Related Experiment Video
Updated: Jun 5, 2026
Long-term Behavioral and Reproductive Consequences of Embryonic Exposure to Low-dose Toxicants
Published on: March 6, 2018
Species-specific dibutyl phthalate fetal testis endocrine disruption correlates with inhibition of SREBP2-dependent
Kamin J Johnson1, Erin N McDowell, Megan P Viereck
1Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA. johnson@medsci.udel.edu
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.
Insights
Phthalate exposure in fetal rats disrupts male reproductive development by impairing Leydig cell function. This study reveals dibutyl phthalate (DBP) inhibits cholesterol synthesis and steroidogenesis in rat fetal testes, unlike in resistant mice.
Area of Science:
- Endocrinology
- Reproductive Toxicology
- Developmental Biology
Background:
- Phthalate esters are endocrine disruptors linked to male reproductive malformations.
- The precise molecular mechanisms by which phthalates affect fetal Leydig cell function remain unclear.
- Species-specific responses to phthalate exposure suggest differential regulatory pathways.
Purpose of the Study:
- To investigate the molecular mechanisms underlying phthalate-induced disruption of fetal Leydig cell steroidogenesis.
- To compare the effects of dibutyl phthalate (DBP) on lipid metabolism and steroidogenic pathways in susceptible (rat) and resistant (mouse) fetal testes.
- To elucidate the role of sterol regulatory element-binding protein 2 (SREBP2) in phthalate-mediated effects on cholesterol synthesis in Leydig cells.
Main Methods:
- Bioinformatic analysis of fetal testis gene expression microarray data from DBP-exposed rats and mice.
- In vivo exposure of pregnant rats to DBP during critical developmental periods (gestational days 16-20).
- Measurement of testis cholesterol levels, gene expression (Srebf2, cholesterol synthesis genes), and SREBP2 protein localization via immunostaining and Western blot.
Main Results:
- DBP exposure significantly inhibited lipid metabolism and steroidogenic pathways in fetal rat testes, but induced them in mice.
- A strong correlation was observed between DBP-induced steroidogenic inhibition and reduced cholesterol synthesis in rat testes.
- DBP exposure decreased SREBP2 expression specifically in fetal rat Leydig cells, without altering total SREBP2 protein levels.
Conclusions:
- Phthalate-induced inhibition of fetal testis steroidogenesis is closely linked to impaired SREBP2-dependent cholesterol synthesis in Leydig cells.
- Differential regulation of lipid metabolism pathways by SREBP contributes to species-specific susceptibility to phthalate toxicity.
- Targeting Leydig cell lipid metabolism pathways may offer therapeutic strategies against phthalate-induced reproductive toxicity.
