Detection of dopaminergic modulators in a tier I screening battery for identifying endocrine-active compounds (EACs)

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2000-05, Vol.14 (3), p.193-205
• Main Authors: O’Connor, John C, Davis, Leonard G, Frame, Steven R, Cook, Jon C
• Format: Article
• Language: English
• Subjects: Androgens - blood; Animals; Apomorphine; Apomorphine - pharmacology; Biological and medical sciences; Body Weight - drug effects; Cell Division - drug effects; Dopamine Agonists - pharmacology; Dopamine Antagonists - pharmacology; Endocrine System - drug effects; Endocrine System - pathology; Endocrine-active compounds; Estradiol - blood; Female; General aspects. Methods; Gonadotropins, Pituitary - blood; Haloperidol; Haloperidol - pharmacology; Male; Medical sciences; Organ Size - drug effects; Ovariectomy; Prolactin; Rats; Rats, Sprague-Dawley; Receptors, Estrogen - agonists; Receptors, Estrogen - antagonists & inhibitors; Reserpine; Reserpine - pharmacology; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - genetics; Screening; Stromal Cells - drug effects; Stromal Cells - pathology; Thyroid Hormones - blood; Toxicity Tests - methods; Toxicology; Transformation, Bacterial - drug effects; Transformation, Bacterial - genetics; Uterus - drug effects; Uterus - pathology
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/S0890-6238(00)00069-1

Apomorphine (APO; D 2 receptor agonist), haloperidol (HAL; D 2 receptor antagonist), and reserpine (RES; a dopamine depletor that acts to lower brain dopamine levels by depleting central nervous system monoamines via disrupting storage vesicle function) have been examined in a Tier I screening battery, which has been designed to detect endocrine-active compounds (EACs). The Tier I battery incorporates two short-term in vivo tests (a 5-day ovariectomized female battery and a 15-day intact male battery using Sprague–Dawley rats) and an in vitro yeast transactivation system (YTS). In addition, two blood collection procedures were evaluated for their utility in detecting HAL-induced increases in serum prolactin (PRL) levels (i.e., the stress associated with each procedure). In the in vivo female battery, both HAL and RES increased serum PRL concentrations as expected, although the increase caused by RES was marginal. Increases in serum PRL levels are enhanced when daily dosages are administered via multiple-daily dosing of the test compound, which results in higher sustained blood levels of the test compounds. APO failed to decrease serum PRL concentrations in the female battery. In the in vivo male battery, HAL increased serum PRL concentrations as expected. However, APO and RES failed to affect serum PRL concentrations. The blood collection comparison experiment demonstrated that possible confounding of the data can occur with serum PRL concentrations when animals are exposed to stress. Basal levels of PRL were approximately fourfold higher in animals that were bled via the tail vein procedure when compared to PRL levels from animals that were bled under CO 2 anesthesia at euthanization. As a result of the higher basal PRL levels, the HAL-induced increase in serum PRL concentrations was completely attenuated in the tail-vein bled animals (1.3-fold). In contrast, HAL produced a fivefold increase in serum PRL in animals where blood was collected under CO 2 anesthesia at euthanization. Hence, collection of blood from animals under CO 2 anesthesia at euthanization is an acceptable approach for detection of compounds that increase PRL. In summary, HAL-like compounds would be identified in the Tier I male and female battery primarily via increased serum PRL concentrations. RES-like compounds would be identified in the Tier I male battery via decreased gonadotropins and steroids and possibly in the Tier I female battery by a minimal increase in serum PRL concentrat