Subacute and chronic action of acrylonitrile on adrenals and gastrointestinal tract: Biochemical, functional and ultrastructural studies in the rat

Abstract

A single dose of acrylonitrile can produce fatal adrenal apoplexy within approximately 2 h. Our previous studies also indicate that multiple injections of the chemical cause acute hemorrhagic and occasional nonperforating duodenal ulcers. Other authors have reported increase in gut and lung neoplasia after chronic exposure. The present study was designed to elucidate the subacute and chronic actions of acrylonitrile on the adrenals, stomach and duodenum by correlating biochemical, functional and morphologic investigations, as well as to gain insight into the mechanisms of action of acrylonitrile. Rats were exposed to 0, 0.0001% (1 ppm), 0.002%, 0.01%, 0.05% or 0.2% acrylonitrile in drinking water, or to the same amount of the chemical given through daily gavage, for 7, 21 or 60 days. Acrylonitrile caused a time- and dose-dependent decrease in plasma corticosterone levels; aldosterone was affected only by the 'high' dose and prolonged time of exposure. Young rats were more susceptible than adults to this action of acrylonitrile. The adrenal cortex, especially the zona fasciculata, was atrophic in rats that had ingested the nitrile through drinking water. At 0.05% and 0.2%, it also caused decreased food intake and body weight gain. The adrenals were enlarged with a hyperplastic zona fasciculata after daily doses of a bolus of acrylonitrile. Ingestion of the chemical did not interfere with compensatory enlargement of the adrenal gland following unilateral adrenalectomy. On the other hand, the ACTH-induced elevation of corticosterone plasma concentration was significantly attenuated by acrylonitrile in drinking water. Electron microscopy of the adrenal glands revealed no consistent changes in the steroid-producing cells. We thus postulate that accelerated turnover of circulating corticoids and/or interference with the secretion or action of ACTH may primarily be responsible for the decreased plasma levels of corticosterone and aldosterone in rats that ingest acrylonitrile. The mucosa in the stomach at the junction of the forestomach and glandular region of animals that had ingested acrylonitrile was hyperplastic. The corpus also showed regional mucosal hyperplasia with the appearance of 'cobble-stoning'. These changes were preceded and associated with an elevated concentration of non-protein sulfhydryls mostly in the mucosa of the glandular stomach. A similar, less prominent elevation also occurred in the proximal duodenum. These alterations may resemble the preneoplastic combination of elevated glutathione and focal hyperplasia described in the liver with hepatocarcinogens.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Gland: Chemically Induced Structural and Functional Changes in the Cortex

“…the syndrome of hypofunctional hyperplastic adrenals or increased corticoid turnover, see pyrazole, above). These results suggest that the effects of acrylonitrile on the adrenals were confounded by its inherent toxicity and consequences of decreased food intake probably originating from an unpleasant taste of acrylonitrile in drinking water even at the relatively low concentration of 0.2% (45). When this confounding factor was removed (e.g., by administering the nitrile by daily gavage), the adrenals responded with hypertrophy and hyperplasia of the cortex.…”

“…5). Pair-feeding with the highest concentration of acrylonitrile (0.2%) also diminished the plasma levels of both corticoids, indicating that the stressor effect and/or decreased food intake were also responsible for the low circulating levels of steroids (45).…”

“…The above mentioned observation, with individual chemicals causing adrenocortical necrosis, were independent observations, Because of the similarity between the adrenocorticolytic acrylonitrile (CH2= CH-CN) and' duodenal ulcerogenic propionitrile (CH,-CH,-CN), and since cysteamine (HS-CH2-CH2-NH2) exerts both actions (29, SO), we performed structure-activity studies on the adrenal damaging and duodenal ulcerogenic action of 56 alkanes and alkenes (45,50). Virtually all these alkyl chemicals were derivatives of the 2 nitriles and cysteamine, and we obtained substantial new information concerning the organ specificity ofthe action of these chemicals (50).…”

“…Zn vi,itro studies (53) were also performed to investigate the possible direct or indirect effect ofacrylonitrile on steroidogenesis (45). To test the hypothesis that acrylonitrile might inhibit the basal and ACTH-stimulated codcosterone production of isolated zona fasciculata cells as well as aldosterone production of isolated zona glomerulosa cells, the cells were incubated with acrylonitrile.…”

Molecular evidences on the benefit of N-acetylcysteine in experimental colitis

“…Non-protein thiols usually scavenge free radicals and protein thiols affect enzyme activity, cell viability and membrane stability. The protective role of thiol compounds, especially GSH, was documented in the stomach and liver [41]. In the colon, thiol blockers, like iodoeactamide or N-ethylmaleimide, are used for the induction of inflammation [42].…”