Species-Specific Dibutyl Phthalate Fetal Testis Endocrine Disruption Correlates with Inhibition of SREBP2-Dependent Gene Expression Pathways
Open Access
- 25 January 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Toxicological Sciences
- Vol. 120 (2), 460-474
- https://doi.org/10.1093/toxsci/kfr020
Abstract
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.Keywords
This publication has 45 references indexed in Scilit:
- Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADLJournal of Lipid Research, 2009
- Side Chain Oxygenated Cholesterol Regulates Cellular Cholesterol Homeostasis through Direct Sterol-Membrane InteractionsOnline Journal of Public Health Informatics, 2009
- Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humansEnvironmental Research, 2008
- Di(n-Butyl) Phthalate Impairs Cholesterol Transport and Steroidogenesis in the Fetal Rat Testis through a Rapid and Reversible MechanismEndocrinology, 2004
- Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testisToxicology Letters, 2004
- Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genesProceedings of the National Academy of Sciences of the United States of America, 2003
- Quantitative Changes in Gene Expression in Fetal Rat Testes following Exposure to Di(n-butyl) PhthalateToxicological Sciences, 2003
- Summaries of Affymetrix GeneChip probe level dataNucleic Acids Research, 2003
- Fetal testosterone insufficiency and abnormal proliferation of Leydig cells and gonocytes in rats exposed to di(n-butyl) phthalateReproductive Toxicology, 2002
- Altered gene profiles in fetal rat testes after in utero exposure to di(n-butyl) phthalate.Toxicological Sciences, 2001