Carcinogenesis, Vol 19, 1019-1027, Copyright © 1998 by Oxford University Press
Q Meng, L Recio, AA Reilly, BA Wong, M Bauer and VE Walker
1,3-Butadiene (BD) is an indirect alkylating agent that has greater cancer
potency in the mouse than in the rat. The purpose of the present study was
to compare the mutagenic potency of BD at the hprt locus of T- lymphocytes
of exposed mice and rats and to determine whether mutations induced in this
marker gene can be used as a quantitative indicator for species differences
in susceptibility to cancer. To this end, experiments were conducted to
define the effects of exposure duration and the time elapsed after
exposures on the frequency of hprt mutations (Mf) in T-cells from female
B6C3F1 mice and F344 rats of similar age (4- 5 weeks) when exposed to BD by
inhalation. The accumulation of hprt mutations in T-cells from thymus was
assessed in animals necropsied 2 weeks after exposure to 0 or 1250 ppm BD
for 1 or 2 weeks, while the time course for the appearance of hprt mutant
T-cells (i.e., the phenotypic expression and cell migration) in thymus and
spleen was evaluated in animals necropsied at weekly/biweekly intervals up
to 10 weeks after exposure for 2 weeks. At necropsy, T-cells were isolated
from thymus and spleen and cultured in the presence of IL-2, concanavalin
A, and 6-thioguanine (Walker and Skopek, Mutat. Res., 288, 151-162, 1993).
BD exposures of 1 and 2 weeks led to mutagenic effects in mouse thymus,
with the average Mfs being 3- and 5-fold greater than background values,
respectively. In rat thymus, there was only a 1.7- fold increase in Mfs
after 2 weeks of BD exposure. In the mutant expression experiment, hprt Mfs
in thymus and spleen of both species increased for several weeks
post-exposure and then declined. Hprt Mfs in thymus reached maximum levels
at 2 weeks post-exposure in mice (Mfs = 11.3 +/- 2.4 x 10(-6)) and at 3
weeks post-exposure in rats (4.9 +/- 1.2 x 10(-6)), while hprt Mfs in
spleen reached peak levels at 5 weeks post-exposure in mice (19.7 +/- 1.9 x
10(-6)) and 4 weeks post-exposure in rats (10.1 +/- 1.8 x 10(-6)).
Background Mfs for mouse and rat thymus and spleen ranged from 1.6 +/- 0.3
x 10(-6) to 3.0 +/- 1.1 x 10(- 6). Statistical analyses of the hprt Mf data
for spleen demonstrated that, under these exposure conditions, the
mutagenic potency of BD (represented by the difference in the areas under
the phenotypic expression curves of treated versus control animals) was
5-fold greater in mice than in rats. The magnitude of the species
differences in mutagenic potency, observed after 2 weeks of BD exposure,
resembles the species differences in metabolism more closely than the
species differences in cancer potency.
ARTICLES
Comparison of the mutagenic potency of 1,3-butadiene at the hprt locus of T-lymphocytes following inhalation exposure of female B6C3F1 mice and F344 rats
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201-0509, USA.
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