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
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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DOI：
10.1093/toxsci/kfu149
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发表时间：
2014-10-01
影响因子：
3.8
通讯作者：
Gray, L. Earl, Jr.
中科院分区：
文献类型：
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作者：
Beverly, Brandiese E. J.;Lambright, Christy S.;Gray, L. Earl, Jr.
哺乳动物雄性生殖道的性别分化在一定程度上是由胎儿雄激素的产生所驱动的。在子宫内，一些邻苯二甲酸酯（PEs）会改变胎儿睾丸间质细胞的分化，降低几个与类固醇合成/转运相关基因的表达，从而降低胎儿雄激素和胰岛素样因子3（Insl3）激素水平。辛伐他汀（SMV）是一种降胆固醇药物，它直接抑制羟甲基戊二酸单酰辅酶A（HMG - CoA）还原酶。SMV也可能破坏类固醇的生物合成，但作用方式（MOA）与邻苯二甲酸酯不同。由于胆固醇是类固醇激素生物合成的前体，我们假设在性别分化的关键时期子宫内暴露于SMV会降低胎儿睾丸睾酮（T）的产生，而不影响参与胆固醇和雄激素合成及转运的基因。其次，我们假设SMV和一种邻苯二甲酸酯（可能具有不同的作用方式）的混合物会以累加的方式降低睾酮水平。怀孕的斯普拉格 - 道利大鼠从妊娠第14 - 18天口服给予SMV、邻苯二甲酸二戊酯（DPeP）或SMV加DPeP，并在妊娠第18天对胎儿进行评估。在妊娠第18天，SMV降低了胎儿睾酮的产生以及血清甘油三酯、低密度脂蛋白、高密度脂蛋白和总胆固醇水平，并下调了胎儿睾丸中的两个基因，这两个基因与邻苯二甲酸酯所改变的基因不同。当SMV和DPeP作为混合物给药时，胎儿睾酮的产生以累加的方式显著降低，从而表明即使化学物质显示出不同的作用方式，它们的混合物也能对胎儿睾酮的产生诱导累加效应。
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.