Abstract

One prominent symptom of acute toxicity from 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) is a loss of adipose tissue and body weight, a phenomenon known as the wasting syndrome. In the current study, we examined the effect of TCDD on glucose transport in mice. A single intraperitoneal dose of TCDD (116 micrograms/kg) resulted in a time-dependent decrease in transport activity in adipose tissue and brains of C57BL/6 mice. Reduction of transport occurred within 24 hr in both tissues. In adipose tissue a slight recovery was observed by 30 days, but in the brains of treated animals glucose transport was significantly decreased even at the latest time. A comparison of dose-response relationships for several tissues between C57BL/6 (TCDD-responsive) and DBA/2J (TCDD-nonresponsive) mice showed parallel curves, with the C57BL/6 animals showing a 10-20-fold greater sensitivity. The estimated ED50 values for reduction of transport in adipose tissue were 50 micrograms/kg and 800 micrograms/kg for the C57BL/6 and DBA/2J strains, respectively. Treatment of isolated adipose tissue in culture with TCDD and two biphenyl congeners produced a decrease in transport activity that matched the rank order of aryl hydrocarbon receptor affinity for the compounds. Immunoblotting for the adipose-type (type 4) glucose transporter (GLUT) showed a 40% decrease in the membrane fraction of adipose tissue from C57BL/6 mice treated with 116 micrograms/kg TCDD for 40 hr. A similar decrease in the brain-type GLUT1 was observed in the plasma membrane fraction of brain tissues isolated from the same animals. Analysis of RNA for the corresponding GLUT4 and GLUT1 genes showed a dramatic decrease in GLUT4 mRNA as early as 24 hr after treatment. In contrast, the level of GLUT1 mRNA increased slightly in the brains of treated mice. We conclude that regulation by TCDD of glucose transport activity in mice is an aryl, hydrocarbon receptor-dependent process and that the adipose-type GLUT4 appears to be regulated at the mRNA level, whereas the brain-type GLUT1 is affected mainly at the protein level.