Differential Effects of Flutamide and Di-(2-ethylhexyl) phthalate on Male Reproductive Organs in a Rat Model

Abstract

Abstract. Endocrine disruptors (EDs) with androgenic and anti-androgenic effects may alter reproductive function by binding to androgenic receptors (AR) and inducing or modulating AR-dependent responses in the male reproductive system. However, the molecular mechanism(s) underlying these events remains unclear. In the present study, pregnant Sprague Dawley (SD) rats were treated with testosterone propionate (TP), flutamide (Flu) and di-(2-ethylhexyl) phthalate (DEHP) from gestation days (GD) 11 to 21. Interestingly, maternal exposure to Flu or DEHP caused fluctuations in the neonatal levels of serum testosterone (T) and luteinizing hormone (LH). Serum testosterone and LH were upregulated by Flu, but these hormones were down-regulated by DEHP. The anogenital distances (AGD) of male newborns were determined at post-neonatal days (PND) 1, 21 and 63. Male rats treated prenatally with DEHP (100 mg/kg mother's body weight) or Flu showed an AGD shorter than that of control rats. At PND 63, sperm concentration, viability and motility were reduced in the maternal DEHP and Flu-treated groups. The numbers of seminiferous tubules were reduced in the Flu and DEHP-treated offspring when compared with the vehicle-and TPtreated groups, and the tubules of the testes at PND 63 were disrupted by a high dose of Flu. In addition, we found differential gene expression patterns by microarray analysis following ED exposure, particularly in sex determinationrelated genes. Although Flu and DEHP are considered to be identical with regard to their anti-androgenic effects, their effects on developing male reproductive organs were distinct, suggesting that Flu competes with endogenous T, while DEHP influences a different step in androgenesis. Key words: Flutamide, Male reproduction, Phthalate (J. Reprod. Dev. 55: [400][401][402][403][404][405][406][407][408][409][410][411] 2009) ecently, environmental, anti-androgenic compounds have been recognized as endocrine disruptors (EDs) because of their hormone-like activities. Anti-androgenic chemicals have the potential to interfere with male reproductive development and function in humans and animals. The EDs are thought to act via many mechanisms, such as by decreasing androgen synthesis, exerting effects on the pituitary-gonadal axis and/or blocking the androgen receptor (AR) [1,2]. The consequences of these actions may cause abnormal hormonal regulation and gene expression.It has been demonstrated that the AR plays a critical role in control of male sexual differentiation. During mammalian sex differentiation, the androgens, testosterone (T) and its metabolite dihydrotestosterone (DHT), produced by the fetal/neonatal male during sexual differentiation are critical factors in the male phenotype [3]. Sex development continues postnatally with the onset of secondary sexual characteristics at puberty and the acquisition of reproductive capacity. In addition, the differentiation of the Wolffian structures (e.g., the epididymis, vas deferens and seminal vesicles) appears to be T-mediated, while ma...

In Utero Exposure to Phthalate Downregulates Critical Genes in Leydig Cells of F1 Male Progeny

“…In the current study in utero exposure of DEHP down regulated the gene expression of StAR with a maximum decrease observed in 100 mg DEHP‐treated rats. This is in agreement with inhibitory effect of MEHP primary metabolite of DEHP on steroidogenesis in immature and adult Leydig cell in vitro mediated by StAR protein [Vo et al, ]. Cyp11a1 a monooxygenase, is necessary for the synthesis of cholesterol and steroids, and a decrease in the expression level of Cyp11a1 following in utero DEHP exposure was identified in the present study, in line with the previous demonstrations [Borch et al, ].…”

Altered Expression of 3β‐HSD, CYP17 and 17β‐HSD in the Foetal Porcine Gonads in Response to Anti‐androgen Flutamide Exposure

“…On the other hand, maternal exposure to flutamide decreased the expression of 3β‐HSD gene in the foetal rat testes (Vo et al. ). We have found that the gestational exposure to flutamide altered 3 β ‐HSD mRNA expression in the foetal porcine testes.…”

Effects of the commercial antiandrogen flutamide on the biomarkers of reproduction in male Murray rainbowfish (Melanotaenia fluviatilis)

“…Several studies have demonstrated demasculinization of male offspring after in utero exposures to flutamide. The antiandrogenic effects included impairment of sperm motility, reduced penile length, decreased testosterone concentrations, shorter anogenital distance, and reduction in the Sertoli cell number [10][11][12].…”