MD, N Kenney, A Stoica, L Hilakiva-Clarke, B Singh, G Chepkko, R
Clarke, PF Sholler, AA Lirio, C Foss, R Reiter, B Trock, S Paik
and MB Marin. 2003. Cadmium mimics the in vivo
effects of estrogen in the uterus and mammary gland. Nature
Medicine, online 13 July 2003.
these findings, Johnson et al. confirm earlier
indications that cadmium acts an estrogen mimic report that
the action occurs with detectable effects at astoundingly
low levels of cadmium in the affected tissues in the rats
they studied. Direct measurements of cadmium confirmed that effects
were caused at concentrations in tissue of one hundred-thousandth
of a part per billion, or 1/100th of a part per picogram, or less.
The authors speculate that cadmium effects on mammary gland development
may be important to causation of breast cancer.
did they do? Johnson et al. conducted a series
of relatively classic experiments to test the estrogenicity of compounds
in live animals. Importantly, however, they conducted their experiments
using very low levels of cadmium, and complemented their measurements
of effects with direct measurements of cadmium in the tissues affected
asked 3 questions:
exposure to cadmium affect organs targeted by estrogen?
To answer this they first surgically removed the ovaries of young
female rats, allowed them to recover, and then injected the rats
with a single dose of 5 µg/kg cadmium. One group of rats serving
as a positive control instead received a pellet implant releasing
60µg/kg/day estradiol. A third group was injected with both
cadmium and the anti-estrogen, ICI-182-780. Responses in each of
these groups was compared to untreated controls, whose ovaries had
also been removed.
uterine responses in these animals were examined 4 days later, and
the mammary gland responses 4 and 14 days later. At the levels of
exposure used in the experiments, there were no signs of overt toxicity,
nor alterations in body weight.
weight increased 1.9-fold in cadmium-treated animals compared to
controls. The estradiol positive control also increased relative
to untreated control, by 3.8 times. Exposure to ICI-182-780 eliminated
the cadmium effect, indicating it is mediated by an estrogen receptor.
Histological examination of the uterine tissues was also consistent
with an estrogenic response, and differed substantially from the
in mammary tissue were also consistent with estrogen exposure. Epithelial
density in cadmium-exposed animals increased significantly compared
to controls, and similarly to animals exposed to estradiol. As with
uterine tissue, the response was eliminated by adding the anti-estrogen
cadmium mimic the effects of estradiol on gene expression? Johnson
et al. measured the effect of cadmium on gene activation
of genes well established to be under estrogenic control, PGR and
C3. To do this they measured changes in the amount of messenger
RNA produced by exposure to estradiol and cadmium. Changes were
caused by activation of the genes that produce the messenger RNA.
estradiol exposure as a positive control, they first found that
estradiol treatment produced a 3-fold increase in PGR messenger
RNA and a 124-fold increase in C3 mRNA in the uterus compared to
controls (untreated females with ovaries removed). In mammary glands,
estradiol increased PGR mRNA and C3 mRNA by 42-fold and 416-fold,
animals exposed to cadmium the increases compared to controls were
also large: uterine expression of PGR and C3 mRNA increased 2-fold
and 12-fold respectively. In mammary glands the increases were 9-fold
and 16-fold compared to controls. These changes were highly significant
statistically, and were blocked by adding ICI, the anti-estrogen,
indicating the responses are mediated by the estrogen receptor.
exposure to cadmium in the womb affect development? Johnson
et al. here took advantage of the well-established impacts
of in utero exposure to estrogen on the rate of sexual
development, mammary gland development and body weight. Estradiol
exposed females reach sexual maturity faster than unexposed (or
less exposed). In their experiments, cadmium mimicked the effect
of estradiol on each of these endpoints. At low exposure levels,
cadmium decreased the time needed to reach sexual maturity, increased
adult body weight, and altered the structure of the mammary glands.
does it mean? Most toxicological studies heretofore with
cadmium have worked in the range of 1-5 milligrams per kilogram
(parts per million) and higher. Johnson et al. chose instead
to use cadmium levels in these experiments relevant to human environmental
exposures. They delivered doses of 0.5 - 60 micrograms per kilogram
(parts per billion), less than 1% of the usual level. At this low
range, their experiments revealed dramatic responses to cadmium
mediated by the estrogen receptor. The prior work at high doses
was uninformative about these low dose responses, a pattern explored
from a theoretical and regulatory perspective by Welshons
et al. earlier in 2003.
et al.'s measurements went one step farther than simply
knowing how much cadmium was delivered by injection. Using a highly
sensitive technique, they measured cadmium levels in the affected
tissues directly. This technique is capable of measure down well
below 1 part per billion. They found the cadmium levels in mammary
gland tissue and in the uterus to often be below the limits of detection
using their instruments, even in treated animals with responses
caused by cadmium. "When detectable in the uterus or
mammary gland, the amount of cadmium was approximately 10-2
pg per g of tissue (10-5 parts per billion)." This
staggering result reinforces the conclusions by Welshons et
al. that traditional studies of contaminants at toxicological
levels can be expected to miss responses at lower, "physiological"
levels mediated by hormone receptors.
et al. note that the range of exposures they use in their
experiments are similar to dietary guidelines from the World Health
Organization and to estimates of daily dietary exposures in the
US, Germany, the UK and Sweden. The highest exposures occur in children
between the ages of 1 and 6 years. They also note that cadmium levels
found typically in human breast tissue are far above the levels
measured in animals exposed in their experiments, in which mammary
gland development had been altered significantly, in ways consistent
with heightened risk of mammary gland tumors. They suggest
it would be appropriate for more research into links between cadmium
exposure and breast cancer risk.