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

AX5-171
Table AX5-10.5. Lead-induced Liver Hyperplasia: Mediators and Molecular Mechanisms
Concentration Duration Species Blood Lead Effects a Reference
— — Rat — Apoptosis plays a major role in the regressive phase of Pb nitrate induced
hepatic hyperplasia as detected by the apoptotic bodies by in situ end
labeling and HandE sections of the hepatic tissue. HandE scores mostly
cells in apoptosis phase II, ISEL (in situ end labeling) scores for cells in
phase I. Combination of these two methods is suggested for the better
understanding of the extent and nature of apoptotic process in liver cells
treated with chemicals.
A. Pb nitrate,
100 µM/kg b.wt,
intra-gastric
B. Diethyl
nitrosoamine
200 mg/kg b.wt, i.p.
0–100 µM Pb
sulphate, Pb
monoxide, Pb
chloride and Pb
acetate up to 1 mM,
culture media.
Choline 1g/kg/d in
drinking water
Pb nitrate, 75 µM/kg
b.wt, single i.v.
75 µmol/kg b. wt. Pb
nitrate in adult and 20
µg/mL in the young,
i.v.; single dose
3 and 15 days Male Wistar
Albino rats
Multiple time points
ranging from 24 h
up to 7 days
0, 20, and 24 h Male and female
rats , partial
hepatectomy
6 h–4 wks Adult male Albino
rats
Analyses at 72 h Male Wistar
Albino rats
— Mitogenic stimuli (3 days Pb nitrate treatment) and complete regression
(15 days after the treatment), affected the apoptosis differentially.
Influence of apoptosis Vs necrosis on the growth of hepatocytes initiated
by diethyl nitrosamine followed by Pb nitrate treatment indicated that the
regenerative response elicited by a necrogenic dose of CCL4 promoted
GSTP (Placental glutathione), a pre-neoplastic marker positive cells as
against the Pb nitrate that induced the apoptosis.
REL liver cells — Pb compounds showed a dose and time related effect on REL liver cell
proliferation with varying potencies specific to the different Pb salts.
Pb acetate was the most effective and Pb monoxide, the least effective.
On 1 hr treatment none of the compounds tested affected the intracellular
communication.
— PKC isozymes during liver cell regeneration— PKC δ showed a
pronounced increase 20h after partial hepatectomy. α, β, and Zeta at 24 h
corresponding with S-phase. Sexual dimorphism matching with sexual
differences in DNA synthesis was evident. Administration of choline was
able to modulate the protein kinase C isozyme pattern in females in
relation to DNA synthesis and c-myc expression. Taken together the data
positively implicates α, β, and Zeta in growth after partial hepatectomy
and δ in negative regulation.
— Pb induced significant increase in liver weight. Increased 3H Thymidine
incorporation. Pb induces extensive hypomethylation in treated rat livers.
Site-specific effect on methylation was confirmed at Hpa II, Msp I,
Hae III.
— Effect of Pb nitrate on the 5- methyl deoxy cytidine (5-mdcyd) content and
the HpaII, MSPI, Hae III restriction patterns of hepatic DNA from young,
middle aged and senescent rats. The results indicated that the methylation
pattern of genomic DNA changed significantly with age and the
methylation patterns were differentially affected in all the three
populations.
Nakajima et al.
(1995)
Columbano et al.
(1996)
Apostoli et al.
(2000)
Tessitore et al.
(1995)
Kanduc et al. (1991)
Kanduc and Prisco
(1992)