RC, AM. Davis, JP Lariviere, and JW Hamilton 2001. Arsenic Alters
the Function of the Glucocorticoid Receptor as a Transcription Factor.
Environmental Health Perspectives 109:245-251.
coverage of this research]
[29 Aug 2002: EPA
assumption about risks of old arsenic treated decks and playground
et al. demonstrate that, at extremely low levels
of exposure—levels far too low to call cell damage
or 'traditional' toxicity—arsenic alters hormonal function
in the glucocorticoid system. The metal interferes with glucocortoid
signaling necessary to turning on genes involved in tumor suppression
and other activities. By preventing these genes from turning on,
arsenic may increase the risks of cancer. This new result may require
radical strengthening of arsenic exposure standards, because it
takes place at levels far beneath current safety thresholds.
glucocorticoid system is centrally involved in a wide range of physiological
processes, ranging from the control of growth to glucose regulation
and protein metabolism [More...].
By implication, disrupting the glucocorticoid system can have profoundly
negative impacts on development and health. Dysfunction in the glucocorticoid
system has been linked to weight gain/loss, protein wasting, immunosuppression,
insulin resistance (which can lead to diabetes), osteoporosis, growth
retardation, and hypertension and hypertension.
et al. show that very low levels of arsenic--equivalent
to about 10 parts per billion-- selectively inhibit the ability
of glucocorticoid and its receptor to turn on genes normally under
glucocorticoid control. The levels capable of endocrine disruption
are far below those necessary to cause cell toxicity. And in an
on NPR's Living on Earth Dr. Josh Hamilton, one of the authors
of the study, comments that
doses that we're using in cell culture that cause these endocrine-like
effects are well below any levels that caused any signs of
toxicity in the cells. In fact, we were down in what's called
the nanomole range, or parts per trillion, and still seeing
these effects. Now, if you look at what people are exposed to,
it suggests to us that we could see these endocrine effects
quite reasonably, probably, at the levels that people are exposed
to here in the U.S."
of the Hamilton interview on Living on Earth]
et al. speculate that this low level endocrine disruption
may be involved in links between chronic exposure to low amounts
of arsenic and several human diseases, including cancer and diabetes.
alterations in GR function may play an important role in the
mechanism of arsenic carcinogenesis. ... GR has been suggested
to play a fundamental role in carcinogenesis in both lung and
skin in experimental animal models. "
are known to suppress tumor growth. It may be that arsenic suppression
of glucocorticoid activity reduces the effectiveness of glucocorticoid
go on to observe:
if environmentally relevant doses of arsenic are able to suppress
the normal function of GR as a mediator of gene regulation,
as suggested by our results, we hypothesize that this may contribute
to its ability to promote tumorigenesis and contribute to other
pathophysiological states in these tissues. This unique mechanism
would suggest further that arsenic may be able to act synergistically
with other toxic and carcinogenic agents to increase disease
risk, which is supported by epidemiological data that indicate
a synergistic increase from cigarette smoking and exposure to
arsenic. Because arsenic contamination of drinking water is
widespread in the United States and elsewhere, and it is usually
found in combination with many other toxic chemicals at most
Superfund and other toxic waste sites, these combined exposures
may represent a significant human health risk. "
findings should stimulate the US EPA to lower exposure standards
to arsenic. EPA had developed new standards in the final days of
the Clinton Administration, decreasing them from 50 ppb to 10 ppb,
but in March 2001 the Bush Administration announced it was withdrawing
them because, according to Administrator Christie Todd Whitman,
"the science is squishy." Given the 1999 conclusion by
Academy of Sciences that the old standards "could easily
result" in a 1 in 100 risk of cancer to people drinking arsenic-contaminated
water, Whitman's assertion is ludicrous. The Academy is habitually
extremely conservative on all matters chemical, yet concluded that
the old standards were inadequate. The New
York Times reported (21 March 2001) that Whitman's decision
reflected intense political pressure from mining interests, whose
operating costs would rise if the new standards were enforced. The
Times also observed that mining companies were significant financial
contributors to the Bush 2000 presidential campaign.
is unique (to date) about the mechanism discovered by Kaltreider
et al. is that arsenic's disruption of the glucocorticoid
system takes place after the hormone-receptor complex enters the
the nucleus, arsenic interferes with the way that the glucocorticoid-receptor
complex activates genes.
hormone disruptors act by (1) affecting the amount of hormone (either
by increasing/decreasing hormone synthesis or increasing/decreasing
hormone metabolism) or (2) by interfering with the binding of the
hormone with its receptor. In contrast, Kaltreider et al.
found no indication that arsenic intefered with hormone-receptor
binding or entry of the complex into the nucleus. Their data indicate
that changes in the system instead took place within the nucleus
and involved selective inhibition of DNA transcription that normally
would have been stimulated by the glucocorticoid-GR complex.
The detailed mechanisms of the interference are not yet known.
disruption by PCBs has already been documented,
and appears to work because PCBs interfere with glucocorticoid-receptor
binding. This PCB effect may underlie the ability of PCBs to affect
immune system function.