2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases release of luteinizing hormone and follicle-stimulating hormone from the pituitary of immature female rats in vivo and in vitro.
Recent findings that serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were dramatically increased in weanling female Sprague-Dawley (S-D) rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prompted a more detailed study to define the effect and to investigate its mechanism(s). Dose-response and time-course studies were performed in vivo. Single doses (0.03-30 micrograms/kg) of TCDD were administered orally by gastric intubation to 22-day-old female rats. Control animals received vehicle (corn oil) only, whereas naive controls were treated with an empty intubation syringe. Trunk blood was collected after decapitation at various time points during the subsequent 72 hr. Concentrations of LH and FSH were determined in serum by radioimmunoassays (RIA). Two distinct peaks of both hormones were detected. The first, at 1 hr, appeared to be a non-specific response to vehicle as it was present in both vehicle control and TCDD-treated animals, but not in naive control animals. The second peak, at 24 hr, occurred only in animals dosed with TCDD. Gonadotropin levels in these animals were dose-dependently elevated. The ED50 was about 5 micrograms/kg with a maximum elevation of 15- and 20-fold for LH and FSH, respectively. Subsequently, in vitro studies were conducted in cultured pituitary halves and in primary pituitary cell cultures exposed to gonadotropin releasing hormone (GnRH) and/or TCDD. The amount of LH released into the media was measured by RIA. TCDD caused a dose-dependent release of LH from pituitary halves with an ED50 of about 0.1 nM. This effect was abolished in calcium-free medium but was not attenuated by an GnRH antagonist. Further in vitro studies were conducted in primary pituitary cell cultures. Although the cells responded to GnRH very well, no effect of up to 100 nM TCDD on the release of gonadotropins was detected. The results suggest that TCDD induces dose-dependently a brief release of gonadotropins in immature female rats. This effect is at least partially due to an effect of TCDD in the pituitary. Increased release of gonadotropins as a result of TCDD treatment depends on the action of calcium but does not occur via activation of GnRH receptors. However, cells in a primary pituitary culture do not respond to TCDD with increased release of gonadotropins, suggesting that the effect of TCDD in the pituitary is mediated by a factor present in pituitary halves but not in primary cell culture.
Li
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Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160, USA.
Johnson
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Rozman
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D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000072317:Polychlorinated Dibenzodioxins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone