Maternal Exposure to Dibutyl Phthalate (DBP) or Diethylstilbestrol (DES) Leads to Long-Term Changes in Hypothalamic Gene Expression and Sexual Behavior.

Damien Hunter,Ravinder Anand-Ivell,Navdeep Mann,Richard Ivell,Kee Heng

doi:10.3390/ijms22084163

Abstract

Xenobiotic exposure during pregnancy and lactation has been linked to perinatal changes in male reproductive outcomes and other endocrine parameters. This pilot study wished to assess whether brief maternal exposure of rats to xenobiotics dibutyl phthalate (DBP) or diethylstilbestrol (DES) might also cause long-term changes in hypothalamic gene expression or in reproductive behavior of the resulting offspring. Time-mated female Sprague Dawley rats were given either DBP (500 mg/kg body weight, every second day from GD14.5 to PND6), DES (125 µg/kg body weight at GD14.5 and GD16.5 only), or vehicle (n = 8–12 per group) and mild endocrine disruption was confirmed by monitoring postnatal anogenital distance. Hypothalamic RNA from male and female offspring at PND10, PND24 and PND90 was analyzed by qRT-PCR for expression of aromatase, oxytocin, vasopressin, ER-alpha, ER-beta, kisspeptin, and GnRH genes. Reproductive behavior was monitored in male and female offspring from PND60 to PND90. Particularly, DES treatment led to significant changes in hypothalamic gene expression, which for the oxytocin gene was still evident at PND90, as well as in sexual behavior. In conclusion, maternal xenobiotic exposure may not only alter endocrine systems in offspring but, by impacting on brain development at a critical time, can have long-term effects on male or female sexual behavior.

Highlights

Environmental endocrine disruption caused by exposure during development to common manmade chemicals can lead to several possible phenotypic outcomes
Much attention has been given to xenobiotics acting on the male reproductive system [1], largely because the testes are actively differentiating at a time during gestation when the placental barrier appears to be quite permeable, and because the phenotypic readout of such disruption is visible shortly after birth
The findings indicate subtle but persistent persistent in sexual hypothalamic expression, as well as long-term changes to sexchanges in hypothalamic gene expression, as well as long-term changes to sexual behavior

Summary

Introduction

Environmental endocrine disruption caused by exposure during development to common manmade chemicals can lead to several possible phenotypic outcomes. Diethlystilbestrol (DES) and dibutyl phthalate (DBP) are two well-characterized endocrine disrupting substances In rodents, these compounds appear to impact target genes within Leydig cells during embryonic development, such as INSL3 [3,4] or some steroidogenic enzymes [5]. While DES, as a model estrogen, is thought to be a preferential ligand for estrogen receptor beta (ERβ, Esr2), neither DBP nor its major active metabolite monobutyl phthalate have been shown to interact directly with any steroid-activated transcription factor [6]. Both substances, appear to exert similar phenotypic effects on the male reproductive system [3,4]. When applied acutely and in moderate amounts to pregnant rats within the so-called masculinization window in the latter half of gestation, both compounds appear to affect fetal testis function resulting in a reduction of fetal testosterone [7,8]

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