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The Plasticizer Diethylhexyl Phthalate Induces Malformations by Decreasing Fetal Testosterone Synthesis Durin Sexual Differentiation in the Male Rat
Citation:
Parks, L. G., J S. Ostby, C R. Lambright, B D. Abbott, G R. Klinefelter, N. J. Barlow, AND L. E. Gray Jr. The Plasticizer Diethylhexyl Phthalate Induces Malformations by Decreasing Fetal Testosterone Synthesis Durin Sexual Differentiation in the Male Rat. TOXICOLOGICAL SCIENCES 58(2):339-49, (2000).
Impact/Purpose:
To test Phthalate esters for transgenerational reproductive toxicity.
Description:
Phthalate esters (PE) like 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 PEs have not been adequately tested for transgenerational reproductive toxicity. This is cause for concern because several recent investigations have shown that DEHP, BBP, DBP and DINP disrupt reproductive tract development of the male rat in an antiandrogenic manner. The present study explored whether the antiandrogenic action of DEHP occurs by 1) inhibiting testosterone (T) production or 2) inhibiting androgen action by binding to the androgen receptor (AR). Maternal DEHP treatment (750 mg/kg/day GD14-PND3) caused a reduction in T production, and 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 reduced testis weight. Histopathological evaluations revealed that testes in the DEHP treatment group displayed enhanced 3beta-HSD staining and increased numbers of multifocal areas of Leydig cell hyperplasia as well as multinucleated gonocytes as compared to controls. In contrast to the effects of DEHP on T levels in vivo, neither DEHP nor its metabolite MEHP displayed affinity for binding to the human AR at concentrations up to 10?M in vitro. These data indicate that DEHP is acting as an antiandrogen by reducing T to female levels in the fetal male rat during a critical stage of reproductive tract differentiation.
