Acute effects of hexabromocyclododecane on Leydig cell cyclic nucleotide signaling and steroidogenesis in vitro.
Hexabromocyclododecane (HBCDD), an additive brominated flame retardant routinely added to various consumer products, was reported to have toxic effects upon biota, including endocrine disruption. In this study, the potential toxicity of HBCDD was tested in peripubertal rat Leydig cells in vitro during 6h exposure. HBCDD inhibited human chorionic gonadotropin- and forskolin-supported cAMP accumulation and steroidogenesis. It also inhibited basal cAMP production, but elevated basal steroidogenesis. The expression of several cAMP-dependent genes, including steroidogenic acute regulatory protein, cholesterol side chain cleavage enzyme, and 3β-hydroxysteroid dehydrogenase, was also inhibited by HBCDD treatment. Nevertheless, this was not accompanied by a decrease in steroidogenic acute regulatory protein expression, as documented by western blot analysis, and activity of steroidogenic enzymes, as documented by unaffected steroidogenesis in the presence of permeable 22(R)-hydroxycholesterol. However, HBCDD caused significant decrease in mitochondrial membrane potential in untreated and human chorionic gonadotropin-treated cells. This indicates that HBCDD acute toxicity in Leydig cells reflects changes in mitochondrial membrane potential-dependent cAMP production and basal and cAMP-regulated cholesterol transport. This in turn facilitates basal but inhibits cAMP-dependent steroidogenesis. Acute effects of HBCDD treatment on transcription are also indicative of its sustained effects on Leydig cell function.
Laboratory for Ecotoxicology, Department of Biology and Ecology, University of Novi Sad Faculty of Sciences, 21000 Novi Sad, Serbia.
Svetlana
S
Fa
Kristina
K
Pogrmic-Majkic
Vanja
V
Dakic
Sonja
S
Kaisarevic
Jelena
J
Hrubik
Nebojsa
N
Andric
Stanko S
SS
Stojilkovic
Radmila
R
Kovacevic
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000728:Androgens / Q000032:analysis; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000737:chemistry; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005411:Flame Retardants / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D009711:Nucleotides / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D000098682:Steroidogenic Acute Regulatory Protein
D000728:Androgens; D006063:Chorionic Gonadotropin; D017077:Culture Media, Conditioned; D004785:Environmental Pollutants; D005411:Flame Retardants; D006842:Hydrocarbons, Brominated; D009711:Nucleotides; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D005576:Colforsin; D011374:Progesterone; C089796:hexabromocyclododecane; D000242:Cyclic AMP; D015096:3-Hydroxysteroid Dehydrogenases; D002786:Cholesterol Side-Chain Cleavage Enzyme; D006152:Cyclic GMP