A study of the mechanism of butachlor-associated gastric neoplasms in sprague-dawley rats

Thake, Daryl C.; Iatropoulos, Michael J.; Hard, Gordon C.; Hotz, Kathy J.; Cx, Wang; Williams, Gary M.; Wilson, Alan G. E.

doi:10.1016/s0940-2993(11)80295-2

Cited by 30 publications

(38 citation statements)

References 25 publications

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“…At a dose level that induced mild mucosal atrophy, but was not sufficient to induce hypoacidity, there was no hypergastrinemia and there were no gastric tumors Thake, Iatropoulos, et al 1995).…”

Section: Profound Mucosal Atrophy In the Fundic Regionmentioning

confidence: 96%

“…42, No. 2, 2014 CONSENSUS DIAGNOSES AND MODE OF ACTION FOR THE FORMATION OF GASTRIC TUMORS Thake, Iatropoulos, et al 1995). Therefore, although butachlor induced a mild mucosal atrophy in the 1,000-ppm dose group, there was no hypoacidity or hypergastrinemia (serum gastrin in mid-dose was 98 pg/ml vs. 75 pg/ml in control), so there were no resulting tumors.…”

Section: Hypergastrinemiamentioning

confidence: 97%

“…42, No. 2, 2014 CONSENSUS DIAGNOSES AND MODE OF ACTION FOR THE FORMATION OF GASTRIC TUMORS 391 (i.e., parietal, chief, or ECL cells) were not recognizable Thake, Iatropoulos, et al 1995). Parietal cell number measurements in the alachlor gastric tumor promotion study demonstrated that after 1 year of treatment with 126 mg/kg/day, the numbers of parietal cells were profoundly reduced to 7% of the control value (Branch and Thake 1995;Heydens et al 1999;Tatematsu and Thake 1996).…”

Section: Loss Of Parietal Cellsmentioning

confidence: 99%

“…c Dietary concentrations adjusted after 20 weeks to maintain a constant dose in mg/kg/day over the 52-week study. A long-term (22 month) bioassay was also conducted (2-year mechanism study, Table 1) by feeding butachlor to female rats to help elucidate the MOA that was responsible for induction of the gastric tumors in the original cancer study Thake, Iatropoulos et al 1995). Histopathologic, histochemical, and immunohistochemical evaluations were performed using (primarily fundic) stomach tissue from rats; additional end points measured included mucosal thickness, mucosal cell proliferation, gastric acid secretion, serum gastrin levels, and receptor binding (for cholecystokinin/gastrin binding sites in tumors).…”

Section: Two-year Cancer Bioassays With Alachlor and Butachlormentioning

confidence: 99%

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Consensus Diagnoses and Mode of Action for the Formation of Gastric Tumors in Rats Treated with the Chloroacetanilide Herbicides Alachlor and Butachlor

Furukawa

Harada²,

Thake³

et al. 2013

Toxicol Pathol

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A panel of pathologists (Panel) was formed to evaluate the pathogenesis and human relevance of tumors that developed in the fundic region of rat stomachs in carcinogenicity and mechanistic studies with alachlor and butachlor. The Panel evaluated stomach sections stained with hematoxylin and eosin, neuron-specific enolase, and chromogranin A to determine the presence and relative proportion of enterochromaffin-like (ECL) cells in the tumors and concluded all tumors were derived from ECL cells. Biochemical and pathological data demonstrated the tumor formation involved a nongenotoxic threshold mode of action (MOA) initially characterized by profound atrophy of the glandular fundic mucosa that affected gastric glands, but not surface epithelium. This resulted in a substantial loss of parietal cells and a compensatory mucosal cell proliferation. The loss of parietal cells caused a marked increase in gastric pH (hypochlorhydria), leading to sustained and profound hypergastrinemia. The mucosal atrophy, together with the increased gastrin, stimulated cell growth in one or more ECL cell populations, resulting in neoplasia. ECL cell autocrine and paracrine effects led to dedifferentiation of ECL cell tumors. The Panel concluded the tumors develop via a threshold-dependent nongenotoxic MOA, under conditions not relevant to humans.

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Section: Profound Mucosal Atrophy In the Fundic Regionmentioning

confidence: 96%

Section: Hypergastrinemiamentioning

confidence: 97%

Section: Loss Of Parietal Cellsmentioning

confidence: 99%

Section: Two-year Cancer Bioassays With Alachlor and Butachlormentioning

confidence: 99%

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Consensus Diagnoses and Mode of Action for the Formation of Gastric Tumors in Rats Treated with the Chloroacetanilide Herbicides Alachlor and Butachlor

Furukawa

Harada²,

Thake³

et al. 2013

Toxicol Pathol

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“…It has been reported for several chemicals (Poynter & Selway, 1991;Thake et al, 1995) that chronic gastrin stimulation of the enterochromaffin-like (neuroendocrine) cells results in the formation of neuroendocrine tumours of the glandular stomach. Parietal cell cytotoxicity and atrophy of the fundic mucosa, hypochlorhydria and hypergastrinaemia typically accompany the tumorigenic response.…”

Section: (Ii) Ratsmentioning

confidence: 99%