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The effects of simvastatin and dipentyl phthalate on fetal cholesterol and testosterone production
Beverly, B. The effects of simvastatin and dipentyl phthalate on fetal cholesterol and testosterone production. Presented at NIEHS, NIH, NTP Cumulative Effects Research Group, RTP, NC, September 05, 2013.
Sex differentiation of the male reproductive tract in mammals is driven, in part, by fetal androgen production. In utero, some phthalate esters (PEs) alter fetal Leydig cell differentiation, reducing the expression of genes associated with steroid synthesis/transport, and consequently, lowering fetal androgen levels. Simvastatin (SMV) disrupts steroid biosynthesis via a different mode of action (MOA) than the PEs. SMV is a cholesterol-lowering drug that directly inhibits HMG-CoA reductase. As cholesterol is a precursor of steroid hormone biosynthesis, we hypothesized that maternal 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, which have different MOAs, would reduce testosterone levels in an additive manner. Pregnant Sprague Dawley rats were dosed orally with SMV, dipentyl phthalate (DPeP), or SMV plus DPeP from gestational days 14-18, and fetuses were evaluated on GD18. On GD18, SMV lowered T production and serum triglycerides, LDL, HDL, and total cholesterol levels without affecting testis gene expression. When SMV and DPeP were administered as a mixture, fetal T production was significantly reduced in an additive manner, thus demonstrating that a mixture of chemicals can induce dose additive effects on fetal T production even though they display different MOAs.
This is a presentation of original research on the endocrine, genomic and lipid effects of diverse chemicals affect fetal reproductive development during sexual differention. The experiments used individual model chemicals and mixtures of chemicals to determine if chemicals with diverse modes of action acted in a dose additive, cumulative manner on critical regulator molecules. The results contribute the growing body of knowledge indicating that chemicals can produce dose additive, adverse effects even when they disrupt the endocrine system via diverse mechanisms of action.
Record Details:Record Type: DOCUMENT (PRESENTATION/SLIDE)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
TOXICOLOGY ASSESSMENT DIVISION
REPRODUCTIVE TOXICOLOGY BRANCH