MECHANISM BY WHICH 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) REDUCESCIRCULATING MELATONIN LEVELS IN THE RAT

We have previously shown that the prototype for halogenated aromatic h ydrocarbons, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), diminishes se rum melatonin concentration at the same dose in both the most TCDD-sus ceptible (Long-Evans, Turku AB; L-E) and the most TCDD-resistant (Han/ Wistar, Kuopio; H/W) rat strain. The change developed within 24 h and persisted for at least 28 days after TCDD exposure; was independent of the time of day and was not associated with any morphological damage to the pineal gland. In the present study, we investigated the mechani sm of this endocrine effect. Despite a 40-50% decrease in circulating melatonin levels, the pineal content of melatonin, serotonin and 5-hyd roxyindole acetic acid remained unaltered and the rate-limiting enzyme of pineal melatonin biosynthesis, N-acetyltransferase, displayed only a relatively minor suppression in activity (30%) in TCDD-treated L-E rats. Likewise, TCDD did not influence the ability of pineal glands fr om L-E rats to synthesize and secrete melatonin in ex vivo or in vitro experiments. TCDD accelerated the disappearance of exogeneous melaton in from the serum in both rat strains. This enhancement probably did n ot originate in the liver, because liver perfusion studies revealed th at even control rat livers were capable of total melatonin clearance i n spite of the fact that the melatonin concentration far exceeded phys iological levels, Urine excretion of the normal main metabolite of mel atonin, 6-hydroxymelatoninsulfate, was reduced by TCDD treatment in bo th strains. This was accompanied by an altered HPLC pattern of metabol ites, especially in H/W rats. We conclude that TCDD decreases serum me latonin levels in rats by enhancing the peripheral, evidently extrahep atic, metabolism of the hormone.