In utero phthalate effects in the female rat: A model for MRKH syndrome

Bethany R Hannas,Kembra L Howdeshell,Johnathan Furr,L Earl Gray

doi:10.1016/j.toxlet.2013.03.021

Abstract

Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome is characterized by uterine and vaginal canal aplasia in normal karyotype human females and is a syndrome with poorly defined etiology. Reproductive toxicity of phthalate esters (PEs) occurs in rat offspring exposed in utero, a phenomenon that is better studied in male offspring than females. The current study reports female reproductive tract malformations in the Sprague–Dawley rat similar to those characteristic of MRKH syndrome, following in utero exposure to a mixture of 5 PEs. We determined that females are ∼2-fold less sensitive to the effects of the 5-PE mixture than males for reproductive tract malformations. We were not fully successful in defining the critical exposure period for females; however, incidence of malformations was 88% following dosing from GD8 to 19 versus 22% and 0% for GD8–13 and GD14–19, respectively. Overall, this study provides valuable information regarding female vulnerability to in utero phthalate exposure and further characterizes a potential model for the human MRKH syndrome.

Highlights

The widely used plasticizer compounds, phthalate esters, are recognized as reproductive toxicants in the male rat, with fetal exposure during the sexual differentiation period resulting in reproductive tract malformations reminiscent of human testicular dysgenesis syndrome (Fisher et al, 2003; Mylchreest et al, 1999; Sharpe and Irvine, 2004)
We report high incidences of reproductive malformations in the adult female rat following in utero exposure to a mixture of five phthalate esters (PEs)
We do provide evidence to support the hypothesis that the female window is earlier in gestation than the male window which is encompassed by GD14–19 since a low incidence of female reproductive tract malformations were induced with GD8–13 exposure but not GD14–18

Summary

Introduction

The widely used plasticizer compounds, phthalate esters, are recognized as reproductive toxicants in the male rat, with fetal exposure during the sexual differentiation period resulting in reproductive tract malformations reminiscent of human testicular dysgenesis syndrome (Fisher et al, 2003; Mylchreest et al, 1999; Sharpe and Irvine, 2004). Numerous studies focus on male reproductive toxicity of phthalates, whereas very little data is available on phthalate effects in female offspring exposed in utero. We previously reported the ability to use individual phthalate potencies to predict the effects of a mixture of five phthalates on fetal male testicular androgens following in utero exposure (Howdeshell et al, 2008). The postnatal study was designed to test the hypothesis that the postnatal effects following in utero exposure the same mixture correlate with the fetal effects in the male rat (Howdeshell et al, 2008), we serendipitously discovered extreme reproductive malformations in the female offspring. The second study of the current investigation was designed to define the critical exposure periods for inducing female reproductive tract malformations

Methods

Results

Conclusion