GENDER DIFFERENCES IN THE MECHANISM OF DIOXIN TOXICITY IN RODENTS ANDIN NONHUMAN-PRIMATES

This study examined the differences in mechanisms of toxicity when adi pose cells from males and females were exposed to 2,3,7,8-tetrachlorod ibenzo-p-dioxin (TCDD). Glucose uptake by adipose tissue in vitro was decreased significantly in male guinea pigs within 1 d of intraperiton eal injection of TCDD, but there was no significant effect in females, even at 28 d after treatment. A similar difference between male and f emale guinea pigs was detected in the effect of TCDD on lipoprotein li pase (LPL) activity, except that a significant decrease in LPL activit y was observed 28 d after treatment, Experiments with adipose tissue e xplants from untreated guinea pigs and macaques revealed similar gende r differences in the effect of TCDD in vitro on glucose uptake and LPL activity, Both time-course studies and dose-response studies with TCD D in vitro confirmed the greater sensitivity of male tissues to TCDD t oxicity, TCDD induced lipid peroxidation in the adipose tissues of mal e guinea pigs, while it had no effect in females, H-3-TCDD binding aff inity studies in adipose explant tissues showed that tissues from male guinea pigs and monkeys had a higher binding capacity for TCDD than f emale 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 cytosoli c protein phosphorylation decreased, In a cell-free system in the abse nce 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 sl ower response. TCDD induced the DNA binding of AP-1 in adipose tissues of male guinea pigs, but in female tissues TCDD reduced the DNA bindi ng of AP-1, In summary, the results of this study demonstrate gender d ifferences in the response of nonreproductive cells to TCDD, Some of t hese differences involve different mechanisms of toxicity in both the cytoplasmic and nuclear compartments of the cell.