Gene expression profiling of androgen receptor antagonists in the rat fetal testis reveals few common gene targets

Abstract

The androgen receptor (AR) is expressed in the fetal testis; however, the role of AR in fetal testicular development is poorly understood. Disrupted AR activity and subsequent gene expression alterations may disturb developmental programming of the fetal testis and result in testicular abnormalities later in life. The present study was performed to examine global gene expression patterns in rat fetal testis following in utero exposure to various AR antagonists. Pregnant Sprague-Dawley rats were treated with flutamide (50 mg/kg/day), linuron (50 mg/kg/day), vinclozolin (200 mg/kg/day), p,p'-DDE (100 mg/kg/day) or corn oil vehicle by gavage daily from gestation day (GD) 12-19. Testes were isolated on GD 19, and AR immunostaining, histology, and global changes in gene expression were determined. There were no alterations in the pattern or expression level of AR and no apparent histological changes in the fetal testes in any treatment group. Microarray analysis using Dunnett's test with multiple testing correction revealed no significant gene expression alterations following exposure to flutamide, linuron, vinclozolin, and p,p'-DDE. A less stringent analysis yielded some chemical specific effects on gene expression, and these effects were further evaluated by real-time RT-PCR. Vinclozolin treatment reduced the expression of several genes involved in cholesterol biosynthesis, though the testosterone levels were unchanged in the fetal testes in any treatment group. In flutamide, linuron, and p,p'-DDE treatment groups, the expression of hemoglobin Y, beta-like embryonic chain (Hbb-y) was reduced. Myomesin 2 (Myom2) expression was increased following linuron treatment. Given the lack of a common set of genes and the absence of overt histopathology, we conclude that the fetal testis is not a major target for AR activity at this stage of development although some cell-type specific gene expression changes cannot be ruled out.

Androgen Receptor Roles in Spermatogenesis and Fertility: Lessons from Testicular Cell-Specific Androgen Receptor Knockout Mice

“…However, recent studies using the transgenic Tfm mouse model (109), gene expression profiling of androgenregulated transcripts in neonatal mice testis (117), and combinations of hormonal manipulations in neonatal rat (118) suggested that androgens/AR might play a role in Sertoli cell proliferation, especially during early postnatal testis development. Another study using gene expression profiling of AR antagonists in the fetal rat testis suggested that the fetal testis is not a major target for AR activity during this stage of testis development, and results indicated that there are no overt histology changes and no common set of gene targets among various treated groups and the control group (119).…”

Corn oil as a vehicle in drug development exerts a dose‐dependent effect on gene expression profiles in rat thymus

“…Corn oil (CO) is one of the most common vehicles used for water‐insoluble agents in toxicity studies. Although some biologic effects on animals of CO have been reported – for example, that CO and diet could influence the reproduction and the kidney in female Sprague–Dawley rats (Sato et al , ), promote azoxymethane‐induced colon cancer development (Wu et al , ) and enhance hepatic lipid peroxidation in rats (Fang and Lin, ) – CO is still widely used as the vehicle for water‐insoluble agents in drug development (Bradford et al , ; Guerra et al , ; Poon et al , ; Lai et al , ; Xu et al , ; Patel et al , ), including recent molecular‐level studies of water‐insoluble agent effect on animal gene expression (Jacobus et al , ; Joseph et al , ; Mu et al , ; Satterfield et al , ; Aragon et al , ). It had been reported that CO could regulate genes related to cholesterol or fatty acid metabolism, which were tested only in rat liver (Takashima et al , ).…”