PMID- 16375936
OWN - NLM
STAT- MEDLINE
DCOM- 20060717
LR  - 20121115
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 213
IP  - 2
DP  - 2006 Jun 1
TI  - Mechanisms of action underlying the antiandrogenic effects of the fungicide 
      prochloraz.
PG  - 160-71
AB  - 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.
FAU - Laier, Peter
AU  - Laier P
AD  - Department of Toxicology and Risk Assessment, Danish Institute for Food and 
      Veterinary Research, Morkhoj Bygade 19, DK-2860 Soborg, Denmark.
FAU - Metzdorff, Stine Broeng
AU  - Metzdorff SB
FAU - Borch, Julie
AU  - Borch J
FAU - Hagen, Marie Louise
AU  - Hagen ML
FAU - Hass, Ulla
AU  - Hass U
FAU - Christiansen, Sofie
AU  - Christiansen S
FAU - Axelstad, Marta
AU  - Axelstad M
FAU - Kledal, Thuri
AU  - Kledal T
FAU - Dalgaard, Majken
AU  - Dalgaard M
FAU - McKinnell, Chris
AU  - McKinnell C
FAU - Brokken, Leon J S
AU  - Brokken LJ
FAU - Vinggaard, Anne Marie
AU  - Vinggaard AM
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060110
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Androgen Antagonists)
RN  - 0 (Fungicides, Industrial)
RN  - 0 (Gonadal Steroid Hormones)
RN  - 0 (Imidazoles)
RN  - 99SFL01YCL (prochloraz)
SB  - IM
MH  - Adrenal Cortex/cytology/drug effects
MH  - Analysis of Variance
MH  - Androgen Antagonists/*toxicity
MH  - Animals
MH  - Body Weight/drug effects
MH  - Cell Line
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Feminization/*chemically induced/embryology
MH  - Fungicides, Industrial/toxicity
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Developmental/*drug effects
MH  - Genitalia/*drug effects/embryology
MH  - Gonadal Steroid Hormones/metabolism
MH  - Humans
MH  - Imidazoles/*toxicity
MH  - Leydig Cells/drug effects
MH  - Male
MH  - Maternal Exposure
MH  - Mice
MH  - Nipples/drug effects/embryology
MH  - Pregnancy
MH  - Rats
EDAT- 2005/12/27 09:00
MHDA- 2006/07/18 09:00
CRDT- 2005/12/27 09:00
PHST- 2005/08/31 00:00 [received]
PHST- 2005/10/12 00:00 [revised]
PHST- 2005/10/26 00:00 [accepted]
PHST- 2005/12/27 09:00 [pubmed]
PHST- 2006/07/18 09:00 [medline]
PHST- 2005/12/27 09:00 [entrez]
AID - S0041-008X(05)00618-6 [pii]
AID - 10.1016/j.taap.2005.10.013 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2006 Jun 1;213(2):160-71. doi: 
      10.1016/j.taap.2005.10.013. Epub 2006 Jan 10.