A biphasic effect of the fungicide prochloraz on aldosterone, but not cortisol, secretion in human adrenal H295R cells--underlying mechanisms.
The widely used imidazole fungicide prochloraz displays anti-androgenic effects partly via inhibition of testicular steroidogenesis and testosterone secretion. Adrenal steroidogenesis and hormone secretion may also be a target of this endocrine disruptor. Herein, we demonstrate a dose-dependent inhibition of cortisol secretion and a biphasic effect on aldosterone secretion, with a 2-fold stimulation at low concentrations and a strong inhibition at high concentrations, following prochloraz treatment (0-10 microM) of human adrenocortical H295R cells. Analysis of the dose-dependent effects of prochloraz on the secretion of steroidogenic intermediates suggested that the observed effects on cortisol and aldosterone secretion might be mediated by inhibition of the steroidogenic steps catalysed by CYP17A1 and CYP21A2. The inhibition of CYP17A1 was reflected on the level of expression of steroidogenic genes as analysed by quantitative RT-PCR. In addition, analysis of enzyme activity showed a dose-dependent inhibitory effect of prochloraz on the activity of CYP17A1 and CYP21A2, but not CYP11B1. We have demonstrated specific effects of prochloraz on adrenal steroidogenic pathways and hormone secretion via inhibition of steroidogenic CYP enzymes. The disruption of adrenal hormone secretion may result in altered endocrine homeostasis and affect human health.
Ohlsson
Asa
A
Swedish University of Agricultural Sciences, Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, SE 75007 Uppsala, Sweden.
Ullerås
Erik
E
Oskarsson
Agneta
A
D000311:Adrenal Glands / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000450:Aldosterone / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003345:Corticosterone / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005659:Fungicides, Industrial / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007093:Imidazoles / Q000633:toxicity*; D011374:Progesterone / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018076:DNA, Complementary; D005659:Fungicides, Industrial; D007093:Imidazoles; D000450:Aldosterone; D011374:Progesterone; D012313:RNA; C045362:prochloraz; D003345:Corticosterone; D006854:Hydrocortisone