Chemistry Reference
In-Depth Information
The inconsistent fi ndings of the impact of this
ALAD polymorphism on lead levels and toxicity
between different studies could be the result of dif-
ferent ways of selecting study subjects (e.g., from
highly exposed environments or the general popu-
lation, from lead levels in blood, or biomarkers of
effect). Another problem regarding study design is
the use of different statistical methods for analyzing
interaction, which makes it diffi cult to compare the
different studies. Thus, these data should still be
interpreted with caution. Another reason for con-
trasting fi ndings could be that
ALAD
may have
impact, depending on the genetic background, and
incoherent observations are made when different
populations are studied. To explain the differ-
ences between populations, more genes related to
lead metabolism and effects have to be analyzed in
association with lead markers of toxicity.
In summary, at high levels of exposure and in
comparison with
ALAD
-1 subjects, heterozygous or
homozygous
ALAD
-2 carriers seem to have increased
blood levels, lower levels of ZPP and plasma
aminolevulinic acid, and perhaps lower amounts of
chelatable lead. Theses associations are consistent
with those reported by Scinicariello and colleagues
(2006), who used meta-analyses to summarize the
current state of knowledge. Still, much is unknown
of genotypic effect modifi cations of lead on the bone,
kidney, and the neurological system, and whether
or not there are similar effects of
ALAD
genotype in
the general low-exposed population as seen for high
levels of exposure.
Korean battery workers, individuals with the BB and
Bb genotypes displayed higher blood and tibia lead
levels (Schwartz
et al.
, 2000), as well as diastolic blood
pressure, compared with participants with the bb gen-
otype (Lee
et al.
, 2001). Also Theppeang and cowork-
ers reported higher patella lead levels among VDR BB
carriers compared with bb carriers (Theppeang
et al.
,
2004). In a study on renal function in Korean lead
workers, the
Bsm
I polymorphism of
VDR
, as well as
endothelial nitric oxide synthase (
NOS3
), involved
in nitric oxide production were analyzed for possible
effect modifi cation (Weaver
et al.
, 2003). However, no
obvious association was present for
VDR
and either
lead levels or markers for renal function.
Studies analyzing gene-gene interactions for
ALAD
and
VDR
or different polymorphisms within
VDR
are
very few in the literature. However, in the aforemen-
tioned study on Korean battery workers (Schwartz
et al.
, 2000), the authors analyzed the frequency of
combined genotypes of
ALAD
and
VDR
among
exposed subjects and controls and found that there
was a tendency among exposed subjects homozygous
for
ALAD
-1 to lack the
VDR Bsm
I bb genotype. Among
the controls, the opposite genotype distribution was
seen. This fi nding could indicate a genotype selection
among the exposed workers.
3.3.4.3 HFE
Lead is also linked to the uptake of iron in the gas-
trointestinal tract: when the sources of iron are limited,
lead absorption is increased (Cheng
et al.
, 1998). As
previously mentioned, the autosomal genetic disease
hemochromatosis is caused by mutations in the
HFE
gene. The
HFE
gene is mutated at amino acid posi-
tion 282, which leads to a cysteine-tyrosine exchange,
among 85% of the affected. Another variant of this
gene, His63Asp, is also associated with hemochro-
matosis, but with a lower penetrance (Waheed
et al.
,
1997). Because mutations in the
HFE
gene affect iron
uptake, variants of this gene or others affecting the
iron status might have a modifying effect on the levels
of lead as well. Barton
et al.
(1994) showed that sub-
jects who were homozygous for the Cys282Tyr muta-
tion had increased blood lead and that there was an
allele-dosage effect. On the other hand, in a Swedish
study, the blood lead levels were lower among hemo-
chromatosis-affected subjects than among the controls
(Åkesson
et al.
, 2000). Similarly, Wright
et al.
(2004)
showed among elderly men that carriers of at least
one variant
HFE
allele from Cys282Tyr or His63Asp
were associated with lower levels of blood or bone
lead. Adjusted analysis showed that one
HFE
variant
was independent factor for signifi cantly lower levels
of lead in patella.
3.3.4.2 VDR
Lead uptake increases when calcium resources are
limited (Mahaffey
et al.
, 1986). Thus, genetic differ-
ences in calcium absorption might, in turn, modify
lead levels. Lead binds to calcium proteins, which
are regulated by the vitamin D endocrine system
and the vitamin D receptor (VDR). VDR displays
polymorphisms, and Ames
et al.
(1999) demonstrated
that the
VDR Fok1
genotype FF increases bone min-
eral density and calcium absorption by 30-40%
among healthy children 7-12 years of age. Haynes
and coworkers (2003) have shown that children from
New York with the Ff genotype displayed lower
blood lead than the FF genotype after exposure to
fl oor dust lead, suggesting that this genotype is an
effect modifi er of the relationship of fl oor dust lead
and blood lead concentrations.
Another polymorphism of
VDR
, labeled
Bsm
I, is
affecting the bone mineral density: decreased den-
sity has been reported in those with the BB compared
with the bb genotype (Cooper and Umbach, 1996). In
