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Simvastatin and dipentyl phthalate lower testosterone production and exhibit dose additive effects on the fetal testis via distinct mechanistic pathways
Citation:
Beverly, B., C. Lambright, J. Furr, H. Sampson, G. Travlos, B. McIntyre, P. Foster, V. Wilson, AND E. Gray. Simvastatin and dipentyl phthalate lower testosterone production and exhibit dose additive effects on the fetal testis via distinct mechanistic pathways. Presented at Society of Toxicology Meeting, March 10 - 14, 2013.
Impact/Purpose:
This abstract will be presented at the Society of Toxicology meeting March 10-14, 2013 in San Antonio, TX
Description:
Sex differentiation of the mammalian reproductive tract is a highly regulated process that is driven, in part, by fetal testosterone (T) production. In utero exposure to phthalate esters (PE) during sex differentiation can result in reproductive tract malformations in rats. PE alter the expression of genes associated with steroid synthesis/transport and cholesterol biosynthesis. Simvastatin (SMV) is a choesteroI-lowering drug that interferes with cholesterol biosynthesis. As cholesterol is a precursor for steroid biosynthesis, we proposed that like PE, maternal exposure to SMV during the critical period of sex differentiation would lower fetal T by altering genes involved in cholesterol biosynthesis. Timed pregnant Sprague Dawley rats were dosed orally with 15.6, 31.25, or 62.5 mg/kg/d SMV from GD14- GD18. Testicular T production on GD18 was measured by RIA and changes in gene expression in fetal testes and livers were assessed by quantitative rt-PCR. Circulating lipid concentrations were also measured in dams and fetuses. SMV lowered fetal testicular T production and altered several genes involved in cholesterol biosynthesis in the fetal liver. Triglycerides, LDL, HDL, and cholesterol were also lowered significantly in the fetal circulation, while lipids in the dam were not. Unlike PE, SMV did not alter genes associated with sexual differentiation or development. In a second experiment, dams were dosed with 62.5 mg/kg/d SMV, 50 mg/kg/d dipentyl phthalate (DPeP, a PE), or a mixture of both. SMV and DPeP reduced fetal T production to 44.3 and 37.5% of the control values, respectively, but the SMV/DPeP mixture reduced T production to 19.9% of control. These studies suggest that although SMV and DPP affect two different pathways, they exhibit dose additive effects within the fetal testis. Abstract does not reflect the policy of the EPA. Support provided by USEPA/NTP IA# RW-75-92285501