AV Delgado DJ Kohler ML Salin BA Pruitt SuffixJr (2000) ArticleTitleEffects of heme proteins on nitric oxide levels and cell viability in isolated PMNs: a mechanism of toxicity J Leukoc Biol 67 357–68 Occurrence Handle1:CAS:528:DC%2BD3cXkvVygtbc%3D Occurrence Handle10733096
JL Fleiss (Eds) (1981) Sampling method I: naturalistic or cross-sectional studies. Statistical Methods for Rates and Proportions, 2nd edn. John Wiley & Sons New York 64–74
Carcinogenicity Assessment of Chlordane and Heptachlor/Heptachlor Epoxide. Office of Pesticide and Toxic Substances. US Environmental Protection Agency, Washington, DC, 1986.
LJ Guillette PM Vonier JA McLachlan (2002) ArticleTitleAffinity of the alligator estrogen receptor for serum pesticide contaminants. Toxicol 181–182 151–154
RA James I Hertz-Picciotto E Willman JA Keller MJ Charles (2002) ArticleTitleDeterminants 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 Occurrence Handle1:CAS:528:DC%2BD38XmvFSntb8%3D Occurrence Handle12117636
J Hergenrather G Hlady B Wallace E Savage (1981) ArticleTitlePollutants in breast milk of vegetarians. New Eng J Med 304 792 Occurrence Handle1:STN:280:DyaL3M7itlSjuw%3D%3D Occurrence Handle7464895
PC Dagnelie WA van Staveren AH Roos LG Tuinstra J Burema (1992) ArticleTitleNutrients and contaminants in human milk from mothers on macrobiotic and omnivorous diets Eur J Clin Nutr 46 355–366 Occurrence Handle1:STN:280:DyaK383ovFKntQ%3D%3D Occurrence Handle1600934
V Beral V Bull R Doll R Peto G Reeves (2002) ArticleTitleBreast 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
AA Jensen (1983) ArticleTitleChemical Contaminants in Human Milk Residue Rev 89 1–128 Occurrence Handle1:CAS:528:DyaL3sXlslChtL8%3D Occurrence Handle6316441
M Sim A Forbes J McNeil R Graham (1998) ArticleTitleTermite control and other determinants of high body burdens of cyclodienes insecticides Arch Environ Health 53 114–121 Occurrence Handle1:CAS:528:DyaK1cXivVSjsbc%3D Occurrence Handle9577934
S Taguchi T Yakushiji (1988) ArticleTitleInfluence of termite treatment in the home on the concentration of chlordane concentration in human milk Arch Environ Contamin Toxicol 17 65–71 Occurrence Handle1:CAS:528:DyaL1cXltV2mug%3D%3D
J Foidart C Colin X Denoo J Desreux A Beliard S Fournier B de Lignieres (1998) ArticleTitleEstradiol and progesterone regulate the proliferation of human breast epithelial cells Fertil Steril 69 963–969 Occurrence Handle1:STN:280:DyaK1c3lt1WrsQ%3D%3D Occurrence Handle9591509
F Chang TY Lee G Linares-Cruz S Fournier B de Lignieres (1995) ArticleTitleInfluences of percutaneous administration of estradiol and progesterone on the human breast epithelial cell cycle in vivo Fertil Steril 63 785–791 Occurrence Handle1:STN:280:DyaK2M7ps1yqsg%3D%3D Occurrence Handle7890063
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.
L Okoumassoun D Averill-Bates M Marion F Denizeau (2003) ArticleTitlePossible mechanisms underlying the mitogenic action of heptachlor in rat hepatocytes Toxicol Appl Pharmacol 193 356–369 Occurrence Handle1:CAS:528:DC%2BD3sXpvVWktLg%3D Occurrence Handle14678745
EJ Calabrese (2001) ArticleTitleEstrogen and related compounds: Biphasic dose responses Crit Rev Toxicol 31 503–515 Occurrence Handle1:CAS:528:DC%2BD3MXmsVOhu7Y%3D Occurrence Handle11504177
GB Stefano V Prevot J Beauvillain C Fimiani I Welters P Cadet C Breton J Pestel M Salzet TV Bilfinger (1999) ArticleTitleEstradiol coupling to human monocyte nitric oxide release is dependent on intracellular calcium transients: Evidence for an estrogen surface receptor J Immunol 163 3758–3763 Occurrence Handle1:CAS:528:DyaK1MXmt1yjur4%3D Occurrence Handle10490972
GB Stefano P Cadet C Breton Y Goumon V Prevot JP Dessaint J Beauvillain AS Roumier I Welters M Salzet (2000) ArticleTitleEstradiol-stimulated nitric oxide release in human granulocytes is dependent on intracellular calcium transients: evidence of a cell surface estrogen receptor Blood 95 3951–3958 Occurrence Handle1:CAS:528:DC%2BD3cXktFChtLw%3D Occurrence Handle10845933
D Fulton J Gratton TJ McCabe J Fontana Y Fujio K Walsh TF Franke A Papapetropoulos WC Sessa (1999) ArticleTitleRegulation of endothelium-derived nitric oxide production by the protein kinase Akt Nature 399 597–601 Occurrence Handle10.1038/21218 Occurrence Handle1:CAS:528:DyaK1MXjvFegu78%3D Occurrence Handle10376602
T Simoncini E Rabkin JK Liao (2003) ArticleTitleMolecular basis of cell membrane estrogen receptor interact with phosphatidylinositol 3-kinase in endothelial cells Arterioscler Thromb Vascular Biol 23 198–207 Occurrence Handle1:CAS:528:DC%2BD3sXptFyqtw%3D%3D
D Chen IM Bird J Zheng RR Magness (2003) ArticleTitleMembrane 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
K Sak H Everaus (2004) ArticleTitleNongenomic effects of 17beta-estrodiol-diversity of membrane binding sites J Steroid Biochem Mol Biol 88 323–325 Occurrence Handle1:CAS:528:DC%2BD2cXktVKqurs%3D Occurrence Handle15145442
L Li P Haynes JR Bender (2003) ArticleTitlePlasma membrane localization and function of the estrogen receptor α variant in human endothelial cells PNAS 100 4807–4812 Occurrence Handle1:CAS:528:DC%2BD3sXjt12nsbg%3D Occurrence Handle12682286
A Nadal AB Ropero O Laribi M Maillet E Fuentes B Soria (2000) ArticleTitleNongenomic 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 Occurrence Handle1:CAS:528:DC%2BD3cXnsF2qsbs%3D Occurrence Handle11027358
T Nguyen D Brunson CL Crespi BW Penman JS Wishnok SR Tannenbaum (1992) ArticleTitleDNA damage and mutation in human cells exposed to nitric oxide in vitro PNAS 89 3030–3034 Occurrence Handle1:CAS:528:DyaK38XitV2msLk%3D Occurrence Handle1557408
S Tamir SR Tannenbaumm (1996) ArticleTitleThe role of nitric oxide (NO) in the carcinogenic process. Biochim Biophys Acta 1288 F31–F36 Occurrence Handle8876631
RR Monson S Yen B MacMahon S Warren (1976) ArticleTitleChronic mastitis and carcinoma of the breast Lancet 2 224–226 Occurrence Handle1:STN:280:DyaE283hvFWjug%3D%3D Occurrence Handle59241
S Reveneau L Arnold G Jolimoy S Hilpert P Lejeune V Saint-Giorgio C Belichard J Jeannin (1999) ArticleTitleNitric oxide synthase in human breast cancer is associated with tumor grade, proliferation rate, and expression of progesterone receptors Lab Invest 79 1215–1225 Occurrence Handle1:CAS:528:DyaK1MXntFOmsL4%3D Occurrence Handle10532585
LL Thomsen DW Miles L Happerfield LG Bobrow RG Knowles S Moncada (1995) ArticleTitleNitric oxide synthase activity in human breast cancer Br J Cancer 72 41–44 Occurrence Handle1:CAS:528:DyaK2MXnvFyisLk%3D Occurrence Handle7541238
W Tschugguel W Knogler K Czerwenka M Mildner W Weninger R Zeillinger JC Huber (1996) ArticleTitlePresence of endothelial calcium-dependent nitric oxide synthase in breast apocrine metaplasia Br J Cancer 74 1423–1426 Occurrence Handle1:CAS:528:DyaK28XntVOis74%3D Occurrence Handle8912539
L Thamrongwittawatpong Y Sirivatanauksorn JJ Batten RC Williamson AK Kakkar RT Mathie (2001) ArticleTitleThe effect of NG-monomethyl-L-arginine and tamoxifen on nitric oxide production in breast cancer cells stimulated by oestrogen and progesterone Eur J Surg 167 484–489 Occurrence Handle1:CAS:528:DC%2BD3MXmvVamsr8%3D Occurrence Handle11560381
DC Jenkins IG Charles LL Thomsen DW Moss LS Holmes SA Baylis P Rhode K Westmore PC Emson S Moncada (1995) ArticleTitleRole of nitric oxide in tumor growth PNAS 92 4392–4396 Occurrence Handle1:CAS:528:DyaK2MXls1aksrw%3D Occurrence Handle7538668
M Iscan T Coban I Cok D Bulbul BC Eke S Burgaz (2002) ArticleTitleThe organochlorine pesticide residues and antioxidant enzyme activities in human breast tumors: is there any association Breast Cancer Res Treatm 72 173–182 Occurrence Handle1:CAS:528:DC%2BD38XktVSmtrk%3D
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Cassidy, R.A., Natarajan, S. & Vaughan, G.M. The link between the insecticide heptachlor epoxide, estradiol, and breast cancer. Breast Cancer Res Treat 90, 55–64 (2005). https://doi.org/10.1007/s10549-004-2755-0
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DOI: https://doi.org/10.1007/s10549-004-2755-0