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

Abstract

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.

Increased cancer burden among pesticide applicators and others due to pesticide exposure

“…Of the remaining 8 studies, the results were mixed. While 4 studies 163,165,169,170 did not observe an association between OC concentrations, the other 4 studies 164,166,168,171 did observe positive associations.…”

“…In our current review, we update the literature since 2002. We identified 11 published studies 32,[162][163][164][165][166][167][168][169][170][171] that reported on associations between measured serum, plasma, or adipose tissue concentrations of OC insecticides and breast cancer, which were not included in either the review by Calle et al or Lopez-Cervantes et al 160,161 Two studies 162,167 were excluded from our review because risk estimates (eg, ORs) were not reported. A third study 32 was excluded because the case definition included prevalent breast cancer.…”

Molecular Mechanisms of Pesticide Toxicity

“…In addition to tumor promotion-induced endocrine disruption mechanisms, pesticides may be directly or indirectly mutagenic through free radical production (Cassidy et al, 2005) and may cause both tumor initiation and subsequent tumor promotion by inhibiting Gap junctional intercellular communication (GJIC) (Kang et al, 1996). Inhibition of GJIC has clearly been shown in normal epithelial breast tissue exposed to relatively high concentrations of organochlorine pesticides.…”

Adipose tissue concentrations of persistent organic pollutants and total cancer risk in an adult cohort from Southern Spain: Preliminary data from year 9 of the follow-up

“…However, there have been conflicting reports on the relationship between exposure to low levels of POPs, such as those occurring in the general population, and cancer risk, with some studies reporting positive associations but many others finding no evidence to support a causal association (Cassidy et al, 2005;Charlier et al, 2003;Cohn et al, 2010;Gatto et al, 2007;Govett et al, 2011;Hardell et al, 2006;Hoyer et al, 2001;Laden et al, 2001;Lopez-Carrillo et al, 2002;Lopez-Cervantes et al, 2004;Mozzachio et al, 2008;Pavuk et al, 2004;Recio-Vega et al, 2011;Snedeker, 2001;Soto and Sonnenschein, 2010;Svensson et al, 1995;Ward et al, 2000;Wolff et al, 2000;Xu et al, 2010).…”