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1333043 
Journal Article 
Abstract 
Di(n-butyl) phthalate interferes with fetal testicular steroidogenesis at the level of cholesterol transport and cleavage 
Thompson, C; Ross, SM; Gaido, KW 
2003 
1 
Toxicologist
ISSN: 0731-9193 
72 
S-1 
273 
English 
WOS:000181518501333 
The phthalate ester di(n-butyl) phthalate (DBP) produces antiandrogenic effects on male reproductive development in rats. In the fetus, these effects are mediated, not by interaction with the androgen receptor, but rather through diminution of testosterone (T) production by the testes. Previous studies have shown that several genes involved in cholesterol transport and steroidogenesis are downregulated at the mRNA level following in utero exposure to DBP. The purpose of this study was to make a functional determination of the points in the cholesterol transport and steroidogenesis pathways affected by DBP. We cultured fetal testis explants with T precursors and assessed cholesterol uptake and T production. Pregnant Sprague-Dawley rats were treated with 500 mg/kg DBP or corn oil control via oral gavage from gestational days 12 to 19. Following the final treatment, testes were removed from the fetuses and cultured for 3 h with 3H-cholesterol, leuteinizing hormone (LH), Bt2-cAMP, 22(R)-hydroxycholesterol, pregnenolone, progesterone, or 17-hydroxyprogesterone. T production in unsupplemented cultures of DBP-exposed testis was roughly 10% of that seen in corn oil controls (164.7 +/- 32 pg/h vs. 1684.1 +/- 347 pg/h). Both control and treated explants could be stimulated by LH or Bt2-cAMP, but T production by DBP-treated testes remained less than 50% of control levels. Incorporation of 3H-cholesterol by mitochondria of DBP-treated explants was 67% of that observed in controls, although this difference was not statistically significant (p = 0.08). Pregnenolone, progesterone, and 17-hydroxyprogesterone all significantly increased T production compared to unsupplemented DBP-treated explants. However, there was no significant difference between the unsupplemented explants and those treated with the membrane-permeable 22(R)-hydroxycholesterol. These data indicate that the toxic effects of DBP on the fetal testis are mediated at the level of cholesterol cleavage by P450 scc and possibly at the level of cholesterol transport into the mitochondria. 
42nd Annual Meeting of the Society of Toxicology 
Salt Lake City, UT 
March 9-13, 2003