PMID- 21266533
OWN - NLM
STAT- MEDLINE
DCOM- 20110715
LR  - 20211020
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 120
IP  - 2
DP  - 2011 Apr
TI  - Species-specific dibutyl phthalate fetal testis endocrine disruption correlates 
      with inhibition of SREBP2-dependent gene expression pathways.
PG  - 460-74
LID - 10.1093/toxsci/kfr020 [doi]
AB  - Fetal rat phthalate exposure produces a spectrum of male reproductive tract 
      malformations downstream of reduced Leydig cell testosterone production, but the 
      molecular mechanism of phthalate perturbation of Leydig cell function is not well 
      understood. By bioinformatically examining fetal testis expression microarray 
      data sets from susceptible (rat) and resistant (mouse) species after dibutyl 
      phthalate (DBP) exposure, we identified decreased expression of several metabolic 
      pathways in both species. However, lipid metabolism pathways transcriptionally 
      regulated by sterol regulatory element-binding protein (SREBP) were inhibited in 
      the rat but induced in the mouse, and this differential species response 
      corresponded with repression of the steroidogenic pathway. In rats exposed to 100 
      or 500 mg/kg DBP from gestational days (GD) 16 to 20, a correlation was observed 
      between GD20 testis steroidogenic inhibition and reductions of testis cholesterol 
      synthesis endpoints including testis total cholesterol levels, Srebf2 gene 
      expression, and cholesterol synthesis pathway gene expression. SREBP2 expression 
      was detected in all fetal rat testis cells but was highest in Leydig cells. 
      Quantification of SREBP2 immunostaining showed that 500 mg/kg DBP exposure 
      significantly reduced SREBP2 expression in rat fetal Leydig cells but not in 
      seminiferous cords. By Western analysis, total rat testis SREBP2 levels were not 
      altered by DBP exposure. Together, these data suggest that phthalate-induced 
      inhibition of fetal testis steroidogenesis is closely associated with reduced 
      activity of several lipid metabolism pathways and SREBP2-dependent 
      cholesterologenesis in Leydig cells.
FAU - Johnson, Kamin J
AU  - Johnson KJ
AD  - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, 
      Delaware 19803, USA. johnson@medsci.udel.edu
FAU - McDowell, Erin N
AU  - McDowell EN
FAU - Viereck, Megan P
AU  - Viereck MP
FAU - Xia, Jessie Q
AU  - Xia JQ
LA  - eng
GR  - P20RR020173/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110125
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Endocrine Disruptors)
RN  - 0 (Sterol Regulatory Element Binding Protein 2)
RN  - 2286E5R2KE (Dibutyl Phthalate)
RN  - 3XMK78S47O (Testosterone)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Dibutyl Phthalate/*toxicity
MH  - Dose-Response Relationship, Drug
MH  - Endocrine Disruptors/*toxicity
MH  - Female
MH  - Gene Expression Regulation, Developmental/*drug effects
MH  - Gestational Age
MH  - Leydig Cells/drug effects/metabolism
MH  - Male
MH  - Maternal Exposure/adverse effects
MH  - Mice
MH  - Organogenesis/*drug effects
MH  - Pregnancy
MH  - Rats
MH  - Rats, Inbred F344
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Species Specificity
MH  - Sterol Regulatory Element Binding Protein 2/*genetics
MH  - Testis/*drug effects/embryology
MH  - Testosterone/biosynthesis
PMC - PMC3061485
EDAT- 2011/01/27 06:00
MHDA- 2011/07/16 06:00
PMCR- 2012/04/01
CRDT- 2011/01/27 06:00
PHST- 2011/01/27 06:00 [entrez]
PHST- 2011/01/27 06:00 [pubmed]
PHST- 2011/07/16 06:00 [medline]
PHST- 2012/04/01 00:00 [pmc-release]
AID - kfr020 [pii]
AID - 10.1093/toxsci/kfr020 [doi]
PST - ppublish
SO  - Toxicol Sci. 2011 Apr;120(2):460-74. doi: 10.1093/toxsci/kfr020. Epub 2011 Jan 
      25.