title: Simvastatin and dipentyl phthalate lower ex vivo testicular testosterone production and exhibit additive effects on testicular testosterone and gene expression via distinct mechanistic pathways in the fetal rat.
abstract: 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 several genes associated with steroid synthesis/transport, and consequently, lowering fetal androgen and Insl3 hormone levels. Simvastatin (SMV) is a cholesterol-lowering drug that directly inhibits HMG-CoA reductase. SMV may also disrupt steroid biosynthesis, but through a different mode 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, which may 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 fetal T production and serum triglycerides, low density lipoprotein, high density lipoprotein, and total cholesterol levels, and downregulated two genes in the fetal testis that were different from those altered by PEs. 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 additive effects on fetal T production even though they display different MOAs.
authors: Reproductive Toxicology Branch, Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, MD-72, 109 TW Alexander Dr., Research Triangle Park, North Carolina 27711 Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee 37831.
authors: Brandiese E J
authors: BE
authors: Beverly
authors: Reproductive Toxicology Branch, Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, MD-72, 109 TW Alexander Dr., Research Triangle Park, North Carolina 27711.
authors: Christy S
authors: CS
authors: Lambright
authors: Reproductive Toxicology Branch, Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, MD-72, 109 TW Alexander Dr., Research Triangle Park, North Carolina 27711.
authors: Johnathan R
authors: JR
authors: Furr
authors: Reproductive Toxicology Branch, Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, MD-72, 109 TW Alexander Dr., Research Triangle Park, North Carolina 27711.
authors: Hunter
authors: H
authors: Sampson
authors: Reproductive Toxicology Branch, Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, MD-72, 109 TW Alexander Dr., Research Triangle Park, North Carolina 27711.
authors: Vickie S
authors: VS
authors: Wilson
authors: National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors: Barry S
authors: BS
authors: McIntyre
authors: National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors: Paul M D
authors: PM
authors: Foster
authors: National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors: Gregory
authors: G
authors: Travlos
authors: Reproductive Toxicology Branch, Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, MD-72, 109 TW Alexander Dr., Research Triangle Park, North Carolina 27711 emgray@mindspring.com.
authors: L Earl
authors: LE
authors: Gray
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005865:Gestational Age; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008055:Lipids / Q000097:blood; D008297:Male; D018811:Maternal Exposure; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D017207:Rats, Sprague-Dawley; D012733:Sex Differentiation; D019821:Simvastatin / Q000633:toxicity*; D013737:Testis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis*; D046509:Tissue Culture Techniques
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D010795:Phthalic Acids; D013739:Testosterone; C032279:phthalic acid; D019821:Simvastatin
keywords: cholesterol; phthalates; sexual differentiation; simvastatin; steroidogenesis