NDLI: 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

Content Provider	PubMed Central
Author	Beverly, BrandieseÂ e. Â j. Lambright, Christy S. Furr, Johnathan R. Sampson, Hunter Wilson, Vickie S. Mcintyre, Barry S. Foster, PaulÂ m. Â d. Travlos, Gregory Gray, L. Earl
Copyright Year	2014
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.
Related Links	http://dx.doi.org/10.1093/toxsci/kfu149
Ending Page	537
Page Count	14
Starting Page	524
File Format	PDF
ISSN	10960929
e-ISSN	10960929
Journal	Toxicological Sciences
Issue Number	2
Volume Number	141
Language	English
Publisher	Oxford University Press
Publisher Date	2014-10-01
Access Restriction	Open
Rights Holder	Oxford University Press
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Toxicology

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A Mixture of Five Phthalate Esters Inhibits Fetal Testicular Testosterone Production in the Sprague-Dawley Rat in a Cumulative, Dose-Additive Manner

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Dipentyl Phthalate Dosing during Sexual Differentiation Disrupts Fetal Testis Function and Postnatal Development of the Male Sprague-Dawley Rat with Greater Relative Potency than Other Phthalates

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

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