Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz.
The fungicide prochloraz has got multiple mechanisms of action that may influence the demasculinizing and reproductive toxic effects of the compound. In the present study, Wistar rats were dosed perinatally with prochloraz (50 and 150 mg/kg/day) from gestational day (GD) 7 to postnatal day (PND) 16. Caesarian sections were performed on selected dams at GD 21, while others were allowed to give birth to pups that were followed until PND 16. Prochloraz caused mild dysgenesis of the male external genitalia as well as reduced anogenital distance and retention of nipples in male pups. An increased anogenital distance indicated virilization of female pups. Effects on steroidogenesis in male fetuses became evident as decreased testicular and plasma levels of testosterone and increased levels of progesterone. Ex vivo synthesis of both steroid hormones was qualitatively similarly affected by prochloraz. Immunohistochemistry of fetal testes showed increased expression of 17alpha-hydroxylase/17,20-lyase (P450c17) and a reduction in 17beta-hydroxysteroid dehydrogenase (type 10) expression, whereas no changes in expression of genes involved in testicular steroidogenesis were observed. Increased expression of P450c17 mRNA was observed in fetal male adrenals, and the androgen-regulated genes ornithine decarboxylase, prostatic binding protein C3 as well as insulin-like growth factor I mRNA were reduced in ventral prostates PND 16. These results indicate that reduced activity of P450c17 may be a primary cause of the disrupted fetal steroidogenesis and that an altered androgen metabolism may play a role as well. In vitro studies on human adrenocortical carcinoma cells supported the findings in vivo as reduced testosterone and increased progesterone levels were observed. Overall, these results together indicate that prochloraz acts directly on the fetal testis to inhibit steroidogenesis and that this effect is exhibited at protein, and not at genomic, level.
Laier
Peter
P
Department of Toxicology and Risk Assessment, Danish Institute for Food and Veterinary Research, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark.
Metzdorff
Stine Broeng
SB
Borch
Julie
J
Hagen
Marie Louise
ML
Hass
Ulla
U
Christiansen
Sofie
S
Axelstad
Marta
M
Kledal
Thuri
T
Dalgaard
Majken
M
McKinnell
Chris
C
Brokken
Leon J S
LJ
Vinggaard
Anne Marie
AM
D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects; D000704:Analysis of Variance; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D005262:Feminization / Q000139:chemically induced* / Q000196:embryology; D005659:Fungicides, Industrial / Q000633:toxicity; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005835:Genitalia / Q000187:drug effects* / Q000196:embryology; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D007985:Leydig Cells / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D009558:Nipples / Q000187:drug effects / Q000196:embryology; D011247:Pregnancy; D051381:Rats
D000726:Androgen Antagonists; D005659:Fungicides, Industrial; D012739:Gonadal Steroid Hormones; D007093:Imidazoles; C045362:prochloraz