ToxSci Advance Access published online on March 22, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm062
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Time–dependent and compartment-specific effects of in utero exposure to di(n-butyl) phthalate on gene/protein expression in the fetal rat testis as revealed by transcription profiling and laser capture microdissection
* CXR Biosciences Ltd, James Lindsay Place, Dundee Technopole, Dundee DD1 5JJ, UK
MRC Human Reproductive Sciences Unit, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
1 To whom correspondence should be addressed: CXR biosciences Ltd, James Lindsay Place, Dundee Technopole, Dundee DD15JJ, Scotland. Contact details Email: simonplummer{at}cxrbiosciences.com, cliffelcombe{at}cxrbiosciences.com, Phone:+44-1382432163, Fax:+44-1382432153
Received December 21, 2006; revision received March 15, 2007; accepted March 15, 2007
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Abstract |
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We undertook transcription profiling of fetal testis RNA on gestational days e15.5, 17.5 and 19.5 in offspring from dams treated daily from e12.5 with 500mg/kg di(n-butyl) phthalate (DBP). At e17.5-19.5 reduced expression of genes involved in cholesterol uptake/metabolism and steroidogenesis were identified in DBP-exposed animals, including scavenger receptor-B1, HMGCoA synthase, steroidogenic acute regulatory protein, Cyp11a and Cyp17. Genes encoding inhibin-
, phosphatidylethanolamine-binding protein (PEBP) and cellular retinoic acid binding protein 2 (CRABP2) were also down-regulated. Most of the aforementioned genes are regulated by steroidogenic factor 1 (SF1), but no consistent change in SF1 mRNA or protein expression was detected. Expression of the aforementioned genes was unaffected at e15.5, but expression of other genes was significantly altered (mostly upregulated).
To gain further insight, RNA from interstitial (INT) and seminiferous cord (CORD) tissue obtained by laser capture microdissection (e19.5) was used for transcription profiling. This confirmed most gene expression changes identified for whole testes, but some were remarkably compartment-specific. Inhibin-, PEBP and CRABP2 gene expression were all down-regulated in INT but not in CORD, as confirmed by immunohistochemistry; similarly, SCARB1 was downregulated 4.6-fold in INT but only 2.3-fold in CORD. DBP-induced gene expression changes specific to CORD involved small magnitude (<2-fold) reductions or upregulation. These results extend earlier findings and point to the Leydig cells as a primary target of DBP-induced dysfunction. The observed gene expression changes, and their compartmentalisation, suggest a possible role for peroxisome proliferator-mediated alteration of co-factor availability as a mechanism underlying DBP-induced Leydig cell dysfunction.
Key Words: testicular dysgenesis syndrome; di(n-butyl)phthalate; Leydig cell; Sertoli cell; microarray analysis.
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