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Dose additive effects of simvastatin and dipentyl phthalate on testosterone production in the fetal testis: A cummulative risk perspective
Brandiese, B., G. Travlos, B. McIntyre, P. Foster, V. Wilson, AND E. Gray. Dose additive effects of simvastatin and dipentyl phthalate on testosterone production in the fetal testis: A cummulative risk perspective. Presented at Mid Atlantic Research Symposium, Blacksburg, VA, May 21, 2013.
This abstract will be presented at the Mid Atlantic Research Symposium, Blacksburg, VA May 21, 2013
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 cause reproductive tract malformations in rats. PE alter the expression of genes associated with steroid synthesis/transport and cholesterol biosynthesis. Simvastatin (SMV) is a cholesterol-lowering drug that inhibits HMG-CoA reductase. As cholesterol is a precursor for steroid biosynthesis, we proposed that maternal exposure to SMV during the critical period of sex differentiation would lower fetal T and result in corresponding alterations in cholesterol- and androgenmediated gene expression. Timed pregnant SD rats were dosed orally with SMV from GD14-GD18. T production on GD18 was measured by RIA, and changes in gene expression in maternal and fetal tissues were assessed by quantitative rt-PCR. Circulating lipids were also measured in dams and fetuses. SMV lowered fetal T production, altered several genes involved in cholesterol biosynthesis in the maternal liver, and lowered lipids in the fetus but not in the dam. Unlike PE, SMV did not alter genes associated with sex differentiation. In a second experiment, dams were dosed with SMV, dipentyl phthalate (DPeP, a PE), or both. SMV and DPeP alone reduced fetal T production to 44.3 and 37.5% of control values, respectively, but the mixture reduced T production to 19.9% of control. These studies suggest that although SMV and DPeP affect different pathways, they exhibit dose additivity within the fetal testis. Abstract does not reflect the views of the EPA.