Journal Article

Species-Specific Dibutyl Phthalate Fetal Testis Endocrine Disruption Correlates with Inhibition of SREBP2-Dependent Gene Expression Pathways

Kamin J. Johnson, Erin N. McDowell, Megan P. Viereck and Jessie Q. Xia

in Toxicological Sciences

Volume 120, issue 2, pages 460-474
Published in print April 2011 | ISSN: 1096-6080
Published online January 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr020
Species-Specific Dibutyl Phthalate Fetal Testis Endocrine Disruption Correlates with Inhibition of SREBP2-Dependent Gene Expression Pathways

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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: phthalate; developmental toxicity; prenatal; reproductive and developmental toxicology; sterol regulatory element–binding protein; fetal testis; endocrine disruptors; microarray

Journal Article.  7290 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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