Carcinogenesis, Vol 18, 675-680, Copyright © 1997 by Oxford University Press
BI Ghanayem, MR Elwell and SR Eldridge
Acrylonitrile (AN) and methacrylonitrile (MAN) are two major industrial
nitriles used in the production of plastics and acrylic fibers. Whereas AN
is a potent acute toxin and carcinogenic in rats, little is known regarding
MAN. Current work is part of an overall effort designed to assess the
potential toxicity/carcinogenicity of MAN. The present study compares the
ability of the two chemicals to induce epithelial proliferation and
apoptosis in the forestomach (FS; a target of AN carcinogenicity), liver
and glandular stomach (non-targets of AN carcinogenicity) of male F344
rats. AN was administered to rats daily, by gavage, for 6 weeks, at 0.43
and 0.22 mmol/kg. MAN was administered at 0.87 and 0.43 mmol/kg. Both AN
and MAN induced a dose-dependent increase in epithelial cell proliferation
in the FS of male F344 rats as determined by bromodeoxyuridine (BrdU)
incorporation into DNA. In contrast, AN, but not MAN caused a
dose-dependent increase in the thickness of the forestomach squamous
mucosa. This increased thickness (hyperplasia) was reflected by an increase
in the number of total epithelial cells per unit length of mucosa. At doses
of AN and MAN which induced a 2.3-fold increase in BrdU incorporation,
apoptosis was 5- and 18-fold greater than controls, respectively. Although
both MAN and AN caused a similar increase in cell proliferation, the
relatively more prominent increase in the apoptotic index of the squamous
epithelium of rats exposed to MAN may explain the lack of a detectable
increase in the thickness of the mucosa compared to that seen with AN. The
disruption of the balance between FS mucosal cell proliferation and
apoptosis in favor of a net increase in the number of FS epithelial cells
per unit length may contribute to the carcinogenicity of AN. In conclusion,
present work demonstrated that AN selectively induced a net enhancement in
FS cell proliferation, a site of its carcinogenicity. On the other hand,
MAN-induced FS cell proliferation was associated with a parallel increase
in apoptosis. The relatively greater increase in apoptosis by MAN may have
compensated for the increase in FS mucosal cell proliferation and the lack
of observable change in the FS thickness.
ARTICLES
Effects of the carcinogen, acrylonitrile, on forestomach cell proliferation and apoptosis in the rat: comparison with methacrylonitrile
NIH/NIEHS, RTP, NC 27709, USA.
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