Mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reduces circulating melatonin levels in the rat.
We have previously shown that the prototype for halogenated aromatic hydrocarbons, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), diminishes serum melatonin concentration at the same dose in both the most TCDD-susceptible (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 mechanism of this endocrine effect. Despite a 40-50% decrease in circulating melatonin levels, the pineal content of melatonin, serotonin and 5-hydroxyindole 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, TSDD did not influence the ability of pineal glands from L-E rats to synthesize and secrete melatonin in ex vivo or in vitro experiments. TCDD accelerated the disappearance of exogenous melatonin from the serum in both rat strains. This enhancement probably did not originate in the liver, because liver perfusion studies revealed that even control rat livers were capable of total melatonin clearance in spite of the fact that the melatonin concentration far exceeded physiological levels. Urine excretion of the normal main metabolite of melatonin, 6-hydroxymelatoninsulfate, was reduced by TCDD treatment in both strains. This was accompanied by an altered HPLC pattern of metabolites, especially in H/W rats. We conclude that TCDD decreases serum melatonin levels in rats by enhancing the peripheral, evidently extrahepatic, metabolism of the hormone.
Pohjanvirta
R
R
National Public Health Institute, Department of Toxicology, Kuopio, Finland.
Laitinen
J t
Jt
Vakkuri
O
O
Lindén
J
J
Kokkola
T
T
Unkila
M
M
Tuomisto
J
J
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D009638:Norepinephrine / Q000494:pharmacology; D009924:Organ Culture Techniques; D010477:Perfusion; D010870:Pineal Gland / Q000187:drug effects / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D000072317:Polychlorinated Dibenzodioxins; C054513:6-sulfatoxymelatonin; D008550:Melatonin; D009638:Norepinephrine