Data from two studies presented at the 88th Annual Meeting of the American
Association for Cancer Research (AACR) have added evidence to support an
association between environmental estrogens and breast cancer. Lifetime
exposure to endogenous estrogens is known to be a risk factor for breast
cancer. However, there is uncertainty about whether environmental estrogens
such as DDT are definitively linked to breast cancer. Two large epidemiological
studies conducted in the 1990s produced conflicting findings regarding
the correlation between increasing concentrations of DDT metabolites and
incidence of breast cancer. Moreover, little is known about the potential
mechanisms by which endogenous or environmental estrogens convert normal
breast epithelial cells into abnormal cells.
Scientists from the Karmanos Cancer Institute in Detroit examined the
effects of estradiol and five closely related organochlorine pesticides
on cell growth in two estrogen receptor-positive human breast epithelial
cell lines: precancerous cells and human breast cancer cells. Organochlorine
pesticides have been associated with the development of breast cancer because
of their estrogenic properties. Those selected for this study act as estrogens
with actions mediated through the estrogen receptor.
Pesticide Combinations More Lethal
Using a special assay, the investigators found that when the pesticides
were administered individually, they caused the human breast epithelial
cells to proliferate, but only when they were administered at 100- to 1,000-fold
higher levels than estradiol. However, when the pesticides were administered
in combination, they caused cell proliferation similar to that observed
with physiological concentrations of estradiol.
According to study investigator, Malathy Shekhar, PhD, "To date,
there is no conclusive proof that endogenous estrogens cause breast cancer.
The only evidence comes from epidemiological studies showing an association
between an individual's total cumulative exposure to estrogen and breast
cancer. In order to provide stronger evidence for this association, we
studied the possible mechanisms by which estrogens cause malignancy. We
used an estrogen receptor-positive precancerous cell line that we developed."
Dr. Shekhar added, "We found that estradiol and the pesticides
activated estrogen-mediated responses via estrogen receptors on this cell
line, suggesting that some environmental estrogens, particularly in combination,
may be involved in breast cancer progression. This is an important finding
because environmental estrogens such as DDT still pose a threat to humans
even though their use has been banned for many years. Not only does DDT
remain in the environment for many years, but it also concentrates in adipose
tissue in the breast and other organs in the body."
In a second study reported at the AACR Annual Meeting, researchers at
the University of Rochester School of Medicine and Dentistry investigated
whether DDT isomers, different chemical forms of DDT, and their metabolites
can bind to and activate estrogen receptors in humans and act as estrogens.
Results from previous studies had indicated that certain DDT compounds
specifically bind to and activate rodent and avian estrogen receptors,
but no data have been available on how these compounds interact with the
human estrogen receptor at the molecular level.
Rat vs Human Receptors
Experiments conducted by researchers at the University of Rochester
School of Medicine and Dentistry measured the ability of DDT isomers and
metabolites to bind to and activate the human estrogen receptor. The studies
found that many of the DDT compounds had more than 100-fold higher affinities
for the human estrogen receptor than for the rat estrogen receptor. Using
a cellular model that expresses human estrogen receptors and provides a
measurable signal when this receptor is activated, the researchers screened
the DDT compounds for estrogenic activity. They found that the DDT isomers
and metabolites that bound to the human estrogen receptor were able to
activate it in a concentration-dependent manner and elicit an additive
response when administered with another DDT metabolite or with estradiol.
According to study investigator, Clarice W. Chen, MS, "Of particular
significance is the finding that both DDT isomers bind to the human estrogen
receptor, whereas only one binds with measurable affinity to the rat estrogen
receptor. Moreover, many DDT metabolites have a substantially higher affinity
for the human than the rat estrogen receptor, even though the main metabolite
of DDT does not. Our data suggest the metabolites that activate the human
estrogen receptor do so with the same potency as the parent compounds,
and this activation is additive to that of another DDT compound or estradiol.
These findings differ from those using other animal models and suggest
that humans may be more susceptible to DDT metabolites than other species."