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.

Influence of steroids on oxidant generation in activated human granulocytes and mononuclear leukocytes.

Steroids, in particular, 17beta-estradiol (E(2)), have been reported to improve the response to trauma in animal models. In these models, the leukocyte plays a critical role in the inflammatory cascade. We examined the affects of E(2), hydrocortisone (H), progesterone (P(4)), and E(2) with P(4) on oxidant production in human granulocytes (PMNs) and mononuclear leukocytes (MNCs). Each cell type was loaded with 2,7-dichlorodihydrofluorescein and then simultaneously activated with human cytokines (tumor necrosis factor alpha, interleukin-1beta, and interferon gamma) and hemoglobin and inhibited with and without equimolar concentrations of each steroid treatment or nitric oxide (NO) synthesis inhibitors. After incubations of 1 or 5 h, intracellular oxidants were quantified by flow cytometry. Activation by cytokines combined with hemoglobin, resulted in a 450-575% increase in oxidant production that was synergistically greater than the sum of either component alone. Pharmacological levels of E(2) decreased oxidants in MNCs at 1 h. In contrast at 5 h, H decreased oxidants more than E(2). The addition of P(4) to E(2) concentrations almost eliminated oxidants from 1 h-activated MNCs. None of the steroids significantly reduced oxidants in PMNs, suggesting that the E(2) effect on MNCs was not caused by its nonreceptor-mediated antioxidant properties. Because L-NMMA inhibited at least 55% of the total oxidants, part of E(2) dampening effects would be attributed to NO. These results suggest that steroid-attenuated MNC-derived NO may reduce autocrine and paracrine effects on inflammation if appropriate doses of steroids are given soon after injury.

Xenoestrogens: do they lower survival after thermal injury?

The effect of hormone disruptors on human health is an area of recent concern. The authors measured heptachlor epoxide and oxychlordane--the body storage forms of estrogenic insecticides-in the sera of patients with major burns (i.e., 7 survivors and 10 age- and burn-size-matched nonsurvivors) on days 1, 3, 5, 7, and 11 after they had been burned, as well as in 12 age-matched normal controls. During the hypermetabolic phase, serum concentrations of heptachlor epoxide and oxychlordane were greater in nonsurvivors than in controls, and heptachlor epoxide concentrations in nonsurvivors exceeded those in survivors on postburn day 5. The postburn alterations in heptachlor epoxide and oxychlordane concentrations could not be accounted for by changes in concentrations of circulating lipid. These findings, which indicate that xenoestrogens are released from fat depots after thermal injury, suggest a possible contribution to mortality, especially in older patients.