The plasticizer diethylhexyl phthalate induces malformations by decreasingfetal testosterone synthesis during sexual differentiation in the male rat

Phthalate esters (PE) such as DEHP are high production volume plasticizers used in vinyl floors, food wraps, cosmetics, medical products, and toys. In spite of their widespread and long-term use, most PE have not been adequat ely tested for transgenerational reproductive toxicity. This is cause for c oncern, because several recent investigations have shown that DEHP, BBP, DB P, and DINP disrupt reproductive tract development of the male rat in an an tiandrogenic manner. The present study explored whether the antiandrogenic action of DEHP occurs by (1) inhibiting testosterone (T) production, or by (2) inhibiting androgen action by binding to the androgen receptor (AR). Ma ternal DEHP treatment at 750 mg/kg/day from gestational day (GD) 14 to post natal day (PND)3 caused a reduction in T production, and reduced testicular and whole-body T levels in fetal and neonatal male rats from GD 17 to PND 2. As a consequence, anogenital distance (AGD) on PND 2 was reduced by 36% in exposed male, but not female, offspring. By GD 20, DEHP treatment also r educed testis weight. Histopathological evaluations revealed that testes in the DEHP treatment group displayed enhanced 3 beta -HSD staining and incre ased numbers of multifocal areas of Leydig cell hyperplasia as well as mult inucleated gonocytes as compared to controls at GD 20 and PND 3. In contras t to the effects of DEHP on T levels in vivo, neither DEHP nor its metaboli te MEHP displayed affinity for the human androgen receptor at concentration s up to 10 muM in vitro. These data indicate that DEHP disrupts male rat se xual differentiation by reducing T to female levels in the fetal male rat d uring a critical stage of reproductive tract differentiation.