Conazole fungicides inhibit Leydig cell testosterone secretion and androgen receptor activation in vitro
نویسندگان
چکیده
Conazole fungicides are widely used in agriculture despite their suspected endocrine disrupting properties. In this study, the potential (anti-)androgenic effects of ten conazoles were assessed and mutually compared with existing data. Effects of cyproconazole (CYPRO), fluconazole (FLUC), flusilazole (FLUS), hexaconazole (HEXA), myconazole (MYC), penconazole (PEN), prochloraz (PRO), tebuconazole (TEBU), triadimefon (TRIA), and triticonazole (TRIT) were examined using murine Leydig (MA-10) cells and human T47D-ARE cells stably transfected with an androgen responsive element and a firefly luciferase reporter gene. Six conazoles caused a decrease in basal testosterone (T) secretion by MA-10 cells varying from 61% up to 12% compared to vehicle-treated control. T secretion was concentration-dependently inhibited after exposure of MA-10 cells to several concentrations of FLUS (IC50 = 12.4 μM) or TEBU (IC50 = 2.4 μM) in combination with LH. The expression of steroidogenic and cholesterol biosynthesis genes was not changed by conazole exposure. Also, there were no changes in reactive oxygen species (ROS) formation that could explain the altered T secretion after exposure to conazoles. Nine conazoles decreased T-induced AR activation (IC50s ranging from 10.7 to 71.5 μM) and effect potencies (REPs) were calculated relative to the known AR antagonist flutamide (FLUT). FLUC had no effect on AR activation by T. FLUS was the most potent (REP = 3.61) and MYC the least potent (REP = 0.03) AR antagonist. All other conazoles had a comparable REP from 0.12 to 0.38. Our results show distinct in vitro anti-androgenic effects of several conazole fungicides arising from two mechanisms: inhibition of T secretion and AR antagonism, suggesting potential testicular toxic effects. These effects warrant further mechanistic investigation and clearly show the need for accurate exposure data in order to perform proper (human) risk assessment of this class of compounds.
منابع مشابه
Expression of somatostatin receptor type-2 (sst2A) in immature porcine Leydig cells and a possible role in the local control of testosterone secretion
We recently reported that immature porcine Leydig cells express both somatostatin (SRIF) and SRIF receptor type-2 (sst-2) transcripts. The present study was therefore undertaken to assess whether SRIF might exert autocrine actions on these cells through sst2A receptor, one of the two sst2 isoforms known to exert important neuroendocrine and endocrine functions. Using a polyclonal antibody direc...
متن کاملOccult leydig cell tumour and androgen-receptor positive breast cancer in a woman with severe hyperandrogenism
Leydig cell tumours represent more than 75% of all testosterone-secreting ovarian masses. These benign tumours are frequently occult or very small, but cause dramatic virilization. Chronic hyperandrogenism can also induce systemic complications, which increase morbidity and mortality risk. One of the most obvious effects of increased testosterone levels is polycythemia, a complication which ind...
متن کاملThe actions of calcitonin on the TM3 Leydig cell line and on rat Leydig cell-enriched cultures.
Studies demonstrating calcitonin receptors on Leydig cells have suggested that these cells may be one of the many sites affected by this peptide. To investigate this possibility, the effect of synthetic salmon calcitonin on the TM3 Leydig cell line (derived from immature mouse Leydig cells) and on primary Leydig cell-enriched preparations was examined. Synthetic salmon calcitonin stimulated the...
متن کاملLeydig Cell Function in Man
In humans, as in all mammalian males, Leydig cells are the main source of the androgenic hormone, testosterone, which is essential for male sexual differentiation, gamete production and maturation, and development of secondary sexual characteristics. In this chapter, the development, steroidogenic function, and regulation of human Leydig cells are summarized. Clinical aspects of androgen secret...
متن کاملA rare ovarian tumor, leydig stromal cell tumor, presenting with virilization: a case report
Leydig stromal cell tumor is a rare ovarian tumor that belongs to the group of sex-cord stromal tumors. They produce testosterone leading to hyperandrogenism. We present a 41yr old woman with symptoms of virilization and a mass of right adenex via ultra Sonography, and a rise of total and free serum testosterone. An ovarian source of androgen was suspected and a surgery performed. A diagnosis ...
متن کامل