The link between the insecticide heptachlor epoxide, estradiol, and breast cancer

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 17beta-estradiol-(17beta-E2) receptor antagonists and were mimicked by similar concentrations of 17beta-E2. The addition of tumor necrosis factor-alpha (TNF-alpha) 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.