Gender differences in the mechanism of dioxin toxicity in rodents and in nonhuman primates.

This study examined the differences in mechanisms of toxicity when adipose cells from males and females were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Glucose uptake by adipose tissue in vitro was decreased significantly in male guinea pigs within 1 d of intraperitoneal injection of TCDD, but there was no significant effect in females, even at 28 d after treatment. A similar difference between male and female guinea pigs was detected in the effect of TCDD on lipoprotein lipase (LPL) activity, except that a significant decrease in LPL activity was observed 28 d after treatment. Experiments with adipose tissue explants from untreated guinea pigs and macaques revealed similar gender differences in the effect of TCDD in vitro on glucose uptake and LPL activity. Both time-course studies and dose-response studies with TCDD in vitro confirmed the greater sensitivity of male tissues to TCDD toxicity. TCDD induced lipid peroxidation in the adipose tissues of male guinea pigs, while it had no effect in females. 3H-TCDD binding affinity studies in adipose explant tissues showed that tissues from male guinea pigs and monkeys had a higher binding capacity for TCDD than female tissues. TCDD induced a significant reduction in nuclear protein phosphorylation and an increase in cytosolic protein phosphorylation in adipose tissue from male guinea pigs; the effects in female tissues were opposite: nuclear protein phosphorylation increased and cytosolic protein phosphorylation decreased. In a cell-free system in the absence of the nucleus, adipose tissues from male guinea pigs and monkeys responded to TCDD with a rapid stimulation of tyrosine kinase activity but female tissues from both species had a significantly lower and slower response. TCDD induced the DNA binding of AP-1 in adipose tissues of male guinea pigs, but in female tissues TCDD reduced the DNA binding of AP-1. In summary, the results of this study demonstrate gender differences in the response of nonreproductive cells to TCDD. Some of these differences involve different mechanisms of toxicity in both the cytoplasmic and nuclear compartments of the cell.