Dioxin-type chemicals including PCBs are known to cause acute and chronic hyperlipidemia accompanied with the loss of body fat in several experimental animal species. Not only that most of these chemicals are hardly metabolized by detoxification enzymes and coupled with their extreme lipophilicity, concentrate in the adipose tissues where they remain for a long time period, often for the entire lifespan of the animal. We have previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes significant reduction in the lipoprotein lipase (LPL) levels in the adipose tissue of guinea pigs and rabbits. Such an observation helps to explain why in these species the most predominant toxic expression of TCDD is hypertriglyceridemia. We have also found a number of evidence that TCDD causes early atherosclerosis and reduction in the contraction force of the heart atrial muscles. Since lipid metabolism is known to play a vital role in nutritional homeostasis, and since these dioxin-type chemicals are now commonly found in adipose tissues of various animals including humans, we propose to study this further. In more specific terms, we plan to study (1) acute and chronic effects of TCDD on adipose LPL, synthesis and the ability of the affected adipocytes to respond to high glucose to produce LPL, (2) since TCDD causes a drastic increase in protein kinase activities in the adipose, as in the case of other tissues, characterize the nature of protein kinases, and identify the major substrate proteins for those TCDD affected protein kinases, including insulin and B-adrenergic receptor, (3) establish an in vitro adipocytes system which adequately reproduces the effect of TCDD particularly that on LPL synthesis processes, and (4) by using the knowledge gained by the above studies develop a reliable biomarker to indicate the extent of exposure to hardly metabolizable congeners of PCBs, dioxins and PCDFs. The markers proposed for study are levels of mRNA for LPL, 3H-TCDD binding to the adipocyte nuclear receptor, protein kinase C, protein tyrosine kinase (using antibodies against phosphotyrosine), pp6Olsrc (using specific antibody), and (125)I-insulin binding to its receptor.
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