PMID- 17369198
OWN - NLM
STAT- MEDLINE
DCOM- 20070806
LR  - 20161124
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 97
IP  - 2
DP  - 2007 Jun
TI  - Sensitivity of fetal rat testicular steroidogenesis to maternal prochloraz 
      exposure and the underlying mechanism of inhibition.
PG  - 512-9
AB  - The fungicide prochloraz (PCZ) induces malformations in androgen-dependent 
      tissues in male rats when administered during sex differentiation. The 
      sensitivity of fetal testicular steroidogenesis to PCZ was investigated to test 
      the hypothesis that the reported morphological effects from maternal exposure 
      were associated with reduced testosterone synthesis. Pregnant Sprague-Dawley rats 
      were dosed by gavage with 0, 7.8, 15.6, 31.3, 62.5, and 125 mg PCZ/kg/day (n = 8) 
      from gestational day (GD) 14 to 18. On GD 18, the effects of PCZ on fetal 
      steroidogenesis were assessed by measuring hormone production from ex vivo fetal 
      testes after a 3-h incubation. Lastly, PCZ levels in amniotic fluid and maternal 
      serum were measured using liquid chromatography/mass spectroscopy and correlated 
      to the inhibition of steroidogenesis. Fetal progesterone and 
      17alpha-hydroxyprogesterone production levels were increased significantly at 
      every PCZ dose, whereas testosterone levels were significantly decreased only at 
      the two high doses. These results suggest that PCZ inhibits the conversion of 
      progesterone to testosterone through the inhibition of CYP17. To test this 
      hypothesis, PCZ effects on CYP17 gene expression and in vitro CYP17 hydroxylase 
      activity were evaluated. PCZ had no effect on testicular CYP17 mRNA levels as 
      measured by quantitative real-time polymersase chain reaction. However, 
      microsomal CYP17 hydroxylase activity was significantly inhibited by the 
      fungicide (K(i) = 865nM). Amniotic fluid PCZ concentrations ranged from 78 to 
      1512 ppb (207-4014nM) and testosterone production was reduced when PCZ reached 
      approximately 500 ppb, which compares favorably with the determined CYP17 
      hydroxylase K(i) (326 ppb). These results demonstrate that PCZ lowers testicular 
      testosterone synthesis by inhibiting CYP17 activity which likely contributes to 
      the induced malformations in androgen-dependent tissues of male offspring.
FAU - Blystone, Chad R
AU  - Blystone CR
AD  - Department of Environmental and Molecular Toxicology, NC State University, 
      Raleigh, NC 27695, USA.
FAU - Lambright, Christy S
AU  - Lambright CS
FAU - Howdeshell, Kembra L
AU  - Howdeshell KL
FAU - Furr, Johnathan
AU  - Furr J
FAU - Sternberg, Robin M
AU  - Sternberg RM
FAU - Butterworth, Brian C
AU  - Butterworth BC
FAU - Durhan, Elizabeth J
AU  - Durhan EJ
FAU - Makynen, Elizabeth A
AU  - Makynen EA
FAU - Ankley, Gerald T
AU  - Ankley GT
FAU - Wilson, Vickie S
AU  - Wilson VS
FAU - Leblanc, Gerald A
AU  - Leblanc GA
FAU - Gray, L Earl Jr
AU  - Gray LE Jr
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20070315
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Androgen Receptor Antagonists)
RN  - 0 (Fungicides, Industrial)
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoproteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Steroids)
RN  - 0 (steroidogenic acute regulatory protein)
RN  - 3XMK78S47O (Testosterone)
RN  - 409J2J96VR (Androstenedione)
RN  - 4G7DS2Q64Y (Progesterone)
RN  - 4TI98Z838E (Estradiol)
RN  - 68-96-2 (17-alpha-Hydroxyprogesterone)
RN  - 99SFL01YCL (prochloraz)
RN  - EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase)
SB  - IM
MH  - 17-alpha-Hydroxyprogesterone/blood/metabolism
MH  - Amniotic Fluid/metabolism
MH  - Androgen Receptor Antagonists
MH  - Androstenedione/blood/metabolism
MH  - Animals
MH  - Body Weight/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Estradiol/biosynthesis/blood
MH  - Female
MH  - Fetus/drug effects/metabolism
MH  - Fungicides, Industrial/pharmacokinetics/*toxicity
MH  - Gene Expression/drug effects
MH  - Imidazoles/pharmacokinetics/*toxicity
MH  - Male
MH  - Phosphoproteins/biosynthesis
MH  - Pregnancy
MH  - Progesterone/biosynthesis/blood
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Rats
MH  - Steroid 17-alpha-Hydroxylase/antagonists & inhibitors/biosynthesis/genetics
MH  - Steroids/*biosynthesis
MH  - Testis/*drug effects/embryology/*metabolism
MH  - Testosterone/biosynthesis/physiology
EDAT- 2007/03/21 09:00
MHDA- 2007/08/07 09:00
CRDT- 2007/03/21 09:00
PHST- 2007/03/21 09:00 [pubmed]
PHST- 2007/08/07 09:00 [medline]
PHST- 2007/03/21 09:00 [entrez]
AID - kfm055 [pii]
AID - 10.1093/toxsci/kfm055 [doi]
PST - ppublish
SO  - Toxicol Sci. 2007 Jun;97(2):512-9. doi: 10.1093/toxsci/kfm055. Epub 2007 Mar 15.