Chemistry Reference
In-Depth Information
has no recognized function. Of the remainder, 24% are
involved with uranium stress response (signal transduc-
tion/traffi cking or calcium handling), whereas fewer
are associated with cell development, differentiation,
or proliferation, followed by cell defense, structure, or
metabolism. Currently, there are no biomarkers of effect
specifi c to uranium, but new candidates could include
either a set of 18 deregulated genes that were common
among the exposure groups or a set that were down-
regulated at all doses with a corresponding loss of pro-
teins (e.g., HSP90, which prevents irreversible protein
aggregation in stressed microtubules). The temporal
profi les of expression for selected genes (3 up-regulated
and 3 down-regulated) as a function of uranium con-
centration seemed to suggest a concentration threshold.
This occurred between toxic adaptation (at 0.25 nmol/L
U, producing 30% lethality and a complex sinusoidal
gene response that returned to normal at 24 hours) and
overt toxicity (at 0.5 nmol/L U, causing 50% lethality and
similar but diverging sinusoidal response). The profi le
shapes indicate that cytotoxic doses of uranium elicit a
complex response from renal cells.
Tolson
et al
. (2005) studied alterations in the heat
shock protein (Hsp) response as an adaptive mechanism
for attenuating the renal toxicity of uranium. They pre-
treated rats with a dose of 5 mgU/kg for 10 days before
a challenge dose of 10 mgU/kg and observed decreased
necrosis of proximal tubule cells and azotemia in some
animals (called responders) but not in others (termed
nonresponders). Kidney homogenates from these
animals were found to contain increased amounts of
Hsp25, Hsp32, and Hsp70i but not the constitutively
expressed Hsc70. Correlative studies of the proliferating
cell nuclear antigen demonstrated that the cells express-
ing increased amounts of the Hsps were regenerating,
and that only those animals expressing such regen-
eration were protected against subsequent exposure.
Complimentary
in vitro
studies that used RK3E rat and
LLC-PK1 porcine epithelial cells showed that uranium
pretreatment was protective, but Hsps were not induced
by exposure to uranium (as they are for other metals),
and that Hsps induced by thermal stress are cytoprotec-
tive against subsequent uranium exposure. The authors
concluded that the Hsps are not responsible for protec-
tion against uranium toxicity
in vivo
but are involved in
renal tubular epithelial regeneration that subsequently
protects the kidney from uranium. Whether or not the
protection offered during the epithelial repair period
remains after repair was not evaluated. The expres-
sion of Hsps in liver was also evaluated, but uranium
did not alter their levels, indicating they may have no
role in hepatic protection. However, liver is perhaps an
order of magnitude less sensitive than kidney (ATSDR,
1999), and because renal protection seems to require
passing an injury threshold, the liver doses may have
been insuffi cient to have caused the damage needed to
elicited a protective response.
Taulan
et al
. (2004) studied renal toxicogenomic respon-
ses (serial analysis of gene expression) of mice exposed
to uranium in drinking water for 4 months at high dose
levels (80 and 160 mgU/L). They observed alterations in
the expression levels of 200 genes, most of which were
up-regulated. Many of these genes were related to oxi-
dative stress responses, cellular metabolism, ribosomes,
signal transduction, and transport systems. The authors
found that uranium caused the dose-dependent produc-
tion of H
2
O
2
, which can induce oxidative stress, and sug-
gested that oxidative stress plays an important role in the
observed genomic responses.
6.7 Skeletal Mechanism
The presence of uranium can interfere with the initial
deposition of calcium in the bone matrix or with bone
remodeling (Guglielmotti
et al
., 1985). Kurttio
et al
. (2005)
conducted a drinking water study among individu-
als who consumed elevated concentrations of uranium
in well water. A slight statistical association was found
between uranium exposure and CTx (an indicator of
bone resorption, serum type I collagen carboxyl-terminal
telopeptide) for men (
P
= 0.05) but not for women.
6.8 Summary on Mechanisms
Overall, the results of the preceding studies indicate
that the adverse health effects associated with uranium
exposure are from its metallotoxicity and not from its
radiation. Uranium exposures produce cellular toxicity
primarily on renal proximal tubule epithelial cells and on
a number of other cell types through oxidative stress. The
most apparent and noninvasively measurable result is an
increase in the urinary concentration of several substances
that are a direct result or indirect consequence of tissue
damage. There are effects on a number of molecular sys-
tems involved in cell signaling pathways, drug metabo-
lism, gene expression, and apoptosis/necrosis. Some of
these effects seem to be of a primary nature with others
more related to cell adaptation or regeneration. The exact
sequence of events leading up to target cell death is the
subject of ongoing research in a number of laboratories.
7 EFFECTS AND DOSE-RESPONSE
RELATIONSHIPS
The health effects from exposure to uranium by nor-
mal routes (inhalation, oral, and dermal) is primarily to
the kidney. Less severe effects occur to the liver, lung,
and nervous system, and no reproductive or develop-
mental effects are expected to occur except at extreme
