METABOLIC ALTERATIONS FOLLOWING ADMINISTRATION OF 2,3,7,8 - TETRACHLORODIBENZO - PARA - DIOXIN TO RATS.

Abstract

The effects of TCDD on hepatic ornithine decarboxylase (ODC) activity and endocrine function in rats were investigated. Sixteen hours after partial hepatecomy, rats which had been pretreated with TCDD for one week exhibited a 3- to 4-fold increase in ODC activity, while vehicle controls exhibited an 8- to 10-fold increase. ODC induction after either aminophylline or dexamethasone administration, agents which act via cAMP-mediated and direct nuclear events, respectively, also was inhibited by pretreatment with TCDD. RNA polymerase I activity, which positively correlates to ODC activity in growth and development, decreased concomitant with decreased induction of ODC. In unstimulated liver, RNA polymerase I activity, as well as protein, DNA and RNA levels, remained unchanged one week after TCDD. However, TCDD administration resulted in decreased liver concentrations of putrescine and spermidine, but not spermine. Within 2 days following administration of TCDD (45 or 90 μg/kg), rats exhibited hypothermia, hypothyroidism and decreased growth rate compared to pair-fed controls and rats fed ad libitum. Within 2 weeks of the administration of 90 μg TCDD/kg, body temperature had fallen to below 35°C with a low mean value 34.5°C recorded on day 16. Mean body temperatures for control rats ranged from 36.8°C to 37.5°C. One week after the administration of TCDD (45 μg/kg) to rats, serum thyroxine (T₄) and triiodothyronine (T₃) levels declined to 42% and 82% of control, respectively. Mild hypoglycemia occurred subsequent to hypothyroidism and hypothermia. At 1 week after administration of 45 μg TCDD/kg to rats, serum and pancreatic insulin levels were reduced to 25% and 76% of control, respectively. Hypophagia was determined to be responsible for decreased growth rate and hypoinsulinemia, but it could not account for hypothyroidism, hypothermia or hypoglycemia following administration of TCDD. No changes in glucagon or pancreatic, hepatic or serum somatostatin levels were found. Decreased somatostatin in the gastric antrum coincided with a 29% increase in stomach weight. The delayed toxicity of TCDD may be related to these striking hormonal alterations.