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

Abstract

The adrenal cortex is the target of a surprisingly large number of exogenous chemicals. Until recently, the toxic action of these chemicals was discovered serendipitously. Following our observations that acrylonitrile, cystearnine or pyrazole induces hemorrhagic adrenocortical necrosis in the rat, we recently recognized a structure-activity correlation which predicts the adrenocorticolytic property of alkyl chemicals, i.e., 2-3-carbons with double or triple bonds and with nucleophilic terminal radicals (e.g., -CN, -SHY -NH2). On the basis of our results obtained with electron microscopic, histochemical and biochemical studies as well as those of others, we propose the following sequence of events in the pathogenesis of chemically induced adrenocortical necrosis: 1) Depletion of glutathione and increased dopamine concentration in the adrenals; 2) Endothelial damage and rupture of capillary walls in the adrenal cortex due to either direct attack by the chemicals (metabolites) and/or released monoamines; 3) Retrograde embolization of medullary tissue fragments into the cortical capillaries; 4) Enhanced destruction of cortical vascular walls with subsequent platelet aggregation, fibrin deposition which is often associated with a systemic drop in platelet counts, and changes in blood coagulation; 5 ) Escape of plasma and cellular elements of blood into extravascular spaces and damage of adrenocortical parenchymal cells; and 6) Hemorrhage and necrosis in the adrenal cortex. This pathogenetic sequence was investigated in detail with acrylonitrile, and studied in various aspects with thioguanine, cysteamine and pyrazole.

Morphometric and histopathological findings in the adrenal glands of dogs with chronic diseases

“…The coagulative necrosis found in this study differed from the lesions found in adrenal glands exposed to chemical exogenous substances (43), septicemia or high levels of adrenocorticotrophic hormone (33), because the necrosis was at the specific location of the corticomedullary junction and the inflammatory infiltrate was discrete and composed mainly of macrophages without associated hemorrhage.…”

Adrenal toxicology: a strategy for assessment of functional toxicity to the adrenal cortex and steroidogenesis

“…Ribelin, 1984;Szabo and Lippe, 1989;Colby and Longhurst, 1992;Colby, 1996;Rosol et al, 2001) and medulla (e.g. Tucker, 1996;Rosol et al, 2001) largely derived from results of in vivo studies and descriptive histopathological lesions, with the cortex being the most frequently affected site.…”

“…Ribelin, 1984;Szabo and Lippe, 1989;Colby and Longhurst, 1992;Colby, 1996;Raven and Hinson, 1996;Hinson and Raven, 1999;Rosol et al, 2001) and to the adrenal medulla (Tucker, 1996;Hinson and Raven, 1999;Rosol et al, 2001) but the potential molecular basis of such effects has only more recently emerged and this, and toxicologically relevant endocrinology, is discussed later. Identified factors predisposing the adrenal to toxic insult in vivo include: the large number of potential toxicological targets such as receptors, enzymes and peripheral hormone carrier molecules; high vascularity and disproportionately large blood volume received per unit mass; the high content of unsaturated fatty acids in adrenocortical cell membranes susceptible to lipid peroxidation; lipophilicity due to rich cholesterol and steroid content; and the high content of cytochrome P450 (CYP) enzymes present in the adrenal cortex, that normally catalyse steroidogenesis, but which can also produce reactive metabolites of toxicants and hydroxylation reactions that may generate free radicals (e.g.…”

Dual Effects of Prolonged ACTH Stimulation on 4-Hydroxyaminoquinoline 1-Oxide-Induced Adrenocortical Lesions in Rats

“…Among the endocrine tissues, the adrenal cortex appears to be one of the most vulnerable to chemically induced injury and in fact develops neoplastic or non-neoplastic lesions in response to a wide variety of chemicals (4,10,24). 4-Hydroxyaminoquinoline 1-oxide (4HAQO), an intermediate metabolite and possible proximate carcinogenic form of 4-nitroquinoline 1-oxide (12), is both toxic and carcinogenic to organs such as the pancreas and lung in rodents (9,20).…”