Dc. Thake et al., A STUDY OF THE MECHANISM OF BUTACHLOR-ASSOCIATED GASTRIC NEOPLASMS INSPRAGUE-DAWLEY RATS, Experimental and toxicologic pathology, 47(2-3), 1995, pp. 107-116
Long term administration of butachlor to Sprague-Dawley rats in a prev
ious bioassay, resulted in the induction of gastric neoplasms which oc
curred only in the highest dose group (3000 ppm in the diet), primaril
y in females and specifically in the fundic region. The tumors were a
composite of highly undifferentiated enterochromaffin-like (ECL) cells
and mucus producing cells with morphologic characteristics unlike tho
se previously described in the rat stomach. Mucosal atrophy of marked
intensity was a consistent feature of the gastric mucosa in animals fr
om the highest dose group. An additional long term study was conducted
in female Sprague-Dawley rats at dietary levels of 0, 100, 1000 and 3
000 ppm to explore the mechanism(s) involved in the formation of these
neoplasms. Cell proliferation was evaluated in both fundic and pylori
c regions of the stomachs of rats at the multiple time periods from 14
days to 26 months. Mucosal thickness was determined in the fundic reg
ion at the same time intervals as were used for cell proliferations st
udies. Gastric pH and gastric acid production were measured after appr
oximately 21 months of exposure. Serum gastrin levels were analyzed at
14, 60, and 120 days and at 6, 18, and 20 months. Cholecystokinin (CC
K)/gastrin receptor binding studies were conducted on samples of four
tumors and pooled fundic mucosa from five animals in the control group
. Cell proliferation was increased in both the neck and base regions o
f the fundic mucosa at nearly all time points measured from 14 days to
26 months. The magnitude of the changes in the base region were subst
antially greater than those in the neck region. Fundic mucosal thickne
ss was decreased beginning at the 30-day time point and continued at a
ll intervals. being less than one half that of controls at 20 and 26 m
onths. Gastric pH in rats from the highest dose was elevated to nearly
twice control levels at 21 months. Gastric acid secretion was dramati
cally decreased in animals from the 3000 ppm group and was moderately
decreased in the 1000 ppm group at 21 months. Hypergastrinemia was obs
erved at the 3000 ppm level only, beginning at 120 days with progressi
on to extremely high levels by 18 months. CCK/gastrin receptor binding
was demonstrated in all tumors studied, at levels comparable to or hi
gher than that of the pooled control sample. All changes involved only
the fundic region, the site of tumor formation. Tumors occurred only
in animals from the 3000 ppm level, the only level at which hypergastr
inemia occurred. The mechanism responsible for these tumors is unique
for chemical-induced gastric neoplasia in that, fundic mucosal atrophy
with loss of parietal cells was an early change which resulted in neo
plasia through a series of events involving hyperplasia of the gastric
epithelium, sustained hypochlorhydria and hypergastrinemia. Feedback
proliferation and hypergastrinemia resulted in prolonged and sustained
stimulation of stem cells and ECL cells which resulted in the unusual
neoplasms associated with butachlor administration.