Air Quality Criteria for Lead Volume II of II - (NEPIS)(EPA) - US ...

AX5-172
Table AX5-10.5 (cont’d). Lead-induced Liver Hyperplasia: Mediators and Molecular Mechanisms
Concentration Duration Species Blood Level Effects a Reference
10 µmol/100 g body
weight Pb nitrate, i.v.
100 µmol/kg, b. wt.
Pb nitrate, i.v.
Multiple analyses
up to 40 h
Analyses at multiple
time points,
0.25–24 h
Male Wistar rats,
hepatocytes
from partial
hepatectomy and
Pb nitrate
treatment.
Male Wistar
Albino rats
100 µmol/kg b. wt. 8 h Male Sprague
Dawley rats
100 µmol/kg b. wt.,
i.v.
100 µ mol/kg b. wt.,
i.v. Pb nitrate
Multiple analyses
time points,
1–120 h
Analyses at multiple
time points, 8 h to
15 days
— The kinetics of DNA synthesis and expression of Proto oncogenes in
partially hepatectamized liver cells and Pb nitrate treated hepatic cells
indicated peak DNA synthesis after 24 h in the formal and after 36 h in the
later case. Both proliferative stimuli induced c-fos, c-myc and c-Ha Ras
expression. Induced c-myc expression persisted for up to 40h during the
Pb nitrate- induced liver cell proliferation. Pb induces hepatic hyperplasia
through changes in proto-oncogene expression.
— Proliferative stimuli by means of Pb nitrate exposure resulted in increased
expression of c-jun m-RNA where as compensatory regeneration in
partially hepatectamized cells occurred through increased expression of cfos
and c-jun. Different mitogenic stimuli induced differential expression
of these protooncogenes, in addition had a different profile than cells from
partial hepatectomy despite the cell cycle timings being the same in some
cases.
— In rat liver, in addition to a few hepatocytes four types of non parenchymal
cells namely, fibroblasts, macrophages, bile ducts and periductular cells
proliferate in response to Pb nitrate treatment. This growth is not related
to adaptive response secondary to parenchymal enlargement. However,
such growth in parenchymal cells seems dormant and does not play a
functional role in adult liver epithelial growth.
Male Wistar rats — Both mRNA levels and enzyme activity of DNA polymerase β markedly
increased before and/or during DNA synthesis in proliferating hepatocytes
in Pb nitrate treated and partially hepatectomized rats. 5 fold increase in
the enzyme activity was observed 8 h after Pb nitrate administration. In
the regenerative liver cells a 3 fold increase was observed 24–48h after
partial hepatectomy.
Male Wistar rats — Pb nitrate induced Poly (ADP-ribose) polymerase mRNA 24 hr after
exposure. A 2 fold increase in the mRNA levels of the enzyme occurred
2 days after the exposure. Such changes were also observed in hepatic
cells from livers of partial hepatectomy. These changes preceded the
increase in DNA synthesis and remained high during the time of extensive
DNA synthesis.
Coni et al. (1989)
Coni et al. (1993)
Rijhsinghani et al.
(1992)
Menegazzi et al.
(1992)
Menegazzi et al.
(1990)