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

AX5-174
Table AX5-10.5 (cont’d). Lead-induced Liver Hyperplasia: Mediators and Molecular Mechanisms
Concentration Duration Species Blood Lead Effects a Reference
15 mg/kg b. wt.
Pb acetate
Pb nitrate 100 µM/kg
b. wt. i.v. single dose
100 µmol/kg b. wt
Pb nitrate, single, i.v.
100 µmol/kg b. wt.
single i.v.
100 µmol/kg b. wt.
i.v. single dose
100 µmol/kg b. wt.
i.v., single dose
Pb+ LPS group
analyzed after 14 h
and the rest after
24 h after Pb
administration
Multiple time points
of analyses
extending up to 48 h
after treatment
Multiple time points
of analyses up to
48 h
Multiple time points
of analyses up to
80 h
Multiple time points
of analyses up to
24 h
Multiple time point
analyses up to 96 h
Male Sprague
Dawley rat
— Pb augments the lethality of endotoxin lipopolysaccharide (LPS) in rats
and enhances liver injury, which is further enhanced by TNF. Pb + LPS
treatment increased both serum TNF concentrations and TNF area as
compared to LPS alone. simultaneous administration of Pb with either
LPS or TNF, serum aspartate transaminase, alanine transaminase, alkaline
phosphatase, glutamyl trans peptidase and plasma triglyceride levels were
markedly increased.
Male Wistar rats — Pb nitrate and ethylene bromide induce liver cell proliferation via
induction of TNFα. Dexa methasone, a known TNF inhibitor, decreases
TNF expression and liver cell proliferation by these mitogens. These
studies support the fact that TNF might mediate hepatic cell proliferation
by Pb nitrate and ethylene bromide.
Male Sprague
Dawley rats
— Pb nitrate (LN) treatment resulted in increased Brdu incorporation of
hepatocytes and non parenchymal cells at 12 h after treatment and reached
the peak index at 36 h. Rats given a single i.v. of recombinant TNFα
enhanced proliferation in non parenchymal cells after 24 h, the labeling of
hepatocytes at 36 h. NAF, Nafenopin another mitogen which does not
induce liver TNFα, increased the number of labeled hepatocytes without
increasing the labeling of non parenchymal cells indicating that only Pb
nitrate induced proliferation is mediated by TNFα and these mitogens
initiate proliferation in different cells based on their capacity to stimulate
TNFα production.
— Pb nitrate induces liver cell proliferation in rats without accompanying
liver cell necrosis. This proliferation involves enhanced TNF mRNA and
levels but not hepatocyte growth factor. The role of TNF in Pb nitrate
induced liver cell proliferation is supported by the inhibition of TNF and
reduced hepatocyte proliferation by several TNF inhibitors.
Male Wistar rats — Pb nitrate induced liver cell proliferation involves TNF α production,
enhanced NF-κB activation increased hepatic levels of iNos mRNA as
opposed to other mitogens such as Cyproterone acetate or Nafenopine.
Male Sprague
Dawley rats
— The role of neurotrophins, the nerve growth factor (NGF), the brain
derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in Pb
nitrate treated liver cells was studied. LN, treatment resulted in increased
in the levels of NGF, BDNF and NT-3. The increase in neurotrophin
receptors and the gene expression were correlate with liver weights. This
study demonstrates that Pb nitrate induced hyperplasia may be mediated
by neurotrophins.
Honchel et al.
(1991)
Ledda-Columbano
et al. (1994)
Shinozuka et al.
(1996)
Kubo et al. (1996)
Menegazzi et al.
(1997)
Nemoto et al.
(2000 )