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Simvastatin and Dipentyl Phthalate Display Different Mechanisms of Action but Exhibit Dose Additive Effects on Fetal Testicular Testosterone Production in Sprague Dawley Rats
Citation:
Beverly, B., C. Lambright, J. Furr, H. Sampson, G. Travlos, B. McIntyre, P. Foster, V. Wilson, AND E. Gray. Simvastatin and Dipentyl Phthalate Display Different Mechanisms of Action but Exhibit Dose Additive Effects on Fetal Testicular Testosterone Production in Sprague Dawley Rats. Presented at International Congress of Endocrinology Annual Meeting 2014, Chicago, IL, June 21 - 24, 2014.
Impact/Purpose:
This abstract will be presented at the International Congress of Endocrinology Annual Meeting 2014, ICE/ENDO, June 21-24, 2014, Chicago, IL
Description:
Sex differentiation of the male reproductive tract in mammals is driven, in part, by fetal androgen production. In utero exposure to some phthalate esters (PEs) alters fetal Leydig cell differentiation, reducing the expression of several genes associated with steroid synthesis/transport, and consequently, Lowering fetal androgen levels. Simvastatin (SMV) is a cholesterol-lowering drug that directly inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMGC0A) reductase, a coenzyme that facilitates the conversion of HMG-CoA to mevalonate in the cholesterol biosynthetic pathway. SMV may also disrupt steroid biosynthesis, but through a different mechanism of action (MOA) than the PEs. As cholesterol is a precursor of steroid hormone biosynthesis, we hypothesized that in utero exposure to SMV during the critical period of sex differentiation would lower fetal testicular testosterone (T) production without affecting genes involved in cholesterol and androgen synthesis and transport. Secondly, we hypothesized that a mixture of SMV and a PE would reduce testosterone levels in an additive manner. Pregnant Sprague Dawley rats were dosed orally with 0, 15.6, 31.25, or 62.5 mg/kg/day SMV from gestational days (GD) 14-18, and fetuses were evaluated on GD 18. On GD 18, fetal T production and serum triglycerides, LDL, HDL, total cholesterol levels were reduced with increasing doses of simvastatin. In addition, PEs downregulate about a dozen genes in the fetal testes that were unaffected by SMV treatment. Individual administration of SMV (62.5 mg/kg/day) and DPeP (50 mg/kg/day) reduced fetal T production by 44% of control and 37% of control, respectively, p <0.0001 versus control). When SMV and DPeP were administered as a mixture, fetal T production was reduced in, an additive manner (19% of control; p < 0.0001 versus control, SMV, and DPeP), thus demonstrating that a mixture of chemicals can induce additive effects on fetal T production even though they display different modes of action. Abstract does not reflect the views of the EPA. Support provided by USEPAINTP IA#RW-75-92285501