In Utero Exposure to Di-(2-ethylhexyl) Phthalate Exerts Both Short-Term and Long-Lasting Suppressive Effects on Testosterone Production in the Rat1

Abstract

We examined the effects of fetal exposure to a wide range of di-(2-ethylhexyl) phthalate (DEHP) doses on fetal, neonatal, and adult testosterone production. Pregnant rats were administered DEHP from Gestational Day (GD) 14 to the day of parturition (Postnatal Day 0). Exposure to between 234 and 1250 mg/kg/day of DEHP resulted in increases in the absolute volumes of Leydig cells per adult testis. Despite this, adult serum testosterone levels were reduced significantly compared to those of controls at all DEHP doses. Organ cultures of testes from GD20 rats exposed in utero to DEHP showed dose-dependent reductions in basal testosterone production. Surprisingly, however, no significant effect of DEHP was found on hCG-induced testosterone production by GD20 testes, suggesting that the inhibition of basal steroidogenesis resulted from the alteration of molecular events upstream of the steroidogenic enzymes. Reduced fetal and adult testosterone production in response to in utero DEHP exposure appeared to be unrelated to changes in testosterone metabolism. In view of the DEHP-induced reductions in adult testosterone levels, a decrease in the expression of steroidogenesis-related genes was anticipated. Surprisingly, however, significant increases were seen in the expression of Cyp11a1, Cy17a1, Star, and Tspo transcripts, suggesting that decreased testosterone production after birth could not be explained by decreases in steroidogenic enzymes as seen at GD20. These changes may reflect an increased number of Leydig cells in adult testes exposed in utero to DEHP rather than increased gene expression in individual Leydig cells, but this remains uncertain. Taken together, these results demonstrate that in utero DEHP exposure exerts both short-term and long-lasting effects on testicular steroidogenesis that might involve distinct molecular targets in fetal and adult Leydig cells.

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

“…Cytochrome P450scc (Cyp11a1), a monooxygenase, is necessary for the synthesis of cholesterol and steroids, and a decrease in the expression level of Cyp11a1 following DEHP and/or Flu exposure was identified in the present study, in agreement with previous demonstrations [36,38]. During the critical stages of sexual differentiation, treatment with DEHP and/or Flu induced significant downregulation of steroid biosynthesis and metabolism-related genes, such as 3beta-steroid delta isomerase (Hsd3b1) and steroidogenic acute regulatory protein (StAR).…”

“…During the critical stages of sexual differentiation, treatment with DEHP and/or Flu induced significant downregulation of steroid biosynthesis and metabolism-related genes, such as 3beta-steroid delta isomerase (Hsd3b1) and steroidogenic acute regulatory protein (StAR). It has been reported that the short-term and long-lasting effects of DEHP on testicular steroidogenesis are distinct in fetal and adult Leydig cells, and a decrease in the expression levels of steroidogenesis-regulated genes following exposure to this ED exposure is anticipated [38]. As expected, in our present study, a reduction in the expression of testicular steroidogenesis-related factor StAR was observed.…”

Evidence suggesting that di‐n‐butyl phthalate has antiandrogenic effects in fish

“…Although several mammalian studies have also reported elevated plasma androgen concentrations following phthalate exposure at lower doses [30,31], the majority of studies report significant decreases in plasma testosterone concentrations at doses of >500 mg/kg/d [32,33]. It is currently unclear why apparently contradictory effects occur.…”

Disruption of reproductive development in male rat offspring following gestational and lactational exposure to di-(2-ethylhexyl) phthalate and genistein

“…DEHP exerts anti-androgen effect by suppressing fetal testosterone biosynthesis via peroxisome proliferatoractivated receptor (PPARs) activation (Culty et al, 2008), resulting in a series of reproductive tract defects in male off spring (Christiansen et al, 2010;Foster, 2006;Lagos-Cabre & Moreno, 2012;Pocar et al, 2012) .The spectrum of eff ects is characterized by disrupted androgen-dependent development and increased incidence of hypospadias, cryptorchidism, impaired spermatogenesis and testicular cancer, which collectively comprise the testicular dysgenesis syndrome (TDS) (Hu et al, 2009). In both humans and rodents, fetal Leydig and Sertoli cell dysfunction seems to play a vital role in the development of TDS or TDS-like symptoms.…”

“…In both humans and rodents, fetal Leydig and Sertoli cell dysfunction seems to play a vital role in the development of TDS or TDS-like symptoms. In the rat model, DEHP exerts an anti-androgen eff ect mainly by suppressing fetal testosterone biosynthesis (Culty et al, 2008).…”