Relationship of the wasting syndrome to lethality in rats treated with 2,3,7,8-tetrachlorodibenzo- p-dioxin

Abstract

Young adult male Sprague-Dawley rats treated with a LD95 dose of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) exhibited a progressive reduction in feed intake and body weight until death occurred 15 to 32 days post-treatment. The time course and magnitude of weight loss and lethality of pair-fed control rats were essentially identical to that of TCDD-treated rats with each pair-fed control animal dying within 3 days of its TCDD-treated partner. Body composition analysis of the dead animals revealed that the total amounts of protein, fat, water, and ash in the carcasses of TCDD-treated and pair-fed control rats were each reduced to a similar extent. The temporal pattern of daily feed intake in TCDD-treated and pair-fed control rats (3 meals/day) or (1 meal/day) did not influence the results. Studies conducted at LD25-62 doses of TCDD in male Sprague-Dawley rats of differnt ages—weanling (90 g), young adult (275 g), and mature (450 g)—showed that the severity of the wasting syndrome in all age groups was greatest for animals that died. Also, young adult rats treated with a LD25 dose of TCDD that died displayed the same degree of hypophagia and weight loss prior to death as rats administered a LD95 dose. Histopathology of the liver and gastrointestinal tract was compared in TCDD-treated (LD95 dose) and pair-fed control rats killed 1 day before they otherwise would have died. Hepatocytes of TCDD-treated rats were enlarged relative to those of pair-fed control rats and contained nuclei that varied in size and number. Pair-fed control rats exhibited atrophy of the liver cords due to a decrease in the cytoplasmic volume of their hepatocytes. The stomach and small intestine of TCDD-treated rats were histologically similar to those of ad libitum-fed controls. In contrast, the glandular mucosa of the stomach of pair-fed control rats was ulcerated and the intestinal mucosa was atrophied. Stomach ulcers were the source of clotted blood found throughout the gastrointestinal tract of pair-fed control rats but not that of TCDD-treated animals. These findings demonstrate that hypophagia-induced weight loss is one of perhaps several responses that contribute to the death of TCDD-treated rats. That other responses are also involved is suggested by differences between pair-fed control and TCDD-treated rats in the weight and histopathology of certain organs. In addition, gastrointestinal blood loss contributes to the death of pair-fed control rats but not TCDD-treated animals.